LncRNA CCAT2 role in female-related cancer progression and diagnosis: a comprehensive review.

The most common kind of cancer in women worldwide is BC, and metastasis continues to be the main cause of BC-related fatalities [ 54 , 55 ]. Preclinical studies have provided substantial evidence supporting the role of CCAT2 in BC progression. Redis and colleagues reported that CCAT2 is expressed in the majority of BC patient tissues, both in vitro and in vivo [ 56 ]. They also demonstrated that CCAT2 contributes to increased cell motility and confers resistance to 5-fluorouracil in cancer cell lines [ 56 ]. Similarly, Cai et al. showed that silencing CCAT2 suppresses cell proliferation, invasion, and tumor formation by modulating the Wnt and TGF-β signaling pathways in both in vitro assays and xenograft models [ 57 ]. Additionally, Moradi et al. further validated that CCAT2 promotes chemoresistance to tamoxifen (TAM), a standard therapy targeting estrogen receptors in BC. Notably, approximately 40% of estrogen receptor-positive BC patients develop resistance to TAM due to dysregulation of non-coding RNAs. In TAM-resistant MCF7-R cells, CCAT2 regulates the hsa-miR-145-5p/AKT3/mTOR axis, thereby controlling cell cycle progression, migration, and apoptosis [ 58 ]. Accordingly, inhibiting CCAT2 expression represents a potential strategy to enhance the susceptibility of resistant BC cells to TAM. Supporting this, a 2016 study demonstrated that TAM-resistant cells exhibit higher CCAT2 expression compared with TAM-sensitive cells [ 59 ]. Clinical investigations have corroborated the experimental findings by linking CCAT2 expression to breast cancer progression [ 40 , 60 , 61 ]. Approximately two-thirds of patients with BC had elevated levels of CCAT2 expression, which is significantly associated with poorer prognosis and reduced overall survival [ 56 ]. Deng et al. found a significant association between CCAT2 overexpression and the tumor, node metastasis (TNM), and lymph node metastasis (LNM) stage of people with BC. Additionally, they demonstrated how CCAT2 interacted with EZH2 to suppress the production of p15 in BC cells, thereby enhancing the capacity of BC cells to proliferate [ 62 ]. Xu et al. discovered in 2020 that triple-negative breast cancer (TNBC) and breast cancer stem cells (CSCs) had a particular overexpression of CCAT2. According to other study findings, CCAT2 activates the Notch signaling pathway and upregulates the expression of OCT4-polygalacturonase 1 to facilitate the development and spread of tumors in TNBC (Fig. 2 ) [ 63 ]. These studies suggest that CCAT2 not only reflects tumor aggressiveness but may also serve as a prognostic biomarker and potential diagnostic. Several studies have shown the upregulation of CCAT2 expression in BC Table 1 . Fig. 2 lncRNA CCAT2 role in female-related cancer progression. lncRNA CCAT2 plays a significant role in the pathogenesis of various female-related cancers by modulating different microRNAs and cellular signaling pathways, including Wnt/β-catenin and Notch, as well as influencing the expression of intracellular proteins. AKT; Protein Kinase B, PTEN; Phosphatase and Tensin Homolog, PI3K; Phosphatidylinositol 3-Kinase, mTOR; Mammalian Target of Rapamycin, TGFB; Transforming Growth Factor Beta, MAPK1; Mitogen-Activated Protein Kinase 1, miR; MicroRNA, VEGF; Vascular Endothelial Growth Factor, NICD; Notch Intracellular Domain Table 1 LncRNA CCAT2 role in breast cancer progression and metastasis Cancer Expression Model Target/pathway Main findings Refs BC Upregulated BC patient tissue samples. Wnt/β-catenin - Expression of CCAT2↑ -Overexpressed in 25% of BC cases Correlated with earlier stage -lymph node involvement [ 127 ] BC Upregulated MCF7 human BC cell line PI3K/AKT/mTOR -Expression of CCAT2↑ -Regulates TAM resistance in MCF7 BC cells  [ 58 ] BC Upregulated BC patient tissue samples, BC cell lines, including 5-FU resistant versions , Subcutaneous xenograft model in mice mTOR CCAT2 may reduce BC cell chemosensitivity to 5-Fu by activating the mTOR pathway.  [ 93 ] BC Upregulated BC patient tissue samples Cell lines: LCC9, MDA-MB-231 MCF-7/HCC1937 TGF-β - Expression of CCAT2↑ - Downregulation inhibits proliferation, invasion, migration, and ↑ apoptosis  [ 128 ] luminal subtype of BC Down-regulated BC patient tumor tissue samples Luminal BC cell lines: MCF-7, T-47D for in vitro experiments CCAT2 has a dual function in regulating the luminal subtype of BC, depending on its subcellular distribution. [ 129 ] TNBC Upregulated BC cell lines: MDA-MB-231, SUM159, and MCF-10 A-Src cells miR-205 CCAT2 promotes oncogenesis and stemness in triple-negative breast cancer (TNBC)  [ 63 ] BC Upregulated CCAT2 enhances the sensitivity of BC cells to the drug 5-fluorouracil by upregulating microRNA-145 through a mechanism mediated by p53  [ 130 ] BC Upregulated BC patient tissue samples, Cell lines: MDA-MB-231, MCF-7/MCF10A P15, EZH2 CCAT2↑ BC progression↑ by repressing the tumor suppressor gene p15.  [ 62 ] BC Upregulated BC patient tissue samples, Cell lines: MDA-MB-231, MCF-7/Hs578Bst Wnt/β-catenin -Poor prognosis, -Proliferation↑, -Invasion↑, -Tumorigenesis↑ [ 57 ] BC Upregulated blood samples from BC patients The excellent potential of SPRY4-IT1, XIST, and H19 lncRNAs as diagnostic biomarkers to discriminate BC from healthy controls. [ 131 ] BC Upregulated Cell lines: MCF-7, T47 D tamoxifen resistant/MCF-7, T47D–tamoxifen responsive Suppressing CCAT2 expression improves sensitivity to tamoxifen in resistant cells  [ 132 ] BC Upregulated NMBC patients MBC patients Benign breast disease patients Normal controls CCAT2 emerges as a critical factor in BC prognosis, with its expression levels serving as indicators of patient outcomes.  [ 113 ] BC: breast cancer, MBC: Metastatic Breast Cancer, NMBC: Non-Metastatic Breast Cancer, TAM-resistant: tamoxifen-resistant TNCB: triple-negative breast cancer, CCAT2: Colon Cancer Associated Transcript 2, PI3K: Phosphoinositide 3-kinase, Akt: Protein kinase B, EZH2: Enhancer of zest homolog 2, mTOR: Mechanistic target of rapamycin, WNT: Wingless-related integration site, 5-FU: 5-Fluorouracil, MCF-7: Michigan Cancer Foundation-7, TGF-β: Transforming Growth Factor Beta, SPRY4: Sprouty RTK Signaling Antagonist 4, XIST: X-inactive specific transcript, lncRNA CCAT2 role in female-related cancer progression. lncRNA CCAT2 plays a significant role in the pathogenesis of various female-related cancers by modulating different microRNAs and cellular signaling pathways, including Wnt/β-catenin and Notch, as well as influencing the expression of intracellular proteins. AKT; Protein Kinase B, PTEN; Phosphatase and Tensin Homolog, PI3K; Phosphatidylinositol 3-Kinase, mTOR; Mammalian Target of Rapamycin, TGFB; Transforming Growth Factor Beta, MAPK1; Mitogen-Activated Protein Kinase 1, miR; MicroRNA, VEGF; Vascular Endothelial Growth Factor, NICD; Notch Intracellular Domain LncRNA CCAT2 role in breast cancer progression and metastasis - Expression of CCAT2↑ -Overexpressed in 25% of BC cases Correlated with earlier stage -lymph node involvement -Expression of CCAT2↑ -Regulates TAM resistance in MCF7 BC cells BC patient tissue samples, BC cell lines, including 5-FU resistant versions , Subcutaneous xenograft model in mice BC patient tissue samples Cell lines: LCC9, MDA-MB-231 MCF-7/HCC1937 - Expression