Exploring the oncogenic mechanism of plasmacytoma variant translocation 1 (PVT1) gene in solid cancers; emphasis on microRNA regulation pathways.

The miRNA/regulatory gene axis plays a crucial role in PVT1 involvement in carcinogenesis and drug resistance. Depending on the tumor type, different miRNAs are significant in mediating PVT1 effects in malignancies. When PVT1 is upregulated, it primarily modulates the activity of various miRNAs. The sponging function of PVT1 reduces the availability of miRNAs that can influence cellular processes, thereby facilitating tumor progression. Moreover, specific analogs of miRNAs, in conjunction with reduced expression of PVT1 , can further inhibit tumor growth, suggesting a potential collaborative role between miRNAs and PVT1 in regulating tumor progression. However, the mechanisms and relationships involved in these processes still require comprehensive clarification. This area represents a vital focus for future PVT1 research. Exploring the lncRNA-miRNA-mRNA axis offers a promising avenue for identifying effective therapeutic targets across various tumor types. Given PVT1 ’s extensive role as a ceRNA, it stands out as a noteworthy candidate for further investigation. Ultimately, PVT1 is an intriguing lncRNA that holds promise for diverse applications in tumor healthcare, ranging from discovery to therapy. Investigating its correlations with protein-coding genes and epigenetic biomarkers will enhance our understanding of PVT1 ’s functional roles in carcinogenesis. Additionally, processes such as epithelial-mesenchymal transitionwhich appear to be regulated by miRNA and PVT1 , warrant further exploration in future studies.

PVT1 is derived from an intergenic region on chromosome 8 (8q24), and is homologous to the PVT1 gene in mice (chromosome 15) and rats (chromosome 7). The PVT1 locus contains at least 12 exons, resulting in multiple alternatively spliced non-protein coding transcripts. At least 52 ncRNA variants with oncogenic functions, including 26 circular and 26 linear RNA isoforms are distinguished. PVT1 also encodes for 6 miRNAs: miR-1208, miR-1207-5p, miR-1207-3p, miR-1206, miR-1205, and miR-1204, which are showed in the Fig. 1 . The gene can exist in both long, non-coding and circular forms. Among circular RNAs, circ PVT1 is a rather unique RNA that arises from circularization of exon 2 of the PVT1 gene, which encodes a pro-tumor, long, non-coding RNA called lnc PVT1 . The Genotype-Tissue Expression Project (GTEx) and The Cancer Genome Atlas (TCGA) have demonstrated that 14 of PVT1 transcripts are present in tissues at quantifiable levels [ 25 ]. PVT1 has been found to have distinct regulatory activities and mechanisms in several critical biological processes, including cell survival, differentiation, proliferation, and chromatin remodeling. PVT1 contributes to chromatin remodeling and regulation of transcriptional and post-transcriptional events through interaction with other RNAs and various chromatin-based mechanisms [ 26 ]. PVT1 can act as a scaffold, decoy, guide, or enhancer RNA influencing on proteome diversity in human cells [ 27 ]. The 12 PVT1 isoforms have considerably diverse expression patterns across different human tissues: the heart and adrenal gland have the highest expression levels, whereas white blood cells and lymph nodes have the lowest levels [ 6 ]. PVT1 affects the entire gene life cycle, including chromatin remodeling, epigenetic regulation, transcription, post-transcriptional control, and protein metabolism [ 28 ]. PVT1 ’s role in pre-transcriptional control has been extensively researched. With the advancement of sequencing technologies, 98 different PVT1 fusion transcripts, a chimeric RNAs encoded by a fusion of different genes, have been identified in solid tumors and hematological malignancies, which result from rearrangements of the 8q24 chromosomal region [ 29 ]. PVT1 encodes for miRNAs, and studies have demonstrated that miRNAs can operate as tumor suppressors or oncogenes because they are frequently altered in malignancies. PVT1 ’s ability to interact with histone-modifying complexes and mediate epigenetic regulation is one of its characteristics. PVT1 has been shown to act as a signal, guide, or scaffold at the chromatin level, modulating gene expression. Enhancer of zest homolog 2 is an enzymatic subunit and histone methyl transferase of polycomb repressive complex 2 ( PRC2 ), an epigenetic multiprotein complex involved in the progression of cancer and other diseases. EZH2 histone methyl transferase enhancer catalyzes methylation of histone H3 at lysine 27 (H3K27me1/2/3) and induces gene silencing [ 30 ]. PRC2 , an epigenetic modification complex, was identified to interact with PVT1 . PVT1 binds to EZH2 and recruits it to tumour suppressor gene promoter areas, where it promotes histone H3K27 methylation and reduces gene transcription level [ 31 ]. DNA methylation, an epigenetic modification, is also implicated in the activity of PVT1 . It can recruit DNA methyl transferase 1 (DNMT1) to the mir-18b-5p promoter via EZH2 and inhibit miR-18b-5p transcription by DNA methylation [ 31 ]. PVT1 affects gene expression directly by binding to transcription factors (TFs) and influencing polymerase attaching to promotors [ 32 ]. Following transcription, RNA-binding proteins regulate pre-mRNAs by capping, polyadenylation, splicing, editing, and transfer from the nucleus to the cytoplasm. The mRNA stability is critical for translation, thus PVT1 is essential for mRNA splicing, stability, and translation [ 6 ]. Fig. 1 Molecular structure and localization of the human PVT1 gene Molecular structure and localization of the human PVT1 gene PVT1 carcinogenic effects have been confirmed by studies demonstrating its amplification/overexpression in several malignancies [ 33 ]. Currently, there is no single precise PVT1 mechanism of action that appears to be unique to all cancers. Even though when PVT1 is elevated, cancer often progresses. Multiple investigations in cancer regulation have revealed that miRNAs may be “sponged” by PVT1 to limit the miRNAs available to target the biological activity of mRNAs [ 7 ]. PVT1 is implicated in various cancer-related activities, including miRNA expression modulation, protein interactions, regulatory gene targeting, gene fusion. It can also act as a competitive endogenous RNA (ceRNA), regulating other RNA transcripts, competing for the same miRNAs. PVT1 plays a role in several cancer-related pathways, such as TGF-β , KLF5 /β-catenin, STAT3 / VEGFA , and ATM/Chk2/p53, a key regulator of DNA repair and cell cycle progression, as shown at the Fig. 2 . Fig. 2 Regulation of cell cycle progression and DNA repair via PVT1/ATM signaling pathway (abb. PVT1, Plasmacytoma Variant Translocation 1; ATM, Ataxia telangiectasia–mutated gene; SMC1A, structural maintenance of chromosomes 1 A; Chk2, Checkpoint kinase 2; H2AX, H2A histone family member X; Brca1, Breast Cancer gene 1) Regulation of cell cycle progression and DNA repair via PVT1/ATM signaling pathway (abb. PVT1, Plasmacytoma Variant Translocation 1; ATM, Ataxia telangiectasia–mutated gene; SMC1A, structural maintenance of chromosomes 1 A; Chk2, Checkpoint kinase 2; H2AX, H2A histone family member X; Brca1, Breast Cancer gene 1) PVT1 role in drug resistance has also been studied, specifically cisplatin resistance in gastric cancer [ 7 ]. Transcription factors that play critical roles in embryonic development, cell growth, and cell proliferation are also activated in cancer. PVT1 plays a significant role in controlling carcinogenesis by upregulating transcription factors [ 34 ]. MYC , a well-known oncogene situated near PVT1 on chromosome 8, also acts as a PVT1 regulator, as shown at the Fig. 3 . The human PVT1 gene has two non-canonical MYC -binding sites (E-box CACGCG) in the promoter region near the transcription start site [ 35 ]. Other studies on PVT1 - MYC interactions have found established regulatory networks between the two genes [ 36 ]. The co-expression of MYC and PVT1 has been proven in many malignancies [ 37 , 38 ]. In cancer cells, PVT1 has been demonstrated to activate MYC transcription, and MYC has been identified as a PVT1 activator [ 10 ]. The PVT1 promoter, its enhancers, and the MYC promoter are located in the same chromatin region, which forms a distinct self-interacting unit of three-dimensionally organized chromatin. Normally, the PVT1 enhancers interact with its own promoter. However, silencing the PVT1 promoter allows enhancers to bind to the MYC promoter, resulting in malignant phenotype of cells [ 38 ]. In glioma, PVT1 promotes malignant behaviors by targeting miR-190a-5p and miR-488-3p, which in turn regulate the oncogenes transcription, i.a. MEF2C [ 39 ]. PVT1 is linked to a poor prognosis and promotes cell proliferation by epigenetically regulating p15 and p16 in gastric cancer cells [ 31 ]. Also known as CDKN2B and CDKN2A , acts as a tumor suppressors by regulating cell cycle progression [ 40 ]. In gastrointestinal cancers, PVT1 ’s oncogenic role is described by its association with MYC upregulation, miRNA production, competitive endogenous RNA function, protein stabilization, and epigenetic regulation [ 41 ]. These findings, also presented on Fig. 4 , suggest that PVT1 is a key player in cancer progression and may serve as a potential therapeutic target. Fig. 3 Mutual expression regulation of MYC and PVT1 genes (abb. MYC , Cellular myelocytomatosis oncogene; PVT1 , plasmacytoma variant translocation 1) Mutual expression regulation of MYC and PVT1 genes (abb. MYC , Cellular myelocytomatosis oncogene; PVT1 , plasmacytoma variant translocation 1) Summarizing, the PVT1 gene plays diverse regulatory roles in cancer development via chromatin remodeling, transcription, post-transcriptional processing, and epigenetic modifications by interacting with complexes like PRC2 and EZH2 . It exhibits tissue-specific expression and acts as a scaffold, decoy, or guide RNA, promoting cancerous phenotype of cells. Its dysregulation and fusion variants, like PVT1 / PDHX (Pyruvate Dehydrogenase Complex Component X), PVT1 /ATE1 (Arginyltransferase 1), or PVT1 / APIP (APAF1 Interacting Protein), associated with multiple cancers, make it a key focus in cancer genomics and epigenetics research [ 29 ]. Fig. 4 Cell cycle regulation by PVT1 influenced signaling pathways (abb. PVT1 , Plasmacytoma variant translocation 1; MYC , Cellular myelocytomatosis oncogene; MEF2C , myocyte enhancer factor 2 C; GOLPH3, Golgi phosphoprotein 3; HEY2, Hairy/enhancer-of-split related with YRPW motif protein 2; Wnt, Wingless-related integration site; Hes1, Hairy and enhancer of split 1; PI3K, Phosphoinositide 3-kinases; AKT , serine/threonine kinase 1) Cell cycle regulation by PVT1 influenced signaling pathways (abb. PVT1 , Plasmacytoma variant translocation 1; MYC , Cellular myelocytomatosis oncogene; MEF2C , myocyte enhancer factor 2 C; GOLPH3, Golgi phosphoprotein 3; HEY2, Hairy/enhancer-of-split related with YRPW motif protein 2; Wnt, Wingless-related integration site; Hes1, Hairy and enhancer of split 1; PI3K, Phosphoinositide 3-kinases; AKT , serine/threonine kinase 1)

Given PVT1 ’s widespread oncogenic roles across breast, lung, gastric and other cancers, multiple approaches are being developed to block its function. One direct strategy is to use antisense oligonucleotides (ASOs) or small interfering RNAs (siRNAs) against PVT1 . These molecules can degrade the RNA or block its function, leading to reduced cancer cell growth and increased cell death. While this strategy is relatively easy to design and highly specific, delivering these molecules into tumors remains a challenge. During in vitro experiments, siRNAs are simply delivered to the cell though transfection, using transfecting reagents, which is almost impossible in clinical practice. Delivering ASOs are a bit accessible, thus during preclinical studies, the ASO solution is simply injected at tumor surroundings [ 17 , 193 ]. Otherwise, siRNAs and ASOs may be delivered by exosomal and liposomal carriers [ 194 – 198 ]. In gastric cancer models, synthetic ASOs complementary to PVT1 significantly reduced tumor growth: treated cells showed much less proliferation and invasion in vitro, and patient-derived xenograft (PDX) tumors treated PVT1 -ASO grew significantly slower at murine model grafted in vivo [ 193 ]. Similar mechanism examined Qin et al. at head and neck squamous cell carcinoma. Subcutaneously injected PDX treated PVT1 -ASO, showed knocked PVT1 , eliminated cancer-like cells populations, reduced tumor growth and lymph node metastasis also stimulating CD8 + T cell infiltration. Mechanistically, PVT1 inhibition acted in part via the miR-375/ YAP1 axis and by triggering DNA damage responses that promoted immune recruitment [ 17 ]. While ASOs are versatile, and can degrade or block splicing/translation, also acting in nucleus or cytoplasm, siRNAs primarily use the RNAi pathway to slice cytoplasmic mRNA. For example, siRNA knockdown of PVT1 in osteosarcoma cells (U2OS, MG-63) elevated the tumor-suppressor miR-195 and caused cell-cycle arrest, apoptosis and reduced migration; co-inhibition of miR-195 reversed these effects, confirming that PVT1 drives growth by sponging miR-195 [ 199 ]. Similarly in non-small cell lung cancer, PVT1 knockdown (or overexpression of miR-195) inhibited proliferation and increased radiosensitivity via apoptosis induction [ 154 ]. Thus, directly targeting the lncRNA with ASOs/siRNAs releases its bound miRNAs and downstream brakes on cell death, curbing tumor growth [ 154 , 199 ]. These nucleic acid therapies have shown consistent anti-tumor effects in vitro and in vivo, validating PVT1 as a therapeutic target [ 193 ]. Gene-editing technologies like CRISPR/Cas9 offer another way to target PVT1 , cutting-edge approach is to edit or disable the PVT1 gene locus directly. CRISPR/Cas9 can induce permanent loss of function of non-coding genes, and recent studies illustrate its impact on PVT1 . For example, full deletion of PVT1 in HCT116 colorectal cancer cells reduced tumorigenic ability and c- MYC protein levels [ 200 ]. Indeed, experimental PVT1 deletion showed profound phenotypic effects in cells [ 200 ]. In future, CRISPR-based tools might be applied in vivo to silence PVT1 , although delivery and safety hurdles remain. A related strategy is to target the miRNAs regulated by PVT1 . PVT1 acts as a competing endogenous miRNA, sponging it, so therapies can aim to restore or inhibit specific miRNAs in its network. Prominent examples include miR-152, miR-186, miR-195 and the miR-200 family. In gastric cancer, PVT1 binds and represses miR-152 and miR-186, freeing oncogenes CD151 , FGF2 and HIF-1α to enhance proliferation [ 125 , 126 ]. Affecting on these pathways, by knocking down PVT1 or by delivering miRNA mimics—suppresses tumor traits. For instance, overexpressing miR-152 in GC cells (or blocking PVT1 ) reduced migration and sensitized cells to therapy [ 125 ]. Likewise, PVT1 sponging of miR-186 derepresses HIF-1α and promotes invasion; upregulating miR-186 reverses these effects [ 126 ]. These data show that delivering antagomirs or mimics against PVT1 -regulated miRNAs can recapitulate PVT1 inhibition. Another example is miR-1207-5p, one of six miRNAs encoded within the PVT1 transcript. In breast cancer, both PVT1 and its encoded miR-1207-5p are overexpressed and influence cell proliferation. Thus an antagomir against miR-1207-5p could blunt this feed-forward loop [ 7 ]. More broadly, PVT1 is known to inhibit tumor-suppressive miRNAs (e.g. miR-200 family) via various mechanisms. PVT1 recruits the PRC2 component EZH2 to epigenetically silence miR-200b in cervical cancer; blocking EZH2 (or disrupting PVT1 ) restores miR-200 levels and impairs EMT [ 7 ]. In summary, manipulating PVT1 -associated miRNAs – either by oligonucleotides or small molecules that release miRNA repression – can counteract PVT1 -driven growth, invasion and stemness, also potentially overcome drug resistance by reactivating tumor-suppressor pathways. Finally, effective delivery of these therapeutics is crucial. Naked oligonucleotides face rapid degradation and poor tumor uptake. Therefore, nanoformulations are being pursued. Lipid-based nanoparticles and liposomes are especially promising: they can encapsulate ASOs or miRNA modulators and deliver them to the tumor environment. Indeed, lipid nanovesicles greatly enhance tumor delivery of antisense drugs [ 195 , 201 ]. The research indicate that vesicles can raise ASO accumulation in tumors by several-fold and prolong half-life, translating into stronger anti-tumor effects in animal models. Similar strategies could carry PVT1 -targeting siRNA or antagomirs. For example, engineered liposomes carrying miRNA mimics have effectively silenced oncomiRs in vivo, like miRNA-221 and miR-146 in colorectal carcinoma [ 202 , 203 ]. Also, red blood cell–derived extracellular vesicles loaded with ASOs reached leukemic and breast cancer cells in mice [ 204 ]. These advances suggest that PVT1 ASOs or CRISPR components might be delivered in liposomal or polymeric particles to human tumors. In summary, a variety of strategies has been proposed, direct RNA silencing, miRNA modulation, gene editing, and epigenetic inhibition – all converge on PVT1 to impair cancer. In preclinical models they consistently reduce proliferation, induce apoptosis, and suppress tumors resistance to therapy. Although no PVT1 -targeted drug has yet reached late-stage trials, the accumulated evidence and the success of RNA therapies in other diseases indicate high translational potential. Nanoparticle-enabled delivery of PVT1 ASOs or siRNAs, possibly combined with miRNA mimics or epigenetic drugs, could form potent multi-pronged tool against PVT1 -related cancers. Such strategies promise to undermine the growth, survival and drug resistance that PVT1 normally enhance, opening new therapeutic avenues in cancer treatment.

