Exploring the enigma: history, present, and future of long non-coding RNAs in cancer

LncRNA has emerged as a significant biomarker in cancer, offering insights into diagnosis, prognosis, and the prediction of therapeutic responses. The increasing mortality rate from cancer has intensified the search for reliable diagnostic tools, with circulating lncRNAs showing considerable promise. These molecules are being investigated for their potential to detect various cancers early, including hepatocellular carcinoma, colorectal cancer, gastric cancer, renal cell carcinoma, and prostate cancer, through liquid biopsies [ 132 , 139 – 142 ]. Prostate cancer antigen 3 (PCA3) has become an instrumental biomarker for prostate cancer, notably enhancing early detection and screening accuracy beyond traditional prostate-specific antigen (PSA) testing [ 143 ]. The higher specificity of PCA3 helps mitigate the frequency of unnecessary biopsies, presenting a significant advantage over PSA tests, whose levels may vary with prostate size. [ 144 , 145 ]. Notably, PCA3 is the first long noncoding RNA biomarker to gain FDA approval for cancer screening, establishing a groundbreaking precedent in cancer diagnostics [ 144 , 146 ]. In practice, PCA3 is quantified from urine samples obtained post-digital rectal exam, offering a noninvasive assessment tool for men with elevated PSA levels [ 145 ]. The integration of PCA3 into existing diagnostic frameworks is continually advancing, with research efforts focused on improving diagnostic accuracy by combining it with other markers and imaging techniques. Additionally, its potential in personalized medicine is being explored to tailor treatment strategies based on individual biomarker profiles. Specifically, the lncRNA HOTAIR has been identified as a crucial marker in glioma, where its elevated expression correlates with higher disease grades and poorer patient outcomes, highlighting its role in both diagnosis and prognosis [ 147 ]. In addition to their diagnostic utility, lncRNAs serve as valuable prognostic indicators, with HOTAIR standing out for its independent prognostic value in glioma. This finding not only suggests the potential for targeted therapeutic strategies but also underscores the broader applicability of lncRNAs in predicting disease progression. Furthermore, a deep learning study demonstrated the effectiveness of specific lncRNAs in predicting significant disease associations, reinforcing their role in prognosis [ 147 , 148 ].

The modulation of lncRNA expression through RNA interference (RNAi) techniques, such as the use of small interfering RNA (siRNA) or short hairpin RNA (shRNA), offers a targeted approach to silence oncogenic lncRNAs in vivo. For instance, targeting HOTAIR in breast cancer and MALAT1 across various cancers has demonstrated potential in reducing tumor growth and improving prognosis [ 149 , 150 ]. Antisense oligonucleotides (AONs) further enable the selective inhibition of lncRNAs such as GAS5, showing efficacy in tumor reduction [ 151 ]. Conversely, strategies to upregulate lncRNAs, particularly those that act as miRNA sponges or competing endogenous RNAs (ceRNAs), have been explored to counteract oncogenic miRNAs. Techniques employing lentivirus or adeno-associated virus vectors and nanoparticle encapsulation have facilitated the overexpression of lncRNAs such as GAS5 and UCA1, sensitizing cancer cells to radiation or chemotherapy and offering new avenues for overcoming treatment resistance [ 151 – 153 ]. Advances in delivery methods, including the use of nanoparticles such as gold nanoparticles (AuNPs), have enhanced the efficiency of RNAi and AONs in targeting lncRNAs such as NEAT1 and XIST, contributing to tumor growth inhibition and increased survival in preclinical models [ 154 , 155 ]. Additionally, drug inhibitors targeting lncRNAs such as ANRIL have shown promise in diminishing tumorigenicity, highlighting the therapeutic potential of modulating lncRNA activity [ 156 ]. In gastric cancer, the lncRNA CRNDE has been recognized as a crucial modulator of autophagy-related chemoresistance. Elevated CRNDE levels sensitize gastric cancer cells to chemotherapy by suppressing autophagy. Targeting the E2F6-CRNDE axis has emerged as a potential therapeutic strategy against chemoresistance in gastric cancer [ 157 ].