of CCAT2↑ - Downregulation inhibits proliferation, invasion, migration, and ↑ apoptosis BC patient tissue samples, Cell lines: MDA-MB-231, MCF-7/MCF10A BC patient tissue samples, Cell lines: MDA-MB-231, MCF-7/Hs578Bst -Poor prognosis, -Proliferation↑, -Invasion↑, -Tumorigenesis↑ Cell lines: MCF-7, T47 D tamoxifen resistant/MCF-7, T47D–tamoxifen responsive Suppressing CCAT2 expression improves sensitivity to tamoxifen in resistant cells NMBC patients MBC patients Benign breast disease patients Normal controls BC: breast cancer, MBC: Metastatic Breast Cancer, NMBC: Non-Metastatic Breast Cancer, TAM-resistant: tamoxifen-resistant TNCB: triple-negative breast cancer, CCAT2: Colon Cancer Associated Transcript 2, PI3K: Phosphoinositide 3-kinase, Akt: Protein kinase B, EZH2: Enhancer of zest homolog 2, mTOR: Mechanistic target of rapamycin, WNT: Wingless-related integration site, 5-FU: 5-Fluorouracil, MCF-7: Michigan Cancer Foundation-7, TGF-β: Transforming Growth Factor Beta, SPRY4: Sprouty RTK Signaling Antagonist 4, XIST: X-inactive specific transcript, CC remains the second leading cause of cancer-related mortality among young women, with HPV infections accounting for approximately 53,000 deaths annually. Moreover, the incidence of CC continues to rise each year [ 30 , 64 – 66 ]. Emerging research has established that lncRNAs contribute to cancer development by modulating gene regulatory networks and influencing transcriptional processes [ 30 ]. Among these, lncRNA CCAT2 has been identified as a key player in tumorigenesis and represents a promising biomarker for both diagnosis and prognosis in CC [ 67 ]. Moreover, in the research by Wang et al. (2021), CCAT2 expression was assessed in tissues and cell lines derived from CC patients using qRT-PCR [ 30 ]. The results showed significantly elevated CCAT2 levels in CC tissues and in HeLa and SiHa cell lines compared to healthy controls. Mechanistically, CCAT2 was found to interact with miR-493-5p , leading to its upregulation and subsequent repression of CREB1 [ 30 ]. While silencing CCAT2 resulted in marked reductions in cell proliferation, EMT, and invasiveness, both in vitro and in xenograft models [ 30 ]. Additionally, Wu et al. demonstrated that CCAT2 suppression inhibits cell proliferation by inducing G1 phase arrest and apoptosis [ 67 ]. Conversely, CCAT2 promotes the expression of miR-20a , MYC , and miR-17-5p via the WNT signaling pathway, highlighting its critical role in tumor progression. Additional studies have revealed that CCAT2 regulates multiple oncogenic genes, including PI3K , Akt , and Crk , which are central to the growth and progression of various cancers [ 67 ]. Clinical studies further support the oncogenic role of CCAT2 in CC, as Serum CCAT2 levels are significantly higher in CC patients compared to individuals with CIN and healthy controls, correlating with advanced tumor stages and lymph node metastasis [ 64 ]. Notably, CCAT2 expression is elevated in cervical squamous carcinoma (CESC) relative to CIN and healthy individuals [ 68 ]. High CCAT2 expression in cervical squamous cells has been associated with FIGO stage, depth of cervical invasion, and lymph node metastasis. Moreover, patients exhibiting elevated CCAT2 levels tend to have poorer PFS and overall survival (OS) [ 65 ]. Furthermore, the rs6983267 single-nucleotide polymorphism (SNP) has been shown to enhance MYC expression, thereby upregulating CCAT2 through the MYC/Wnt/CCAT2 signaling axis. This SNP is linked to accelerated progression of advanced-stage III cervical squamous cell carcinoma (SCC) compared to lower-grade tumors [ 66 ]. Overall, these findings underscore the critical role of