Despite significant advances in understanding the role of PVT1 and its mechanisms of action in malignancies, much remains to be clarified. Fundamental aspects of PVT1 ’s biology, including its transcription, biogenesis, and alternative splicing, are still not fully understood. Additionally, a broader understanding of PVT1 ’s interactions with downstream molecular regulators across various cancers is essential for its effective clinical application. The targeting of PVT1 in malignancies continues to be a pivotal focus of research. Future studies are needed to elucidate the mechanisms that modulate PVT1 transcripts and their contribution to cancer development. The cumulative evidence suggests that upregulated PVT1 significantly increases the risk of carcinogenesis and tumor metastasis, while also dramatically reducing patient survival, underscoring the potential of PVT1 expression as a prognostic marker in cancer.

The majority of nuclear DNA does not encode proteins. With precise regulation, the non-coding transcripts function to modify biological events like gene expression in different levels and stages. LncRNAs are among the most remarkable ncRNAs with a wide spectrum of action ranging from chromatin structure regulation to formation of miRNAs and biomolecule condensates [ 42 ]. Both normal and diseased conditions are known to be governed by lncRNAs. The roles of PVT1 in cancer promotion are mediated by gene transcription control at various levels and PVT1 impacts all steps of gene processing. PVT1 affects protein-coding genes and therefore enhances tumorigenesis in solid and hematogenic cancers [ 6 , 29 ]. Furthermore, PVT1 acts as miRNA sponger to compete and neutralize the function of some specific miRNAs, affecting various cancer-related processes, as shown in the Fig. 5 [ 43 , 44 ]. Higher levels of PVT1 are correlated with treatment resilience in many tumors. Thus, PVT1 expression could have prognostic values in cancer patients [ 45 ]. The major enhancing impact of PVT1 on cancer development, among others, is known to be established by lncRNA-miRNA-mRNA network activity, with PVT1 as an indirect effector [ 46 ]. It is important to consider the causal effects and regulatory networks/pathways in which PVT1 transcripts take part and their effects on biological and clinical aspects of various solid malignancies. PVT1 plays a pivotal role in tumor immune microenvironment remodeling, favoring immune evasion, affecting i.a. programmed death-ligand 1 ( PD-L1 ) pathway [ 17 , 47 ]. This pathway is normally used by the body to prevent overactive immune responses against native tissues (autoimmunity). However, many cancers exploit this pathway by expressing PD-L1 on their surface, effectively “turning off” immune cells that might otherwise attack them. It has been shown to upregulate PD-L1 expression via pathways involving MYC and STAT3 , suppressing T cell-mediated cytotoxic responses, and facilitating immune escape [ 48 – 50 ]. Moreover, tumor-derived exosomes carrying PVT1 lncRNA act as vehicles for intercellular communication within the tumor microenvironment. Exosomal PVT1 molecules can reprogram recipient adjacent cells, particularly promoting epithelial-mesenchymal transition (EMT), metastasis, drug resistance, autophagy, apoptosis, and cancer cells stemness [ 51 – 53 ]. Thus microenvironment reprogramming creates an environment supporting tumor growth, metastases, and resistance to immunotherapy. In addition, PVT1 influences cytokine secretion, including IL-6 and TGF-β , further suppressing recruitment of regulatory T-cells and enhancing the immunosuppressive conditions [ 54 , 55 ]. While the majority of studies characterize PVT1 as an oncogenic factor, there is conflicting evidence suggesting that its promoter region can act as a tumor suppressor under certain conditions. Cho et al. demonstrated that the PVT1 promoter acts as a tumor-suppressive DNA-binding factor independent of the PVT1 transcript. Using CRISPR interference in breast cancer cell lines, they found that silencing of PVT1 promoter led to increased cell proliferation and tumor growth in vivo. Importantly, this tumor-suppressive function was linked to the promoter region, not the PVT1 lncRNA itself [ 56 ]. Fig. 5 Cancer-related miRNAs sponged by PVT1 . Using colors, miRNAs were grouped according to the processes in which they are involved. According to the miRNA targets prediction database miRDB (Xiaowei Wang’s lab, University of Illinois at Chicago, USA) and miRNAs targeted pathways miRPathDB 2.0 (Center for bioinformatics, Saarland University, Germany) [ 57 , 58 ] Cancer-related miRNAs sponged by PVT1 . Using colors, miRNAs were grouped according to the processes in which they are involved. According to the miRNA targets prediction database miRDB (Xiaowei Wang’s lab, University of Illinois at Chicago, USA) and miRNAs targeted pathways miRPathDB 2.0 (Center for bioinformatics, Saarland University, Germany) [ 57 , 58 ] A significant number of investigations have revealed that PVT1 is upregulated in breast cancer (BC), exerting pro-oncogenic outcomes which could be measured at both molecular and clinical levels. For example, silencing of PVT1 resulted in inhibition of BC cells proliferation and migration via affecting p21 expression [ 59 ]. P21, such as p15, p16, and other cyclin-dependent kinase inhibitors, play a role in regulating cell cycle progression and can act as tumor suppressors. Among other probable or poorly understood mediators, Sex-determining region of Y chromosome-related high-mobility-group box 2 ( SOX-2 ) is a TF which is found to activate PVT1 expression in BC cells [ 60 ]. The effects of PVT1 on BC cell biology occur in different manners. A recent study by Qu et al. depicted that PVT1 is highly expressed in BC cells and this phenomenon is correlated with increased tumor growth, cancer cell division, invasion, and advanced clinical stage. They also reported that PVT1 promotes aerobic glycolysis in BC cells mainly through sponging miR-145-5p. miR-145 has a negative effect on the aerobic glycolysis (also known as Warburg effect ) by suppressing MYC [ 15 , 61 ]. Transcriptional repressor GATA binding 1 ( TRPS-1 ) promotes BC cell proliferation and migration, also affecting cell cycle regulation and EMT while miR-543 acts as its downregulator. Wang et al. demonstrated that miR-543 is sponged and neutralized by PVT1 . Thus, PVT1 enhances BC via regulation of miR-543/ TRPS-1 axis [ 62 ]. Furthermore, Li and colleagues found that PVT1 targets miR-148a-3p which functions as a post-transcriptional regulator for Rho‑associated coiled‑coil containing protein kinase 1 (ROCK-1) gene. By considering upregulation of PVT1 and ROCK-1 in BC cells, the PVT1 /miR-148a-3p /ROCK1 pathway promotes BC cell metastasis and invasion [ 46 ]. Forkhead-box Q1 (FOXQ1) promotes EMT and tumorigenesis in solid tumors. In another report, Liu et al. revealed that PVT1 promotes BC proliferation and invasion both in vitro and in vivo. They also concluded that PVT1 competes and sponges miR-128-3p which is a FOXQ1 repressor and consequently PVT1 /miR-128-3p/FOXQ1 was suggested as a promoting axis in BC. In addition, the RNA-dependent helicase and ATPase UPF1 is bound and downregulated by PVT1 , resulting in augmented BC malignant properties [ 63 ]. In addition to sponging miRNAs, PVT1 has the capability to bind proteins and alter their function. Luo et al. discovered that PVT1 stabilizes nuclear factor erythroid 2 like 2 (Nrf2) protein by binding its degrader ECH-associated protein 1 (Keap1) in triple-negative BC (TNBC) cell line, with the observation of elevated doxorubicin resistance. Therefore, PVT1 /Keap1/Nrf2 axis promotes drug resistance in TNBC cells [ 64 ]. Tang and co-workers, PVT1 suggested as Krueppel-like factor 1 ( KLF-1 ) TF stabilizer which in turn results in β-catenin upregulation and TNBC proliferation and invasion [ 34 ]. Previous investigations have explained the oncogenic roles of PVT1 in cervical cancer (CC) pathogenesis. PVT1 is upregulated in CC tumors compared to normal counterparts. Both linear and circular forms of PVT1 transcripts were depicted to promote CC via multiple processes such as enhancing tumor growth, metastatic capacity, and drug resistance [ 65 , 66 ]. Therefore, it is not surprising that PVT1 may potentially be used as CC marker [ 67 ]. In the majority of cases, PVT1 exerts the oncogenic effect via the regulation of miRNA activities in the CC cells. Gao et al. found elevated levels of