Long noncoding RNAs (lncRNA) have become integral to our understanding of genome evolution, size, and complexity, a process that began in the 1950s. The investigation of the C-value, which measures the DNA content of a haploid genome, revealed intriguing paradoxes, notably the limited correlation between DNA quantity and organismal complexity [ 1 , 2 ]. This “C-value paradox” sparked widespread discussion, particularly with discoveries that some organisms, considered evolutionarily “simpler,” possess genomes significantly larger than those of “higher” organisms, including humans [ 3 , 4 ]. A pivotal moment in resolving this paradox came with the realization that a substantial fraction of the genome is noncoding and not dedicated to protein synthesis [ 5 , 6 ]. Initially, termed “junk DNA,” these noncoding regions, which make up 50–70% of the human genome, were later found to play crucial roles beyond their initial dismissal as genomic filler [ 6 – 11 ]. The 1970s marked the beginning of a shift in perspective with the observation of “pervasive transcription,” indicating that a vast portion of the genome, beyond known coding regions, is transcribed. These RNAs include not only coding genes but also heterogeneous nuclear RNAs (hnRNAs) and other RNA types, such as rRNA and tRNA [ 6 , 12 , 13 ]. The late 1990s and early 2000s brought technological advancements that further illuminated the genome’s transcriptional landscape, such as the recognition of ribozymes in 1989, which highlighted the catalytic capabilities of RNA, and the discovery of XIST in 1991, which provided a new understanding of X chromosome inactivation. The subsequent discovery of lin-4 in 1993 pioneered the exploration of microRNAs (miRNAs), a class of small noncoding RNAs that, similar to lncRNAs, are involved in the posttranscriptional regulation of gene expression [ 14 – 18 ]. Early hypotheses by Jacob and Monod and later by Britten and Davidson proposed regulatory roles for noncoding RNAs, suggesting their involvement in gene expression modulation and signal transmission [ 19 , 20 ]. The discovery of lncRNAs such as H19 and Xist in the early 1990s underscored their significance in epigenetic regulation [ 21 – 24 ]. Challenging the notion of “transcriptional noise” and sparking debates about the functional relevance of these transcripts [ 25 – 28 ]. The ongoing exploration of lncRNA is progressively unveiling the complex mechanisms of gene expression regulation, revealing a complex landscape of genomic functionality that extends significantly beyond the coding sequences traditionally emphasized in molecular biology. This burgeoning field of research, as illustrated in Fig.  1 , promises to substantially deepen our understanding of genome architecture and its regulation, implicating the expression of lncRNAs in pivotal developmental stages, physiological conditions, and a spectrum of pathologies, notably cancer. Fig. 1 Timeline of key discoveries in lncRNA research from 1980 to 2022 Timeline of key discoveries in lncRNA research from 1980 to 2022

The integration of lncRNAs in clinical practice for cancer treatment necessitates accurate RNA analysis to identify and quantify novel RNA species. The unique sequences of lncRNAs and their potential overlap with other RNA types present significant challenges. For example, the HOTTIP lncRNA has been identified as a key regulator in gastrointestinal cancers, presenting new opportunities for diagnosis and treatment. Furthermore, research into plant stress responses and colorectal cancer has underscored the importance of lncRNAs in elucidating disease mechanisms and their utility as biomarkers in exosomes for early detection and intervention [ 113 , 114 ]. The landscape of transcriptomics has been transformed by RNA sequencing (RNA-seq) and other high-throughput sequencing technologies. These advancements allow for comprehensive annotation and quantification of a diverse range of RNAs, encompassing both coding and noncoding transcripts [ 115 ]. The selective