CCAT2 in promoting CC progression and metastasis via multiple signaling pathways. Consequently, CCAT2 emerges as a valuable biomarker for early detection and therapeutic intervention in CC. This review aims to explore the molecular mechanisms by which CCAT2 influences CC progression (Fig. 2 ), while additional studies highlighting the role of CCAT2 in CC are summarized in the Table 2 . Table 2 LncRNA CCAT2 role in cervical cancer progression Cancer Expression Model Target/pathway Main findings Refs. CC Upregulated Serum of CC patients and healthy control CCAT2/Wnt/β-catenin -↑ Serum CCAT2 in CC vs. CIN healthy controls. -↑ CCAT2 expression = advanced tumor stages lymph node metastasis. - Prognostic factor [ 1 ] CC Upregulated CC patients tissue, BALB/c nude mice, HeLa/SiHa cells miR-493-5p/CREB1/CCAT2 - ↑ CCAT2 in CC vs. NC - Knockdown CCAT2 → ↓ proliferation, migration, invasion - CCAT2 acts as a ceRNA → ↑ CREB1 by sponging miR-493-5p [ 2 ] CC Downregulated HeLa, CaSki, SiHa, CCK8 (Dojindo), BD Biosciences 1. CCAT2/MYC/miR-17-5p/miR-20a/TCF7L2/WNT 2. CCAT2/PI3K/Akt/Crk CCAT2 is↑ expressed in HeLa and other CC cell lines - knockdown→↓ cell proliferation, G1 phase arrest,↑ Apoptosis [ 5 ] CC Upregulated CESC patients tissue, qRT-PCR, Kaplan-Meier survival analysis lncRNA CCAT2/FIGO stage/lymph node metastasis/depth of cervical invasion -CCAT2 is ↑ in CESC tissues -↑ expression →advanced FIGO stages, lymph node metastasis, and deeper cervical invasion -Poor prognostic factor for OS and PFS in CSCC patients. [ 3 ] CC Upregulated CESC patients tissue, Healthy females tissue MYC/Wnt/CCAT2 - rs6983267 SNP → Advanced stage III SCC higher grades (G2, G3). - rs6983267 G allele → ↑ MYC transcript levels in CSCC non-cancerous cervical tissues. -rs6983267 SNP → ↑ risk of CSCC in individuals with: Oral contraceptive use, Tobacco smoking, Postmenopausal age [ 4 ] CC Upregulated Serum samples from CESC patients, CIN patients, healthy controls Wnt/MYC/lncRNA CCAT2 lncRNAs (CCAT2, LINC01133, and LINC00511) ↑ in CESC patients’ -high diagnostic potential with an AUC of 0.94 in ROC analysis. [ 6 ] lncRNA: long non-coding RNA, CC: Cervical Cancer, NC: Normal Cells, CIN: Cervical Intraepithelial neoplasia, EMT: Epithelial Mesenchymal Transition, ceRNA: competing endogenous RNA, siRNA: Small Interfering RNA, CESC: Cervical Squamous Carcinoma, ROC: Receiver Operating Characteristics, AUC: Area Under Curve, CCAT2: Colon Cancer Associated Transcript 2, miR-493-5p: MicroRNA 493- 5 prime strand, CREB1: cAMP response element-binding protein 1, CCK8: Cell Counting Kit-8, BD Biosciences: Becton, Dickinson and Company Biosciences, miR-17-5p: MicroRNA 17 − 5 prime strand, miR-20a: MicroRNA 20a, TCF4:TCF7L2: T-cell factor 7-like 2, PI3K: Phosphoinositide 3-kinase, Akt: Protein kinase B, Crk: CT10 regulator of kinase, WNT: Wingless-related integration site, OS: overall survival, PFS: progression-free survival, CSCC: cervical squamous cell cancer, MYC: myelocytomatosis oncogene, SNP: Single Nucleotide Polymorphism, SCC: Squamous Cell Carcinoma LncRNA CCAT2 role in cervical cancer progression -↑ Serum CCAT2 in CC vs. CIN healthy controls. -↑ CCAT2 expression = advanced tumor stages lymph node metastasis. - Prognostic factor - ↑ CCAT2 in CC vs. NC - Knockdown CCAT2 → ↓ proliferation, migration, invasion - CCAT2 acts as a ceRNA → ↑ CREB1 by sponging miR-493-5p HeLa, CaSki, SiHa, CCK8 (Dojindo), BD Biosciences 1. CCAT2/MYC/miR-17-5p/miR-20a/TCF7L2/WNT 2. CCAT2/PI3K/Akt/Crk CCAT2 is↑ expressed in HeLa and other CC cell lines - knockdown→↓ cell proliferation, G1 phase arrest,↑ Apoptosis -CCAT2 is ↑ in CESC tissues -↑ expression →advanced FIGO stages, lymph node