PVT1 in CC cells. PVT1 knockdown in these cells resulted in reduced proliferation and invasion. Using in silico and in vitro approaches, they discovered that PVT1 directly binds and sponges miR-424, the miRNA with antitumor capabilities inducing cell cycle arrest, apoptosis via KDM5B -Notch pathway regulation [ 68 ]. Additionally, Zhang et al. reported that PVT1 epigenetically silences miR-200b through increasing histone H3K27 trimethylation in its promoter region [ 69 ]. According to the literature, miR-200b impedes CC development through various ways such as inhibiting RhoA and increasing tumor radiosensitivity [ 70 , 71 ]. Also, in accordance with Wang and colleagues, the oncogenic impact of PVT1 in CC is related to direct sponging of miR-486-3p. Extracellular matrix protein 1 ( ECM-1 ) gene is an identified target for miR-486-3p that plays positive roles in CC cell viability and proliferation. Intriguingly, MYC was found to positively regulate PVT1 in CC cells, indicating the regulatory axis MYC / PVT1 /miR-486-3p/ ECM-1 in the CC pathology [ 72 ]. Ovarian cancer (OC) is the leading cause of cancer-related mortality among gynecological tumors in women. Many studies have suggested elevated expression of PVT1 in OC tumors facilitates tumor growth and stress resilience as well as metastasis and drug resistance, resulting in unfavorable patient prognosis [ 73 ]. Involvement of PVT1 in regulatory axes of downstream molecules is the major manner to exert its oncogenic potential. Recently, Dong et al. suggested connective tissue growth factor (CTGF) as a mediator for PVT1 activity in OC cells. This protein plays a role in extracellular matrix remodeling and tumor invasion. PVT1 knockdown resulted in CTGF downregulation and reduced OC cell migration [ 74 ]. Also, Chen et al. reported significantly higher PVT1 expression in OC, which was associated with clinicopathological parameters. They additionally found that PVT1 epigenetically represses miR-214 via recruiting the histone methyltransferase EZH-2 to its promoter region [ 75 ]. Regarding other investigations, miR-214 bears tumor-suppressing features in OC cells by regulating mediators such as β-catenin and semaphorin 4D [ 72 , 76 ]. β-catenin is a protein that is generally involved in cell adhesion and intercellular signaling, and while its activation promotes tumor growth, it also acts as a tumor suppressor when regulated by other proteins, such as p53 and some miRNAs. The balance between the activation and suppression of β-catenin is crucial for physiological cell homeostasis, and when the balance is disrupted, it contributes to various cancers, including colorectal, endometrial, and OC [ 77 , 78 ]. Using in silico approach, Ding and colleagues found PVT1 gene the most amplified one among OC cell genome. miRNA-140, whose overexpression resulted in decreased OC cell viability, was reported to be sponged by PVT1 . FOXO4 seems to be capable of binding PVT1 gene promoter and enhancing its transcription, suggesting FOXO4 / PVT1 /miR-140 a functional axis in OC biology [ 79 ]. In addition, miR-133a was discovered to be repressed directly by PVT1 , leading to OC cell cycle progression, tumor proliferation, and invasion [ 80 ]. Argonaute 1 (AGO1) is a factor with increased expression in OC cells, which takes part in post-transcriptional mRNA silencing. According to Wu et al., PVT1 increases AGO1 levels in OC through sponging its regulator miR-148a-3p. Argonaute 1, in turn, promotes tumor cell proliferation and EMT by means of TGF-β / ERK pathway. This makes the PVT1 /miR-148a-3p/ AGO1 / TGF-β axis a considerable functioning machinery and potential therapeutic target [ 81 ]. Circ PVT1 is seemingly overexpressed in OC tumours and facilitates OC cells division and reduces apoptosis. Circ PVT1 is reported upregulated in OC cells by other scientists, as well. A latter study by Li et al. demonstrated that miR-149-5p targets FOXM1 in OC cells. Forkhead Box M1 is overexpressed in OC lesions and leads to increased tumor cell viability; therefore, the circ PVT1 /miR-149-5p/ FOXM1 pathway serves as a potential OC development enhancing factor [ 82 ]. The involvement of PVT1 in progression and proliferation of endometrial carcinoma (EC) has been elucidated in recent years. Due to the fact that PVT1 regulates the GnRH pathway, it could be assumed as a driver mediator in gynecological cancers like EC [ 83 ]. PVT1 suppresses miR-195 expression through enhancing histone methylation H3K27me3 in its promoter and/or direct sponging. Kong et al. revealed that PVT1 expression is associated with EC cell viability, proliferation, and invasion. They also reported that miR-195-5p is a target for PVT1 and is the mediator responsible for tumor suppressive features related with PVT1 downregulation. Considering that fibroblast growth factor receptor 1 (FGFR1) and fibroblast growth factor 2 ( FGF-2 ) are regulated by miR-195-5p and promote EC development via the PI3K/ AKT and MAPK / ERK axes, PVT1 /miR-195-5p/ FGFR1 and PVT1 /miR-195-5p/ FGF-2 pathways are involved in PVT1 -mediated EC development [ 84 ]. Moreover, Cong et al. conducted an in silico and experimental in vivo and in vitro studies to depict the mechanism of PVT1 function. They revealed that miR-612 bear tumor-suppressive characteristics in EC cells via repressing the Centromere protein-H ( CENP-H )/cyclin dependent kinase 1 ( CDK-1 ) oncogenic pathway. By the means of dual-luciferase reporter assay, they suggested miR-612 as a target for PVT1 ; therefore PVT1 /miR-612/ CENP-H/CDK-1 machinery is another part of ceRNA network in which PVT1 promotes EC [ 85 ]. According to the study by Li and colleagues, SOX-2 is a TF that contributes to EC cell proliferation and stemness partly via upregulating Up-frameshift protein 1 ( UPF-1 ). miR-136 is a negative regulator of SOX-2 and may inhibit proliferation and invasive behavior of EC but PVT1 competes and represses its inhibitory function. PVT1 /miR-136/ SOX-2 / UPF-1 is another pathway that promotes EC progression. Interestingly, patients with higher levels of PVT1 had advanced FIGO stages and shorter survival [ 86 ]. The pathogenic role of circRNA PVT1 has been reported in uterine eutopic adenomyosis. Circ PVT1 has been shown to sponge miR-145 in the endometrial adenomyotic cells. miR-145 is a regulator of Talin1 gene; an essential mediator in integrin-mediated signal transduction pathway, inducing cell proliferation and migration. Regarding the upregulation of circ PVT1 and Talin1 as well as miR-145 downregulation in endometrial adenomyosis, the PVT1 /miR-145/Talin1 pathway may serve as a booster mechanism in this disease type [ 87 ]. Recently, increased PVT1 expression was found in prostate cancer which indicated its oncogenic role through enhancing the risk of prostate cancer [ 88 ]. PVT1 expression was reported to be a prognostic and diagnostic biomarker as well as poor survival predictor in prostate cancer [ 89 ]. High expression of PVT1 has been shown to be correlated with negative clinical outcomes. A substantial correlation was indicated between the expression of PVT1 and tumor stage. In addition, PVT1 deletion notably repressed in vivo and in vitro prostate cancer growth, increased apoptosis and decreased MYC expression, thereby suggesting PVT1 as an oncogene and a probable biomarker for prostate cancer diagnosis. Besides, a new genome-wide androgen-correlated function of PVT1 in suppressing signaling genes has been shown in prostate cancer cells [ 90 ]. Moreover, decreased expression of PVT1 was also reported to suppress proliferative and migratory potential of prostate cancer cells through p38 phosphorylation [ 91 ]. PVT1 silencing was shown to have impacts on prostate cancer progression through repressing KIF23 expression by enriching miR-15a-5p, highlighting PVT1 as an potential target for prostate cancer treatment [ 92 ]. MiR-146a was proved to be correlated with the risk of different cancers including prostate cancer [ 93 ]. It has been reported that PVT1 modulated cell viability along with apoptotic response in prostate cancer cells and its function was dependent on miR-146a, focusing on management, diagnosis and prognosis of prostate cancer [ 94 ]. It is reported that PVT1 induced invasion of prostate cancer cells through regulating EMT. Nonetheless, PVT1 could promote EMT via Twist1 overexpression, a transcription factor correlated with EMT. PVT1 induced EMT in prostate cancer cells through regulating PVT1 /miR-186/Twist1, suggesting