extraction of polyadenylated RNA, excluding ribosomal RNA (rRNA), has been instrumental in isolating lncRNAs [ 116 ]. Continued progress, including the creation of libraries depleted of rRNA and the implementation of random priming during cDNA synthesis, has enhanced the precision of characterizing lncRNAs [ 117 ]. Traditional methods, including RT‒qPCR and Northern blotting, are fundamental for the validation and quantification of specific lncRNAs [ 118 ]. Given the vast diversity of lncRNAs, achieving specificity in their study is crucial. Techniques employing RNAe H to target RNA‒DNA hybrids have been developed to identify particular lncRNAs within complex RNA landscapes [ 119 ]. Microarray analysis, using probes designed for specific lncRNA sequences, is an initial screening tool, although its results require rigorous validation due to potential inconsistencies [ 120 ]. The visualization and quantification of lncRNAs within cells are crucial for comprehending their biological functions. Techniques such as RNA fluorescence in situ hybridization (RNA-FISH) are employed to evaluate the spatial distribution of lncRNAs, revealing their interactions with proteins and miRNAs. This approach offers valuable insights into the functional mechanisms of lncRNAs [ 121 ]. Additionally, RNA-FISH has played a crucial role in revealing the interactions between lncRNAs and other cellular components, including proteins and miRNAs [ 122 ]. Recent progress has resulted in the creation of assays characterized by improved sensitivity and specificity. Notably, reverse transcription-droplet digital polymerase chain reaction (RT-ddPCR) is a robust technique for accurately quantifying even low-abundance lncRNAs. Additionally, the rolling circle amplification (RCA) technique represents another innovative method that facilitates the amplification of specific lncRNA sequences to achieve clear and precise detection [ 123 ]. Beyond detection, understanding the function of lncRNAs requires a comprehensive approach. lncRNAs interact with a broad spectrum of molecular entities, including DNA, RNA, microRNA (miRNA), and proteins, thereby influencing gene expression and cellular signaling pathways [ 124 ]. For instance, the lncRNA GAS5 impacts hepatic lipid metabolism, with its knockdown resulting in a reduction in lipid accumulation, suggesting its potential as a target for treating conditions such as NAFLD [ 125 ]. Similarly, the lncRNA MG828507 , located upstream of the FLT1 gene, has been associated with preeclampsia, highlighting its significance in disease pathogenesis [ 126 ]. Computational tools have become invaluable in elucidating lncRNA functions, especially in mapping lncRNA interactions with proteins and RNA. These tools utilize a range of models, from ensemble-based and machine-learning approaches to molecular docking and network analyses, facilitating a deeper understanding of lncRNA roles [ 127 ]. Cutting-edge sequencing technologies, such as Oxford Nanopore, provide thorough insights into the sequences of lncRNAs, while NanoString platforms allow precise detection and quantification without the necessity for amplification or reverse transcription [ 128 , 129 ].

LncRNAs, which are characterized by a length surpassing 200 nucleotides and lack protein-coding capability, are predominantly transcribed by RNA polymerase II. This mirrors the intricate and adaptable nature of mRNA in terms of structure, composition, and function [ 29 , 30 ]. These molecules play pivotal roles in the intricate dance of genomic regulation, engaging with proteins, DNA, and RNA to orchestrate the organization of the genome, cellular architecture, and nuanced layers of gene expression regulation [ 29 , 31 – 33 ]. Their influence extends from the nucleus to the cytoplasm, where they oversee critical processes such as translation, metabolism, and signal transduction, demonstrating a remarkable specificity to tissue types and developmental stages [ 34 – 37 ]. Among the diverse classes of lncRNAs, stand-alone lncRNA, or "lincRNA," represent unique transcription units that operate independently of protein-coding genes. These lncRNAs, including notable examples such as Xist, H19, HOTAIR, and MALAT1, are characterized by their transcription by RNA Pol II, subsequent polyadenylation, and splicing, typically spanning an average length of 1 kb [ 38 – 41 ]. This independence from coding sequences allows them to serve as crucial regulators of gene expression and chromatin architecture. Natural antisense transcripts (NATs) add another layer of complexity, often forming sense‒antisense pairs with coding transcripts, such as Xist/Tsix and Kcnq1/Kcnq1ot1. Despite their abundance, the full extent of the biological functions of NATs remains an area ripe for exploration [ 42 – 46 ]. Similarly, pseudogenes, the genomic remnants once considered mere evolutionary artifacts, have revealed their capacity to influence gene expression, challenging our understanding of genomic ‘junk’ [ 47 – 49 ]. Intriguingly, long intronic ncRNAs, found within the introns of annotated genes, exhibit diverse expression patterns and have been implicated in specific biological processes, such as the regulation of plant vernalization by COLDAIR [ 50 , 51 ]. Moreover, the genomic landscape was further enriched by divergent, promoter-linked, and enhancer-associated RNAs, including TSSa-RNAs, uaRNAs, and PROMPTs. Although these short transcripts are often rapidly degraded, their production at transcription start sites and enhancers hints at potential regulatory roles yet to be fully understood [ 52 – 58 ]. Insights into the multifaceted mechanisms of lncRNA are pivotal for elucidating their roles in diseases, particularly cancer. Studies have highlighted the integration of lncRNAs into cellular molecular networks, underscoring their importance in developing cancer therapies [ 59 – 62 ]. Table 1 categorizes a spectrum of lncRNAs associated with various cancers, delineating their unique roles and actions. These lncRNAs are intricately regulated, integral to the complex network of cellular regulation, and instrumental to both disease pathogenesis and normal physiological processes. They interact with DNA, RNA, and proteins, significantly influencing gene expression (Fig.  2 ). As signals, certain lncRNAs, such as Xist, which is transcribed from the inactive X chromosome, indicate cellular states and trigger X chromosome inactivation [ 63 , 64 ]. Scaffold lncRNA, such as HOTAIR, form structural bases for regulatory complexes, recruiting enzymes for chromatin modification and consequently altering gene expression [ 65 ]. Decoy lncRNA, such as PANDA, bind transcription factors, thereby preventing them from activating proapoptotic genes [ 66 ]. Competing with endogenous RNA (ceRNA), lncRNA can sponge miRNAs, protecting target mRNAs from degradation—a mechanism exhibited by LINC00680, which binds to miR-423-5p to modulate PAK6 expression in esophageal squamous cell carcinoma [ 67 ]. Guide lncRNA, exemplified by MEG3, direct transcriptional machinery to specific genomic regions, modulating gene expression patterns [ 68 ]. Table 1 Roles and regulatory mechanisms of lncRNAs across various cancer types lncRNA Cancer type Role/function Mechanism of regulation Ref TUG1 Bladder cancer TUG1 promotes BC cell proliferation, migration, and invasion Modulate miR-145/ZEB2 axis [ 169 ] TUG1 Bladder cancer Migration and invasion of T24 and EJ cells Promote HMGB1 expression [ 170 ] HOTAIR Breast cancer Promotes tumorigenic activity in breast CSCs Facilitate HSPA1A expression via sequestering miR-449b-5p [ 171 ] LINC00511 Breast cancer Enhanced cellular proliferation, increased sphere-formation capability, elevated expression of stem factors (Oct4, Nanog, SOX2), and heightened tumor growth were observed Modulate miR-185/STXBP4 [ 172 ] LINC02582 Breast cancer Promoted radioresistance Interact with USP7 to deubiquitinate and stabilize CHK1 [ 173 ] LINC00963 Breast cancer Stimulates the proliferation and tumorigenesis of breast cancer cells Inhibits DNA