metastasis, and deeper cervical invasion -Poor prognostic factor for OS and PFS in CSCC patients. - rs6983267 SNP → Advanced stage III SCC higher grades (G2, G3). - rs6983267 G allele → ↑ MYC transcript levels in CSCC non-cancerous cervical tissues. -rs6983267 SNP → ↑ risk of CSCC in individuals with: Oral contraceptive use, Tobacco smoking, Postmenopausal age lncRNAs (CCAT2, LINC01133, and LINC00511) ↑ in CESC patients’ -high diagnostic potential with an AUC of 0.94 in ROC analysis. lncRNA: long non-coding RNA, CC: Cervical Cancer, NC: Normal Cells, CIN: Cervical Intraepithelial neoplasia, EMT: Epithelial Mesenchymal Transition, ceRNA: competing endogenous RNA, siRNA: Small Interfering RNA, CESC: Cervical Squamous Carcinoma, ROC: Receiver Operating Characteristics, AUC: Area Under Curve, CCAT2: Colon Cancer Associated Transcript 2, miR-493-5p: MicroRNA 493- 5 prime strand, CREB1: cAMP response element-binding protein 1, CCK8: Cell Counting Kit-8, BD Biosciences: Becton, Dickinson and Company Biosciences, miR-17-5p: MicroRNA 17 − 5 prime strand, miR-20a: MicroRNA 20a, TCF4:TCF7L2: T-cell factor 7-like 2, PI3K: Phosphoinositide 3-kinase, Akt: Protein kinase B, Crk: CT10 regulator of kinase, WNT: Wingless-related integration site, OS: overall survival, PFS: progression-free survival, CSCC: cervical squamous cell cancer, MYC: myelocytomatosis oncogene, SNP: Single Nucleotide Polymorphism, SCC: Squamous Cell Carcinoma OC represents one of the most aggressive and fatal gynecologic malignancies worldwide, with approximately 230,000 new cases and 140,000 deaths reported annually [ 69 – 72 ]. The poor prognosis of OC is largely attributed to its asymptomatic nature at early stages and the frequent diagnosis at advanced disease states. Growing evidence indicates that lncRNAs, transcripts longer than 200 nucleotides, play crucial regulatory roles in gene expression, tumor initiation, and progression across multiple cancers, including OC [ 69 , 70 , 73 ]. Extensive preclinical studies have demonstrated that CCAT2 is significantly upregulated in EOC cell lines, such as A2780 and SKOV3 , as well as in tumor tissues compared with normal ovarian cells and tissues [ 28 , 70 – 73 ]. Furthermore, functional experiments consistently show that silencing CCAT2 inhibits cell proliferation, migration, and invasion, while promoting apoptosis and inducing cell cycle arrest [ 28 , 70 , 73 ]. For instance, in a pivotal study, Huang et al. (2016) found that CCAT2 promotes OC cell proliferation by modulating MYC -regulated microRNAs, particularly miR-20a and miR-17-5p [ 70 ]. In addition, CCAT2 knockdown suppressed EMT, characterized by an increase in E-cadherin and a decrease in N-cadherin, Twist-related protein 1, and SNAI1 expression in A2780 and SKOV3 cells. Above all, the downregulation of MMP-7 and c-MYC following CCAT2 silencing could be reversed by lithium chloride (LiCl), an activator of the Wnt/β-catenin signaling pathway [ 72 , 73 ], confirming the pathway’s involvement in CCAT2-mediated oncogenic activity. Hua et al. (2018) further revealed that CCAT2 acts as a ceRNA by sequestering miR-424 [ 28 ]. Additionally, inhibition of miR-424 restored the proliferative and invasive capabilities of cells with silenced CCAT2, indicating that CCAT2 promotes tumorigenesis through the CCAT2/miR-424 regulatory axis. In addition, CCAT2 knockdown led to reduced cell proliferation, increased apoptosis, and G0/G1 phase arrest [ 28 ]. Besides, parallel findings showed that SNHG14 , another oncogenic lncRNA, is co-upregulated with CCAT2 in OC tissues and is modulated by miR-203 and miR-124 . Both CCAT2 and SNHG14 exhibited positive correlations with EMT-related