potential modulatory network as a novel target for prostate cancer [ 95 , 96 ]. Bloom syndrome protein ( BLM ) is introduced as another component in the DNA damage repair signaling pathway, and its mutation has been shown to affect prostate cancer risk [ 97 ]. High PVT1 expression is also shown to contribute to the prostate cancer aggressive phenotype through modulating the miR-27b-3p/BLM signaling [ 98 ]. Indeed, single nucleotide polymorphisms (SNPs) are known to play an important role in developing prostate cancer [ 99 ]. The effect of PVT1 and CASC11 on the risk of prostate cancer is attracting more attention currently. SNP of PVT1 and CASC11 has provided more precious information in terms of higher prediction power to the risk of prostate cancer compared to SNP individual impacts on prostate cancer development [ 100 ]. Moreover, the expression of PVT1 seems to be associated with hormone sensitivity as well as androgen receptor status in prostate cancer. If analogous changes can be shown in human malignant lesions, it is possible to use PVT1 as a target in the treatment of advanced prostate cancer [ 101 ]. Previous studies have depicted the oncogenic roles of PVT1 in hepatocellular carcinoma (HCC). Knockdown of PVT1 resulted in apoptosis and growth inhibition of HCC cells. It was reported that PVT1 bound to and stabilized EZH2 , which increased the stability of MDM-2 oncoprotein leading to p53 suppression [ 102 ]. PVT1 also promotes cell cycle progression via phosphorylation and activation of STAT-3 in hepatoblastoma cell lines [ 103 ]. Moreover, PVT1 expression in HCC cells is increased in response to interferon-α (IFN-α). PVT1 was shown to interact with STAT-1 signaling in order to neutralize the impact of IFN-α and protect HCC cells from apoptosis [ 104 ]. lnc PVT1 appears to be a direct miRNA regulator for miR-150 in HCC cells. Hypoxia-inducible protein 2 (HIG-2) appears to act as oncogene through affecting cell proliferation and iron metabolism pathway in HCC. Considering the discovered neutralizing effect of miR-150 on HIG-2, PVT1 /miR-150/HIG-2 axis was supposed to enhance HCC cell proliferation and iron metabolism in hypoxic conditions [ 105 ]. Attempting to explore ceRNA networks in HCC promoting pathways, Su at al. conducted a computational analysis which was confirmed by in vitro study. They found that PVT1 /miR-1258/ DUSP13 axis is involved in lipid metabolism, immunologic features, and microvascular invasion of HCC tumors. Accordingly, PVT1 represses miR-1258 to minimize the DUSP13 negative regulation which finally results in modified lipid oxidation status, altered resident immune cell population, and facilitated HCC invasion and metastasis [ 106 ]. Furthermore, PVT1 may promote HCC metastasis indirectly through upregulating megakaryoblastic leukemia 1 ( MKL-1 ) gene. This effect is established by sponging the MKL-1 regulator miR-3619-5p, constructing the PVT1 /miR-3619-5p /MKL-1 pathway. Interestingly, MKL-1 increases PVT1 transcription in a positive feedback regulation loop via interaction with CArG box in its promoter region [ 107 ]. A positive correlation between PVT1 and Autophagy-related gene 3 (ATG-3) in HCC lesions was demonstrated by Yang and colleagues. ATG-3 is regulated by miR-365 and PVT1 upregulates ATG-3 by miRNA repression. This phenomenon may bring additional understanding for PVT1 role in HCC development, especially during stress conditions [ 108 ]. The orally-administered sorafenib is an approved agent for HCC treatment. It exerts the anti-tumor activity via initiating ferroptosis process, an iron-associated type of regulated cell death. PVT1 was reported to regulate sorafenib resistance. because pleomorphic adenoma gene 1 ( PLAG-1 ) inhibited sorafenib-induced ferroptosis in HCC cells by increasing glutathione peroxidase 4 ( GPX-4 ) expression. miR-195-5p bound and repressed PLAG-1 mRNA translation as well as acted as a prey for PVT1 . Therefore, PVT1 /miR-195-5p/PLAG-1/GPX-4 axis appears to be an attractive target in order to increase sensitivity of HCC cells to sorafenib [ 109 ]. CircRNA PVT1 is highly expressed in HCC cells and its silencing is followed by suppressed tumor proliferation and invasion. The oncogene homebox D3 ( HOXD3 ) is indirectly upregulated by circ PVT1 in HCC cells though sponging its regulator miR-203 [ 110 ]. Parallel results have been reported concerning the role of PVT1 in gallbladder cancer (GBC) pathophysiology. The upregulation of PVT1 in GBC cells has been proven by Chen et al. and its expression can serve as a marker for tumor malignant behavior and shorter patients’ survival. Hexokinase 2 ( HK-2 ) is an enzyme which promotes tumor glucose metabolism via facilitating cellular glucose uptake and enhancing Warburg effect, the metabolic phenomenon where cancer cells preferentially use aerobic glycolysis (glucose metabolism) to produce lactate, even in the presence of sufficient oxygen, to generate ATP for rapid growth. PVT1 indirectly increases HK-2 expression by sponging its regulator miR-143. Thus, PVT1 /miR-143/ HK-2 pathway would be regulator of GBC cell proliferation and invasion [ 33 ]. As a distinct mechanism PVT1 is capable to repress the expression of miR-18b-5p via promoter hypermethylation. Due to the inhibitory impact of miR-18b-5p on HIF-1α , this oncogene is consequently upregulated, resulting in GBC cell growth and invasion [ 111 ]. Myeloid cell leukemia-1 ( MCL-1 ) is an oncoprotein belonging to Bcl-2 family with anti-apoptotic properties in many cancers including GBC. Wang and colleagues found a positive association between circ PVT1 and MCL-1 level in GBC cells. They also revealed that miR-339-3p negatively regulates MCL-1 expression in GBC and is targeted by circ PVT1 [ 112 ]. Similar to other malignancies, PVT1 plays oncogenic roles in pancreatic cancer (PC). PVT1 is upregulated in PC cells compared to the adjacent non-tumoral counterparts and is associated with higher proliferation and invasion of the PC cells. This phenomenon could partly be attributed to the fact that PVT1 increases the expression of mesenchymal markers such as Slug, Snail, β‑catenin, vimentin, and N-cadherin as well as promotes TGF‑β / SMAD signaling [ 113 ]. Exosomes are small extracellular vesicles that facilitate cross-talk between tumor cells via transmitting cellular components and signals within the tumor microenvironment (TME). Sun et al. discovered that in PC cells, PVT1 increases the intracellular transfer of the vesicles as well as their secretion into the TME through upregulating the mediators like YKT6 v-SNARE homolog, vesicle-associated membrane protein 3, and Ras-related protein Rab-7 [ 114 , 115 ]. Also, PVT1 is involved in gemcitabine, commonly used chemotherapeutic agent, resistance of the PC by interacting with EZH-2 [ 116 ]. Bioinformatic and in vitro analysis conducted by Zhao and colleagues revealed that miR-448 is directly bound and sponged by PVT1 in PC cells, reversing the inhibitory impact of the miRNA on plasminogen activator inhibitor 1 RNA-binding protein gene and raising aggressive behavior of PC samples [ 117 ]. Furthermore, Zhou et al. reported that PVT1 makes PC cells resilient to gemcitabine and promotes their viability by augmenting autophagy and influencing Wnt/β-catenin axis. The underlying mechanism was associated with the capacity of PVT1 to sponge miR-619-5p in PC cells. MiRNA-619-5p is a negative regulator for Pygo2 and autophagy-related gene 14 (ATG-14) mRNA which drive Wnt /β-catenin pathway and autophagy machineries in the PC cells, respectively. Therefore, PVT1 /miR-619-5p/ Pygo2 and PVT1 /miR-619-5p/ ATG-14 axes act to increase PC cells viability and gemcitabine resistance. More recently, Liu and co-workers announced that miR-143 is a direct target for PVT1 in the PC cells, which reduces the inhibitory effect of miR-143 on HIF-1α and downstream autophagy-related protein vacuole membrane protein 1 (VMP-1). PVT1 /miR-143/ HIF-1α/ VMP-1 pathway leads to progression of autophagy and gemcitabine resistance in PC tumors [ 118 ]. Finally, according to Sun et al., PVT1 is correlated with shorter patient survival as well as high levels of glycolysis and proliferation in pancreatic ductal adenocarcinoma samples. In described axis, lnc PVT1 inhibits the post-transcriptional regulation of HIF-1α by miR-519d-3p [ 119 ]. Gastric cancer (GC) has brought a significant health concern for many years. Despite application of conventional chemotherapies as well as novel targeted approaches, 5-year