damage and oxidative stress while increasing the sensitivity of breast cancer cells to radiation Modulate miR-324-3p/ACK1 axis [ 174 ] HOTAIR Breast cancer Facilitates the proliferation of breast cancer cells by modulating the cell cycle and apoptosis. Additionally, it enhances DNA repair mechanisms and contributes to radioresistance Modulate EZH2 [ 175 ] H19 Breast cancer Suppression resulted in the inhibition of proliferation, migration, and invasion, coupled with the induction of apoptosis Modulate miR-130a-3p/SATB1 [ 176 ] TRPM2-AS Gastric cancer Promote the proliferation, metastasis and radioresistance Enhance the expression of FOXM1 by acting as a sponge of miR-612 [ 177 ] NEAT1 Gastric cancer Enhanced radio-sensitivity Modulate miR-27b-3p [ 178 ] PCAT1 Cervical cancer The enhancement of radiosensitivity in CC cells through silencing is evident in reduced proliferation, migration, and invasion Modulate miR-128/GOLM1 axis [ 179 ] LINC00958 Cervical cancer Suppresses the proliferation and tumor growth of cervical cancer cells, concurrently fostering apoptosis in these cells Modulate miR-5095/RRM2 [ 180 ] GAS5 Cervical cancer Enhanced radio-sensitivity Modulate miR-106b/IER3 axis [ 181 ] HOTAIR Cervical cancer Nullified the impact of radiation on cell viability and apoptosis in the cells Promote HIF-1α expression [ 182 ] HOTAIR Cervical cancer Suppressed apoptosis and facilitated cellular proliferation, progression of the cell cycle, migration, and invasion, leading to the induction of radioresistance Regulate p21 expression [ 183 ] HOTAIR Colorectal cancer Knockdown weakened cell viability, induced cell apoptosis, inhibited cell autophagy, and enhanced cell radiosensitivity Regulate microRNA-93/ATG12 [ 184 ] Lnc-RI Colorectal cancer Silencing inhibited cell growth and promoted apoptosis rates, increased radiosensitivity Regulate NHEJ repair through miR-4727-5p/LIG4 [ 185 ] LINC00958 Colorectal cancer Stimulated in vitro cell proliferation while inhibiting apoptosis and reducing sensitivity to radiotherapy. Additionally, it facilitated tumor growth in in vivo experiments Modulate miR-422a/MAPK1 axis [ 186 ] EGOT Rectal cancer Knockdown inhibited the proliferation and colony formation, induced the apoptosis and improved the radiosensitivity Modulate miR-211-5p/ErbB4 axis [ 187 ] MAGI2-AS3 Esophageal cancer Promoted cell apoptosis and inhibited proliferation and radio-resistance Down-regulate HOXB7 through interaction with EZH2 [ 188 ] DNM3OS Esophageal squamous cell cancer Enhance radioresistance Regulate DNA damage response [ 189 ] FAM201A Esophageal squamous cell cancer Enhanced the radiosensitivity Regulate ATM and mTOR expression via miR-101 [ 190 ] NORAD Esophageal Squamous cell cancer Knockdown sensitizes ESCC cells to radiation treatment Modulate EEPD1/ATR/Chk1 axis and inhibit pri-miR-199a1 [ 191 ] TUG1 Esophageal squamous cell cancer Knockdown inhibition proliferation and colony formation and induced apoptosis Modulate miR-144-3p and MET/EGFR/AKT axis [ 192 ] MALAT1 Esophageal squamous cell cancer Suppressed the reduction in cell viability induced by irradiation and increased the occurrence of apoptosis Modulate Cks1 expression [ 193 ] HOTAIRM1 Glioblastoma Knockdown reduced cell viability, decreased invasive growth and diminished colony formation capacity Regulate mitochondrial function and ROS levels via TGM2 [ 194 ] HMMR-AS1 Glioblastoma Knockdown inhibits cell proliferation, migration, invasion, and mesenchymal phenotypes Regulate DNA repair proteins ATM, RAD51, and BMI1 [ 195 ] RBPMS-AS1 Glioblastoma Enhanced the radiosensitivity and cell apoptosis while suppressing proliferation Promote NRGN transcription through the miR-301a-3p/CAMTA1 axis [ 196 ] TPTEP1 Glioma Weakened the stemness and radioresistance of glioma in both laboratory and animal testing settings Stimulate the P38 MAPK signaling through interacting with miR‑106a‑5p [ 197 ] linc-RA1 Glioma Promoted glioma radioresistance in vitro and in vivo Prevent H2Bub1/USP44 combination [ 198 ] TP53TG1 