survival rates remain unfavorable. Genetic alterations are a considerable feature of GC tumors [ 120 ]. Statistical analysis have suggested the level of PVT1 in tumors as a potential diagnostic biomarker for GC with acceptable sensitivity and specificity [ 121 ]. PVT1 is an upregulated mediator to render the GC tumors behave more aggressive and malignant. Formation of new blood vessel networks and/or similar structures (i.e., vascular mimicry) to access essential nutrients is a hallmark of cancer. Zhao et al. reported that PVT1 recruits STAT-3 to the promoter region of Slug gene and thereby enhances EMT and vascular mimicry in GC. Patient-derived samples also depicted high levels of PVT1 . In addition, Slug expression correlated with shorter survival, suggesting PVT1 /Slug a probable target pathway in GC treatment [ 122 ]. PVT1 may increase the expression of VEGFA via the same mechanism and upregulate the vascular density in GC tumor mass [ 123 ]. Similar to OC, FOXM1 promotes the GC proliferation and metastasis. As one of the suggested oncogenic roles of PVT1 in GC, Xu and co-workers revealed that PVT1 increases FOXM1 levels in a post-translational manner in this tumor type [ 124 ]. PVT1 as miRNA repressor has also been observed in GC pathology as well. Li et al. reported that PVT1 directly binds and sponges miR-152 in GC cells leading to GC development due to enhanced CD-151 and FGF-2 signaling [ 125 ]. Moreover, Huang et al. found the direct inhibitory effect of PVT1 on miR-186 in GC cells, which in turn augments hypoxia-inducible factor 1 α ( HIF-1α ) expression and tumor-promoting phenotype. Thus, PVT1 /miR-186/ HIF-1α is another oncogenic mechanism in GC [ 126 ]. Role of PVT1 /miR-186 shown at Fig. 6 . miR-16 bears anti-cancer properties in GC tumors and is regulated by other oncogenic ncRNAs [ 127 , 128 ]. For instance, the well-known oncogene CCND1 is repressed by miR-16 in GC cells. PVT1 sponges miR-216 enhancing GC proliferation, considered as the PVT1 /miR-16/ CCND1 pathway [ 129 ]. Eventually, like lnc PVT1 , circ PVT1 depicts higher levels and tumorigenic capacities in GC. According to Li and colleagues, circ PVT1 sponges miR-423-5p and leads to SMAD 3 upregulation, increasing GC cell viability, migration, and invasion [ 130 ]. Fig. 6 Target genes and role of PVT1/miR-186 in various cancers Target genes and role of PVT1/miR-186 in various cancers The colorectal cancer (CRC) development is affected by PVT1 activity. PVT1 is detectable in advanced CRC samples and in metastatic tumors, impacting TGF-β / SMAD and Wnt/β-catenin pathways [ 131 ]. Interestingly, exosomal PVT1 isolated from patients sera could promote metastasis in CRC xenograft model by inducing VEGF , Twist1, vimentin, and MMP-2. miR-152-3p was demonstrated a negative modulator for this phenomenon [ 53 ]. Recent investigations have introduced PVT1 as a miRNA regulator in CRC cells. PVT1 activity is associated with Lin-28 oncoprotein hyperactivity in CRC cells. It is explained by direct miR-128sponging. Intriguingly, Lin-28 negatively impacts the let-7 miRNA family [ 132 ]. Shang et al. reported lnc PVT1 to compete and sponge miR-214-3p in CRC using bioinformatic and confirmatory experimental approaches. Their report also depicted positive correlation between PI3K/ AKT pathway, insulin receptor substrate 1 ( IRS-1 ) and PVT1 , considering the potential of miR-214-3p in repressing IRS-1 . Thus, the PVT1 /miR-214-3p/ IRS-1 axis appears to mediate CRC progression and invasion [ 133 ]. Moreover, PVT1 /miR-16-5p/ VEGFA axis establishes tumorigenic impression in CRC cells, and as a result, the expression of VEGFA is increased. Through its receptor, VEGFA induces AKT signaling cascade and enhances CRC cell proliferation and metastasis [ 134 ]. Moreover, the increased expression of PVT1 has also been reported in CRC cells compared to normal colon epithelium by Yu and co-workers. PVT1 appeared to suppress miR-1207-5p which is a negative regulator of Wnt6 . Hence, the tumorigenic impact of PVT1 partly takes place via the PVT1 /miR-1207-5p/ Wnt6 /β-catenin 2 machinery [ 135 ]. Similarly, high level of PVT1 is associated with advanced tumor grade and reduced patient survival, according to Liu et al. miR-106b-5p serves as a tumor-suppressor in CRC as its overexpression results in inhibition of tumor proliferation and invasion. This miRNA regulates the Notch-inducible secreted ligand four jointed box 1 ( FJX-1 ) gene which is amplified in some cancers including CRC, demonstrating oncogenic features. Considering miR-106b-5p a direct target for PVT1 , Liu et al. suggested the PVT1 /miR-106b-5p/ FJX-1 pathway as another probable therapeutic target for further investigations [ 136 ]. Liu et al. conducted an in silico and in vitro study. They suggested knockdown of PVT1 resulted in increased Bax and cleaved caspase-3 levels. They also discovered that the expression of PVT1 is positively associated with mitogen-activated protein kinase 1 ( MAPK-1 ) expression and negatively correlates with miR-761 levels in CRC cells. Luciferase reporter assay revealed binding sites for miR-761 on both PVT1 and MAPK-1 mRNAs, proposing that lnc PVT1 sponges miR-761 and MAPK-1 is a target for the miRNA. So PVT1 /miR-761/ MAPK-1 pathway is suggested to promote CRC cell division and repress apoptosis [ 137 ]. Finally, PVT1 competes and sponges miR-3619-5p in CRC cells. This miRNA acts to directly suppress the translation of tripartite motif-containing 29 ( TRIM-29 ) mRNA; a ubiquitin E3 ligase which regulates glucose metabolism and positively influences proliferation, migration and gain of mesenchymal phenotype by CRC cells. Consequently, the carcinogenic role of PVT1 is set up partly through the PVT1 /miR-3619-5p/ TRIM-29 axis [ 107 ]. PVT1 is reported to be a main player in carcinogenesis of lung cancer [ 13 ]. A growing number of evidence suggests that increased expression of PVT1 enhanced carcinogenesis in small and non-small cell lung cancer, being a novel diagnostic and prognostic biomarker as well as possible target in lung cancer [ 138 – 140 ]. Moreover, it has been indicated that PVT1 overexpression was correlated with a higher TNM stage and tumor size, as well as shorter overall survival of non-small cell lung cancer patients [ 141 ]. High expression of Yes-associated protein 1 ( YAP1 ) can positively modulate NOTCH1 expression, influencing drug sensitivity and cancer progression in lung cancer. Silencing of PVT1 was reported to inhibit YAP1 expression and activate NOTCH1 signaling accelerating EMT, invasion as well as metastasis in non-small cell lung cancer [ 142 ]. Regulation of miR-497 in lung cancer has been proved by other investigators, showing that PVT1 knockdown suppressed carcinogenesis [ 143 ]. PVT1 has been reported to endogenously compete with miR-128 to regulate vascular endothelial growth factor C ( VEGF C) expression, thereby correlated with lung cancer unfavorable prognosis [ 144 ]. Moreover, PVT1 is shown to sponge miR-361-3p to modulate the expression of sex determining region Y (SRY)-related high mobility group (HMG)-box9 ( SOX9 ) enhancing proliferative capacity, migratory potential and apoptosis in lung cancer [ 145 ]. Another study revealed that deletion of PVT1 suppressed cancer growth, expression of integrin B8, MEK / ERK signaling, and induced the expression of miR-145-5p. It can be concluded that PVT1 / miR-145-5p/ integrin B8 axis can provide a promising avenue for the treatment of non-small cell lung cancer [ 146 ]. It is reported that lncRNAs regulates EZH2 signaling in cancer [ 152 ]. A study revealed EZH2 as miR-526b target gene. It was found that high expression of PVT1 not only indicated poor prognosis but also promoted non-small cell lung cancer progression through targeting miR-526b/ EZH2 modulatory loop, providing novel directions for clinical management of lung cancer [ 147 ]. Bone morphogenetic protein and activin membrane-bound inhibitor ( BAMBI ) belongs to transmembrane glycoprotein family. Its overexpression has been shown in a variety of cancers but mechanism in lung cancer has been scarcely demonstrated [ 148 , 149 ]. It is manifested that PVT1 regulated BAMBI to induce cancer pathogenesis in non-small cell lung cancer through miR-17-5p sponging [ 150 ]. It is also uncovered that circular and chimeric PVT1 transcripts had also functional role in small cell lung cancer [ 29 ]. Yin yang 1 ( YY1 ) transcription factor shows vital functions in tumor progression and clinical potential in