Glioma Promoted the proliferation, colony formation, autophagy, and radioresistance, and restrained the apoptosis Modulate miR-524-5p/RAB5A axis [ 199 ] SNHG18 Glioma Suppressed the radioresistance Inhibit semaphorin 5A [ 200 ] NCK1-AS1 Glioma Knockdown impedes cell proliferation and amplifies cell apoptosis Modulate miR-22-3p/IGF1R [ 201 ] LincRNA-p21 Glioma N/A Regulate β-catenin [ 202 ] LINC01123 Glioma The knockdown resulted in diminished cell proliferation, impaired colony formation capabilities, and heightened susceptibility to apoptosis following 4 Gy X-ray irradiation Modulate miR-151a/CENPB axis [ 203 ] XIST Glioma Knockdown impeded cell proliferation, curtailed invasion, and prompted cell apoptosis by increasing cell sensitivity to X-ray radiation Modulate miR-329-3p/CREB1 axis [ 204 ] LINC00520 Head and neck squamous cell cancer Silencing enhanced radiosensitivity and restrained cell proliferation, invasion, migration, and apoptosis Modulate miR-195/HOXA10 [ 205 ] HOTAIR Laryngeal cancer Reduced laryngeal cancer cell radiosensitivity Modulate miR-454-3p/E2F2 axis [ 206 ] DGCR5 Laryngeal cancer Silencing inhibited the stemness and enhance the radiosensitivity Modulate miR-506/Wnt pathway [ 207 ] DGCR5 Laryngeal cancer Promoted cell proliferation and radioresistance Regulate miR-195 [ 208 ] NEAT1 Nasopharyngeal cancer Suppressed cell growth, invasion, and radiation resistance in laboratory settings and inhibited tumor metastasis in animal studies Modulate miR-101-3p/EMP2 axis [ 209 ] PVT1 Nasopharyngeal cancer The knockdown resulted in decreased cell proliferation, diminished colony formation, reduced tumorigenesis, and heightened radiosensitivity Stabilize HIF-1α through promoting the binding between H3K9ac and TIF1β [ 210 ] linc00312 Nasopharyngeal cancer Enhance the responsiveness of cells to ionizing radiation Target DNA-PKcs and impairing DNA damage repair [ 211 ] LINC00114 Nasopharyngeal cancer Knockdown inhibited proliferation, migration, and radioresistance Regulate ERK/JNK signaling pathway via targeting miR-203 [ 212 ] PVT1 Nasopharyngeal cancer Knockdown inhibited cell proliferation, radioresistance and promoted cell apoptosis Modulate miR-515-5p/PIK3CA [ 213 ] CASC19 Nasopharyngeal cancer Knockdown enhanced apoptosis, radiosensitivity, and suppressed cellular autophagy Promote autophagy via AMPK-mTOR pathway [ 214 ] ANCR Nasopharyngeal cancer The knockdown impeded the growth of NPC cells and reduced their resistance to radiation Inhibit PTEN expression [ 215 ] LINC-PINT Nasopharyngeal cancer Demonstrated responsiveness to DNA damage and decreased cellular tolerance to ionizing radiation both in laboratory experiments and animal models Inhibit DNA damage repair through ATM/ATR-Chk1/Chk2 [ 216 ] PTPRG-AS1 Nasopharyngeal cancer The silencing heightened sensitivity to radiotherapy and induced cell apoptosis, concurrently inhibiting cell migration, invasion, and proliferation Modulate miR-194-3p/PRC1 [ 217 ] MALAT1 Nasopharyngeal cancer Knockdown sensitize to radiation Modulate miR-1/slug axis [ 218 ] ROR Hepatocellular cancer The knockdown diminishes the radiosensitivity of parental HCC cells both in vitro and in vivo by reducing their DNA repair capacity Modulate miR-145/RAD18 axis [ 219 ] GAS5 Hepatocellular cancer Enhanced the radiosensitivity Modulate miR-144-5p/ATF2 axis [ 220 ] MIR22HG Hepatocellular cancer Increase radiosensitivity Promote the production of miR-22-5p [ 221 ] LINC00483 Lung cancer Silencing inhibited cell proliferation, migration, invasion and enhanced radiosensitivity Modulate miR-144/HOXA10 [ 222 ] HOTAIR Lung cancer Reduced radio-sensitivity Regulate β-catenin [ 223 ] AGAP2-AS1 Lung cancer Knockdown reduced radioresistance Modulate miR-296/NOTCH2 [ 224 ] LINC00461 Lung cancer Knockdown promoted cell proliferation, migration and invasion, and enhanced radiosensitivity Modulate miR-195/HOXA10 [ 225 ] KCNQ1OT1 Lung adenocarcinoma Promoted autophagy and radioresistance Induce ATG5/ATG12-mediated autophagy via miR-372-3p [ 226 ] SBF2-AS1 Non-small cell lung cancer Knockdown promoted apoptosis and inhibited proliferation and radioresistance, Modulate microRNA-302a/MBNL3 axis [ 227 ] FAM201A Non-small cell lung cancer Knockdown inhibited proliferation, enhanced apoptosis and radiosensitivity Upregulate EGFR and HIF-1α via miR-370 [ 228 ] PVT1 Non-small cell lung cancer Knockdown inhibited proliferation, enhanced apoptosis and radiosensitivity Regulate miR-195 [ 229 ] CYTOR Non-small cell lung cancer Reduces radiosensitivity Modulate miR-206/PTMA axis [ 230 ] CBR3-AS1 Non-small cell lung cancer knockdown reduced proliferation, invasion, and migration; inhibited cell cycle progression; and promoted apoptosis, radiosensitivity Modulate miR-409-3p/SOD1 [ 231 ] HNF1A-AS1 Non-small cell lung cancer Knockdown inhibited proliferation, enhanced apoptosis and radiosensitivity Modulate miR-92a-3p/MAP2K4/JNK axis [ 232 ] Linc-SPRY3 Non-small cell lung cancer Knockdown increased survival and reduced apoptosis Interact with IGF2BP3 and affect RNA stability in HMGA2 and c-MYC mRNAs [ 233 ] GAS5 Non-small cell lung cancer Suppressed cell proliferation and invasion, and enhanced radiosensitivity Modulate miR-135b [ 234 ] RBM5-AS1 Medulloblastoma Silencing inhibited proliferation and enhanced apoptosis radiosensitivity Stabilization of SIRT6 protein [ 235 ] LINC00518 Melanoma Knockdown inhibited cell invasion, migration, proliferation, and clonogenicity and enhanced radioresistance Regulate glycolysis through an miR-33a-3p/HIF-1α negative feedback loop [ 236 ] LINC01224 Melanoma Knockdown inhibited cell viability and proliferation but enhanced cell apoptosis and radiosensitivity Modulate miR-193a-5p/NR1D2 axis [ 237 ] XIST Neuroblastoma Knockdown inhibited proliferation, enhanced radiosensitivity Modulate the miR-375/L1CAM [ 238 ] LINC01410 Neuroblastoma Knockdown inhibited proliferation and invasion, and increased radiosensitivity Modulate miR-545-3p/HK2 axis [ 239 ] HULC Prostate cancer Knockdown promoted autophagy, apoptosis, and enhanced radiosensitivity Modulate autophagy via Beclin-1 and mTOR [ 240 ] TUG1 Prostate cancer Knockdown inhibited proliferation, enhanced cell apoptosis and radiosensitivity Modulate miR-139-5p/SMC1A axis [ 241 ] GAS5 Prostate cancer Suppressed cell viability and migration, enhanced radiosensitivity Modulate miR-320a/RAB21 axis [ 242 ] LINC02532 Renal cell cancer Knockdown enhanced cell radiosensitivity Modulate miR-654-5p/YY1 axis [ 243 ] SNHG7 Thyroid cancer Promote proliferation and I 131 resistance Modulate miR-9-5p/DPP4 axis [ 244 ] GAS5 Thyroid cancer Promote proliferation and I 131 resistance Modulate miR-362-5p/SMG1 axis [ 245 ] Fig. 2 Functional mechanisms of lncRNA A In response to diverse stimuli, lncRNA regulates signaling pathways by binding to transcription factors. B Acting as miRNA sponges, lncRNA inhibits mRNA degradation. C Serving as scaffolds, lncRNA aids in forming protein complexes, thereby regulating target gene transcription. D LncRNA also guides ribonucleoprotein complexes to specific DNA sequences, influencing gene expression Roles and regulatory mechanisms of lncRNAs across various cancer types Stimulates the proliferation and tumorigenesis of breast cancer cells Inhibits DNA damage and oxidative stress while increasing the sensitivity of breast cancer cells to radiation Functional mechanisms of lncRNA A In response to diverse stimuli, lncRNA regulates signaling pathways by binding to transcription factors. B Acting as miRNA sponges, lncRNA inhibits mRNA degradation. C Serving as scaffolds, lncRNA aids in forming protein complexes, thereby regulating target gene transcription. D LncRNA also guides ribonucleoprotein complexes to specific DNA sequences, influencing gene expression