cancer therapies [ 151 ]. YY1 affects lung cancer progression through activation of PVT1 [ 152 ]. High-energy radiotherapy has been recently introduced as the major nonsurgical treatment for patients suffering from progressed non-small cell lung cancer [ 153 ]. In this case, PVT1 silencing is revealed to trigger non-small cell lung cancer radiosensitivity through miR-195 sponging, giving a new target to increase radiotherapy effectiveness in non-small cell lung cancer [ 154 ]. Moreover, long-term chemotherapy always results in a number of side effects [ 155 ]. Beclin-1 is found first-recognized mammalian protein involved in autophagy [ 156 ]. Regarding regulatory role of Beclin-1 in cancer, PVT1 has been also shown to induce chemotherapy resistance in non-small cell lung cancer via apoptosis and autophagy regulation through miR-216b/Beclin-1 axis. It highlights a promising target for improving chemotherapy effectiveness in non-small cell lung cancer [ 157 ]. Autophagy related protein 5 ( ATG5 ) is thought as a pivotal protein in autophagosome formation, associated with malignant metabolic patterns as well as tumor heterogeneity formation [ 158 ]. PVT1 is involved in hypoxia-enhanced chemoresistance and increased viability along with low rate of apoptotic response via PVT1 /miR-140-3p/ ATG5 axis [ 159 ]. It is also shown that PVT1 modulates hypoxia condition in non-small cell lung cancer through miR-199a-5p, supporting the hypothesis in which PVT1 could be a main probable target for hypoxia treatment in lung cancer [ 160 ]. Given the correlation between genetic polymorphism in PVT1 and lung cancer susceptibility, a study showed that rs13254990 polymorphism in PVT1 gene was correlated with lung cancer risk [ 161 ]. Solute carrier family 2 member 1 ( SLC2A1 ) belongs to the solute carrier family 2 whose deregulation has been reported in cancer [ 162 ]. PVT1 /miR-378c/ SLC2A1 interaction has been observed in lung cancer. A PVT1 deletion reduced the expression of SLC2A1 through miR-378c targeting, repressing lung cancer pathogenesis [ 163 ]. SLC7A5 is another member of solute carrier family whose expression was downregulated through PVT1 deletion. PVT1 along with its associated miRNAs, miR-126, has been uncovered to increase lung cancer cells proliferation through modulating SLC7A5 , shedding light on PVT1 -5/miR-126/ SLC7A5 modulatory axis in lung cancer tumorigenesis [ 164 ]. ALKBH5 as a demethylating enzyme is known to be involved in diff erent pathological processes [ 165 ]. It was demonstrated that ALKBH5 increased the development and angiogenic potential of lung cancer cells via modulating PVT1 expression and stability, providing a possible prognostic tool and potential target for patients suffering from lung cancer [ 166 ]. Modulating interleukin-6 (IL-6), an inflammatory cytokine, through miR-760 sponging has been shown to promote migration and invasion of non-small cell lung cancer cells through PVT1 [ 167 ]. Gene expression deregulation in renal malignancies outlines the indispensable role of PVT1 in renal cancer development [ 168 – 170 ]. A study revealed that the expression of PVT1 was elevated in clear cell renal cell carcinoma and has been associated with advanced TNM stage, histological grade, and worse prognosis. Antiapoptotic effect of PVT1 was also observed through enhanced expression of MCL-1 [ 171 ]. MCL-1 belongs to an anti-apoptotic member of the Bcl-2 family. Overexpression of this protein has been shown in many human malignancies. The PVT1 / MCL-1 axis appears to be promising target for clear cell renal cell carcinoma treatment [ 172 ]. The expression of PVT1 was reported to positively correlate with clinicopathological features, shorter disease-free survival as well as overall survival of clear cell renal cell cancer patients, predicting PVT1 as an independent unfavorable prognosis factor in renal carcinoma [ 173 , 174 ]. PVT1 deletion has been reported to dramatically decrease renal cancer cell viability, invasion, migration and to induce apoptosis which is mostly reversed by miR-16-5p as a target of PVT1 [ 175 ]. B-cell-specific Moloney murine leukemia virus integration site 1 ( BMI-1 ) is a known transcriptional suppressor that participates in carcinogenesis [ 176 ]. In addition, Zinc finger E-box binding homeobox 1 ( ZEB 1) and ZEB 2 belong to a vital transcription factor family in EMT [ 177 , 178 ]. PVT1 has been shown to serve as an oncogenic transcript via miR-200s sponging to modulate the BMI1 / ZEB 1/ ZEB 2 axis, promoting renal cancer progression and providing novel diagnostic targets for such disorder [ 179 ]. It appears that PVT1 participated in renal cancer progression through activating the epidermal growth factor receptor [ 180 ]. Moreover, high PVT1 expression was also shown to affect migratory potential and renal cancer cell viability, highlighting PVT1 as a marker of ongoing pathology [ 181 ]. Hypoxia-inducible factor 1-alpha ( HIF1α ), a vital transcription factor modulating cellular response and homeostasis to hypoxia, is involved in pathogenesis of various tumor types [ 182 ]. One study showed that HIF1α gene was a miR-18a target and fulfill a function of renal cell carcinoma marker [ 65 ]. Another study provided promising insight into the role of HIF2α . HIF2α binding to the PVT1 enhancer led to enhanced expression of PVT1 . Meanwhile, both gain- and loss-of-function investigations exhibited that PVT1 promoted clear cell renal cell carcinoma pathogenesis in terms of proliferative ability, invasion, migration, and angiogenesis. Therefore, PVT1 / HIF2α was demonstrated to participate in the development of renal cancer [ 35 ]. Furthermore, Kinase insert domain receptor ( KDR ) gene encodes for a vital receptor regulating cancer angiogenesis and metastasis [ 183 ]. Renal cancer stem cells have been revealed to support angiogenic response along with differentiative capacity of endothelial progenitor cell, which are regulated by the PVT1 /miR-15b/ KDR axis [ 184 ]. PVT1 -miR-328-3p- FAM193B is introduced as another regulatory loop in renal cancer as PVT1 increased proliferation of clear cell renal cell carcinoma cells through miR-328-3p sponging, leading to upregulated expression of FAM193B , a direct target of miR-328-3p activating the MAPK / ERK and PI3K/ AKT signaling pathways, which could be targets to prevent renal cancer [ 185 ]. Plasmacytoma variant translocation 1 collaborates with machineries in squamous cell carcinoma (SCC) to promote carcinogenesis. Yu et al. found that head and neck SCC ( HNSCC ) samples depict higher levels of PVT1 , which is associated with cancer cells viability and shorter patient survival. The results also showed that PVT1 activates the oncogenic Wnt/β-catenin signaling in this SCC type [ 186 ]. Moreover, PVT1 affects the expression of TGF-β 1 and promotes cervical SCC progression [ 187 ]. More recently, Li and colleagues reported that PVT1 mRNA is elevated in cutaneous SCC (cSCC) cells and mediates the malignant behavior. Both locked nucleic acid (LNA) gapmer-mediated knockdown and CRISPR-Cas9 deletion of PVT1 suppressed tumor growth and activated the p21/CDKN1A axis and cellular senescence [ 188 ]. Furthermore, PVT1 has been found to bind and augment the tumorigenic effects of cytoplasmic 4E-binding protein 1 (4EBP1) in cSCC cells [ 11 ]. According to Qin et al., PVT1 knockdown results in the inhibition of HNSCC cells growth. Moreover, PVT1 enhances cancer cell stemness and reduces CD8 + T cell recruitment. By using database mining tools, they found and experimentally confirmed tumor suppressor miR-375 as a direct target for PVT1 . Considering YAP 1 mRNA as a prey for miR-375, the authors suggested the PVT1 /miR-375/ YAP 1 pathway as the underlying molecular apparatus for reduced chemokine (e.g., IFN-β and CXCL-9) secretion and suppressed immunity in the HNSCC microenvironment [ 17 ]. Sensitivity of HNSCC to the EGFR inhibitor cetuximab is also regulated by PVT1 . PVT1 indirectly suppresses miR-124-3p via promoter hypermethylation, making HNSCC cells more resistant to cetuximab. Meanwhile, miR-124-3p overexpression bears opposite outcome [ 189 ]. Oral SCC (OSCC) originates from mouth stratified epithelial lining. This cancer is characterized by short 5-year survival. The tumorigenic impact of PVT1 has been reported in OSCC as well. PVT1 increases glucose transporter type 1 (GLUT-1) expression in OSCC cells indirectly through sponging its regulatory miRNA miR-150-5p. GLUT-1 appears to advance tumor