Advances in sequencing technologies have significantly refined our understanding of lncRNAs, increasingly distinguishing functional molecules from mere transcriptional noise. This progress, however, underscores the need for rigorous validation to confirm the biological roles of lncRNAs, with current guidelines aiming to streamline these efforts. Emerging at the forefront of cancer research, lncRNAs offer promising avenues for diagnostic and therapeutic innovations due to their involvement in key physiological processes. However, their full impact on cancer progression and utility in clinical settings warrants careful scrutiny, especially considering the potential unintended effects in healthy tissues and the complexity of their molecular pathways. The evolution of lncRNA research necessitates rigorous biological validation using patient samples alongside comprehensive functional studies to harness their potential effectively. Enhancing the sensitivity, specificity, and accuracy of lncRNA biomarkers by employing advanced molecular tools such as RNA-seq, RNA-FISH, ic-SHAPE, and quantitative real-time PCR is crucial. These techniques are essential for accurately measuring lncRNA levels in biological samples, providing insights into their roles in health and disease. Moreover, the safety, toxicity, and side effects associated with lncRNA-targeted therapies require thorough evaluation. Innovations in delivery methods, such as nanoparticle-based systems, and the integration of RNA therapy with other treatments are critical to advancing therapeutic efficacy and improving patient outcomes. Additionally, employing computational methods to understand how lncRNAs predict disease associations is pivotal, utilizing machine learning and other data-driven approaches to model lncRNA interactions and their functional impacts. Although lncRNAs hold significant promise for revolutionizing cancer diagnosis and therapy, realizing this potential involves overcoming numerous challenges. By focusing on these strategic areas, we aim to inspire ongoing research and innovation within the field, advancing toward effective clinical applications of lncRNAs.

The expression of lncRNAs is a key factor in cancer treatment resistance. LncRNAs such as H19 and UCA1 have been implicated in chemoresistance mechanisms in ovarian and gastric cancers, respectively, through their interaction with miRNAs and signaling pathways [ 158 , 159 ]. Targeting these lncRNAs offers a strategy to enhance the efficacy of conventional therapies, such as cisplatin and tamoxifen, and improve patient outcomes. Moreover, the role of lncRNAs in promoting drug resistance through exosomal transfer, as observed with TP73-AS1 in glioblastoma and its contribution to temozolomide resistance, emphasizes the complexity of cancer biology and the potential of lncRNAs as therapeutic targets [ 160 – 162 ]. In cancer therapy, lncRNAs are pivotal for understanding treatment resistance. The expression profiles of these genes can change in response to chemotherapy, radiotherapy, and immunotherapy, affecting treatment outcomes [ 163 ]. For example, the lncRNA SNHG6, which acts as a miR-101 sponge, promotes epithelial–mesenchymal transition (EMT), a process linked to metastasis and resistance, particularly by influencing the responsiveness of breast cancer to tamoxifen [ 164 ]. Similarly, in colorectal cancer, UCA1 has been shown to confer resistance to cetuximab by modulating the miR-495 and HGF/c-MET signaling pathways, indicating its role in therapeutic resistance [ 165 ]. Prostate cancer cells resistant to androgen receptor inhibitors such as enzalutamide exhibit altered lncRNA expression patterns, suggesting a mechanism for the development of resistance [ 166 ]. In chemotherapy-sensitive lung cancer tissues, the lncRNA MEG3 is expressed at lower levels, and its overexpression reduces autophagy levels, thereby enhancing the effectiveness of vincristine in lung cancer chemotherapy [ 167 ]. Reducing the expression of the lncRNA HOXD-AS1 in glioma cells decreased their proliferation, migration, and invasion while increasing their sensitivity to cisplatin (DDP). This effect is mediated through the sequestration of miR-204, suggesting that HOXD-AS1 could serve as a viable therapeutic target for glioma treatment [ 168 ].