progression and invasion in some epithelial malignancies [ 190 ]. In addition, Wang et al. revealed that miR-194-5p is another target for PVT1 in the OSCC cells which suppresses tumor cell proliferation and cisplatin resistance by targeting HIF-1α gene. Thus, besides the PVT1 /miR-150-5p/GLUT-1 axis, the PVT1 /miR-194-5p/ HIF-1α pathway is also involved in oncogenic activity of PVT1 in OSCC progression [ 191 ]. Eventually, Li and colleagues concluded that PVT1 is negatively correlated with esophageal SCC (ESCC) patients survival. Lim and SH3 domain protein (LASP1) is correlated with cell proliferation and migration capacity. As a tumor-suppressor, miR-203 downregulates LASP1 in ESCC cells. This pathway is inhibited by PVT1 according to sponging influence on the miRNA bringing PVT1 /miR-203/LASP1 a probable target among ESCC treatment approaches [ 192 ]. The oncogenic potential of PVT1 across diverse malignancies is mediated through a multifaceted set of mechanisms that converge on transcriptional regulation, chromatin remodeling, ceRNA activity, and tumor–microenvironment modulation. Among these, the most consistently reported and functionally validated mechanism involves its role as a competing endogenous RNA that sponges tumor-suppressive microRNAs, thereby derepressing oncogenic targets. This PVT1 –microRNA–mRNA regulatory network contributes to hallmarks of cancer including sustained proliferation, invasion, epithelial–mesenchymal transition, immune evasion, and therapeutic resistance. Across multiple tumor contexts, as breast, cervical, ovarian, and other described above, PVT1 engages in specific axes such as PVT1 /miR-145/ MYC in breast cancer, PVT1 /miR-424/KDM5B-Notch in cervical cancer, PVT1 /miR-214/β-catenin in ovarian cancer, PVT1 /miR-195/FGFR in endometrial carcinoma, and PVT1 /miR-143/ HIF-1α in pancreatic cancer. Similar ceRNA loops have been identified in gastric ( PVT1 /miR-152/ CD151 , PVT1 /miR-186/ HIF-1α ), colorectal ( PVT1 /miR-214/IRS1, PVT1 /miR-16/ VEGFA ), lung ( PVT1 /miR-145/integrin β8, PVT1 /miR-17/ BAMBI ), and renal cancers ( PVT1 /miR-200/ BMI1 / ZEB ). These examples highlight that the PVT1 –microRNA axis is a unifying molecular signature across solid tumors, despite tumor-type specific partners. Beyond ceRNA activity, PVT1 also influences gene expression via recruitment of chromatin modifiers (e.g., EZH2 -mediated H3K27me3 at miRNA promoters), stabilizes oncogenic proteins (e.g., MYC , Nrf2), and modulates the tumor immune microenvironment through PD-L1 upregulation and exosome-mediated signaling. Notably, circ PVT1 variants further extend these functions by sponging miRNAs such as miR-149 or miR-423, thereby reinforcing proliferative and metastatic programs. Collectively, these mechanistic insights underscore that the oncogenic role of PVT1 is predominantly influenced through its extensive crosstalk with miRNAs, forming a dynamic regulatory complex that integrates transcriptional, post-transcriptional, and epigenetic networks to drive malignant progression and treatment resistance. Thus, therapeutic strategies targeting the PVT1 –microRNA interaction may have a significant potential for targeted oncology.

Despite the increasing number of studies, the precise biological function and mechanisms of PVT1 remain incompletely understood. Adding to the complexity, PVT1 gives rise to a variety of alternatively spliced transcripts and multiple embedded miRNAs. Most studies do not differentiate between these transcript variants, despite growing evidence that individual isoforms may play distinct or even opposing roles [ 17 , 197 ]. This heterogeneity makes it difficult to determine which forms are functionally relevant in different biological or pathological contexts. Another major limitation is the close genomic and functional relationship between MYC and PVT1 [ 205 , 206 ]. The genes are often co-amplified in cancer, and their transcription can be regulated by enhancing common elements, also be mutually regulated by each other. This complicates determination whether observed regulation is caused by PVT1 , MYC , or their interaction. Disentangling their roles is particularly challenging because conventional tools like CRISPR/Cas9 often impact both genes unintentionally due to their proximity and shared regulatory regions. Another challenge is the limited availability of in vivo models and limited experimental methods. Much of the current research on PVT1 is based on in vitro experiments using cancer cell lines, which do not always reflect the complex regulatory environments of living organisms. There is a need for more animal models, such as knockouts or tissue-specific transgenics, to investigate the context-dependent functions of PVT1 under physiological conditions. In summary, significant gaps remain in the current understanding of PVT1 due to its molecular complexity, the confounding influence of the neighbor genes, limitations in current research tools, and the lack of in vivo validation. Addressing these issues will require the development of specific reagents, improved model systems, and integrative studies that can clarify the biological and clinical significance of the gene.

RNAs that are longer than 200 nucleotides and do not have extended open reading frames are known as long non-coding RNAs (lncRNAs) [ 1 , 2 ]. These RNAs play a significant role in regulating cell survival, proliferation, metabolism, differentiation, and other functions [ 3 , 4 ]. Several lncRNAs have been found to play a role in the development of tumors and organs [ 5 ]. lncRNAs were shown to regulate carcinogenesis by affecting oncogenes and/or tumor-suppressor genes [ 6 ]. PVT1 , a human gene that encodes a lncRNA known as Plasmacytoma variant translocation 1, is widely known to be related to cancer [ 7 ]. The gene was first identified at 1985 by Cory et al. during study on chromosomal translocations in murine plasmacytomas. Researchers observed that variant translocations involving chromosomes 6 and 15 occurred near the MYC oncogene, resulting in its activation. This led to the identification of a new locus, termed PVT1 , situated at least 72 kilobases downstream from MYC in murine [ 8 ]. Further studies revealed that the human homologous loci is located at chromosome 8q24.21, approximately 57 kilobases downstream of the MYC oncogene. This region was found to be involved in variant translocations in Burkitt’s lymphoma, suggesting a conserved role across species in lymphoid malignancies [ 9 ]. The first characterization of PVT1 transcripts occurred in 1989 when Shtivelman et al. identified a human transcription unit affected by variant chromosomal translocations in Burkitt lymphoma. They discovered that these translocations disrupted PVT1 , leading to the production of chimeric transcripts [ 10 ]. It has been studied that PVT1 is an essential regulator of gene expression in differentiation, development, heart diseases, and cancers [ 11 , 12 ]. Previous investigations have illustrated that PVT1 has a crucial role in the proliferation and metastasis of tumor cells [ 13 , 14 ]. In several pathologies, such as gastric or breast cancer, PVT1 transfection promote proliferation for even 30%, oppositely PVT1 silencing reduce the proliferation rate for even 30%, also increasing the survival rate fivefold [ 15 , 16 ]. PVT1 is involved in several cancer-related activities, such as alteration of miRNA expression, interactions with proteins, regulation of target genes, and formation of fusion genes. It functions as a competitive endogenous RNA as well [ 7 , 17 ]. According to previous studies, PVT1 plays a significant role in cancer progression [ 18 ]. High expression of PVT1 is linked to advanced clinical stage, lymph node metastasis, and unfavorable overall survival [ 15 ]. PVT1 shares common features with other oncogenic lncRNAs, i.e. it sponges tumor-suppressive miRNAs, regulates epigenetic enzymes like Enhancer of zest homolog 2 ( EZH2 ), and influences cancer cell growth and spread [ 19 – 21 ]. The unique feature of PVT1 s its close link to the MYC oncogene as it often co-amplifies with MYC in cancers like breast, ovarian, and colon cancer [ 22 – 24 ]. Unlike many lncRNAs, PVT1 can promote cancer in MYC -independent manner − through its own transcripts and a unique set of miRNAs. Many splicing variants of PVT1 also let it interact with a wide range of molecules, giving it exceptional versatility in cancer regulation.

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