genes, including WNT4 , TGFB2 , MET , SNAIL1 , and MAPK1 , suggesting a synergistic contribution to OC progression [ 71 ]. Above all, recent findings have linked vitamin D signaling to CCAT2 regulation [ 69 ]. Calcitriol, the active form of vitamin D3, interacts with the vitamin D receptor (VDR) to form a complex with the retinoid X receptor (RXR), which binds to vitamin D response elements (VDREs) on DNA, thereby modulating gene transcription. VDR is notably overexpressed in ovarian tumor tissues [ 69 ]. Experimental studies indicate that calcitriol inhibits OC cell growth, proliferation, and invasion by downregulating CCAT2. Reduced CCAT2 expression diminishes TCF7L2 (also known as TCF4) binding to the MYC promoter, resulting in lower c-MYC protein levels and decreased oncogenic potential [ 69 ]. Clinical observations corroborate these preclinical findings. Hua et al. (2018) reported markedly elevated CCAT2expression in EOC tissues compared with adjacent noncancerous tissues, with high levels correlating with advanced FIGO stage and lymph node metastasis [ 49 ]. Similarly, Huang et al. demonstrated that patients with elevated CCAT2expression experienced significantly shorter PFS and overall survival (OS), highlighting its prognostic significance [ 87 ]. Collectively, these findings establish CCAT2 as a multifaceted oncogenic driver in OC, promoting tumor progression through MYC -dependent signaling, ceRNA activity, and Wnt/β-catenin pathway activation. Moreover, emerging evidence that calcitriol can suppress CCAT2 expression offers new insights into potential therapeutic interventions targeting this lncRNA (Fig.  2 ). A summary of key findings is presented in Table  3 . Table 3 LncRNA CCAT2 role in ovarian cancer progression Cancer Expression Model Target/pathway Main findings Refs. OC downregulated OC cell lines, Normal mice, Intraperitoneal, orthotopic, and metastatic xenograft models of OC CCAT2/c-Myc - Calcitriol ↓ CCAT2 expression in OC cell lines - Calcitriol↓cell proliferation, migration, and invasion - Calcitriol disrupted interaction between CCAT2,TCF4 at MYC promotor→ ↓ c-Myc expression [ 7 ] OC Upregulated OC tissue, Normal ovarian tissue, SKOV3 cell line, IGROV1 cell line ,A2780 cell line, OVCAR3 cell line, HOSE 6.3 cell line CCAT2/MYC/miRNA-17-5p/miRNA-20a - CCAT2 ↑ in OC tissues/cell lines vs. normal tissues/cells - ↑CCAT2 = poor prognosis in OC patients (↓ OS and DFS) - CCAT2 knockdown →↓ cell proliferation, migration, invasion in OC cells [ 8 ] OC Upregulated cell lines (SKOV3, A2780) Wnt/β-catenin - Knockdown of CCAT2 in EOC cells→ ↓ proliferation and invasion - Knockdown of CCAT2 →↓ the expression of MMP-7 and c-MYC [ 11 ] OC Upregulated EOC patient tissues, SKOV3 cell line, OMC685 cell line, A2780 cell line, HO8910 cell line CCAT2/miR-424 -↑ expression of CCAT2 in EOC tissues and cell lines - Knockdown of CCAT2→↓ EOC cell proliferation, ↑apoptosis, induces cell cycle arrest - CCAT2 acts as a sponge for miR-424 (↓ in EOC) - miR-424 inhibitor → reverses effects of CCAT2 knockdown [ 12 ] OC Upregulated OC tissue CCAT1/SNHG14/miR-203/miR-124 - ↑ expression of CCAT1 and SNHG14 in OC - Positive correlation found between CCAT1 and SNHG14 levels and mRNA of 5 protein-coding genes (MAPK1, c-MET, TGFB2, SNAIL1, WNT4) linked to EMT. [ 9 ] OC Upregulated SKOV3, A2780, HO8910, HUM-CELL-0088 CCAT2/Wnt/β-catenin/EMT - CCAT2 promotes EMT in EOC by ↑ Slug and Twist1. [ 10 ] OC: Ovarian Cancer, CCAT2: Colon Cancer Associated Transcript 2, CCAT1: Colon Cancer Associated Transcript 1, SNHG14: Small Nuclear Host Gene 14, MARK 1: Microtubule Affinity Regulating Kinase 1, OS: Overall Survival, DFS: Disease-Free Survival, lncRNA: long non-coding RNA, EOC: Epithelial Ovarian Carcinoma, EMT: Epithelial mesenchymal Transition, TCF4: Transcription Factor 4, MMP7: Matrix Metalloproteinase 7, MYC: myelocytomatosis oncogene, miR 424: MicroRNA 424, c-MYC: cellular myelocytomatosis oncogene, mRNA: MicroRNA, c-MET: Mesenchymal-Epithelial Transition Factor, TGFB2: Transforming Growth Factor Beta 2, SNAIL1: Snail Family Transcriptional Repressor 1, WISP4: WNT4 inducible signaling pathway protein 4, SNAI2: Snail Family Transcriptional Repressor 2, TWIST1: Twist Family BHLH Transcription Factor 1, miR-203: MicroRNA 203, HOSE: Human Ovarian Surface Epithelial cell line, WNT: Wingless-related integration site LncRNA CCAT2 role in ovarian cancer progression - Calcitriol ↓ CCAT2 expression in OC cell lines - Calcitriol↓cell proliferation, migration, and invasion - Calcitriol disrupted interaction between CCAT2,TCF4 at MYC promotor→ ↓ c-Myc expression OC tissue, Normal ovarian tissue, SKOV3 cell line, IGROV1 cell line ,A2780 cell line, OVCAR3 cell line, HOSE 6.3 cell line - CCAT2 ↑ in OC tissues/cell lines vs. normal tissues/cells - ↑CCAT2 = poor prognosis in OC patients (↓ OS and DFS) - CCAT2 knockdown →↓ cell proliferation, migration, invasion in OC cells - Knockdown of CCAT2 in EOC cells→ ↓ proliferation and invasion - Knockdown of CCAT2 →↓ the expression of MMP-7 and c-MYC -↑ expression of CCAT2 in EOC tissues and cell lines - Knockdown of CCAT2→↓ EOC cell proliferation, ↑apoptosis, induces cell cycle arrest - CCAT2 acts as a sponge for miR-424 (↓ in EOC) - miR-424 inhibitor → reverses effects of CCAT2 knockdown - ↑ expression of CCAT1 and SNHG14 in OC - Positive correlation found between CCAT1 and SNHG14 levels and mRNA of 5 protein-coding genes (MAPK1, c-MET, TGFB2, SNAIL1, WNT4) linked to EMT. OC: Ovarian Cancer, CCAT2: Colon Cancer Associated Transcript 2, CCAT1: Colon Cancer Associated Transcript 1, SNHG14: Small Nuclear Host Gene 14, MARK 1: Microtubule Affinity Regulating Kinase 1, OS: Overall Survival, DFS: Disease-Free Survival, lncRNA: long non-coding RNA, EOC: Epithelial Ovarian Carcinoma, EMT: Epithelial mesenchymal Transition, TCF4: Transcription Factor 4, MMP7: Matrix Metalloproteinase 7, MYC: myelocytomatosis oncogene, miR 424: MicroRNA 424, c-MYC: cellular myelocytomatosis oncogene, mRNA: MicroRNA, c-MET: Mesenchymal-Epithelial Transition Factor, TGFB2: Transforming Growth Factor Beta 2, SNAIL1: Snail Family Transcriptional Repressor 1, WISP4: WNT4 inducible signaling pathway protein 4, SNAI2: Snail Family Transcriptional Repressor 2, TWIST1: Twist Family BHLH Transcription Factor 1, miR-203: MicroRNA 203, HOSE: Human Ovarian Surface Epithelial cell line, WNT: Wingless-related integration site EC arising from the uterine lining, represents the most prevalent gynecologic malignancy in industrialized nations [ 74 ]. Although a substantial proportion of patients achieve favorable clinical outcomes, advanced or metastatic EC is associated with poor prognosis, highlighting an urgent need for reliable biomarkers capable of distinguishing aggressive from indolent disease, as well as novel therapeutic strategies [ 74 ]. Preclinical investigations have elucidated the oncogenic role of CCAT2 in EC. For instance, in a study by Xie et al., which analyzed 30 paired EC and adjacent non-cancerous tissues, quantitative real-time qRT-PCR revealed that CCAT2 is markedly overexpressed in EC cells. Additionally, functional assays demonstrated that silencing CCAT2 significantly reduced the viability and migratory capacity of HEC-1 and RL95-2 cell lines while promoting apoptosis [ 75 ]. Mechanistic studies indicate that CCAT2 functions as an endogenous microRNA sponge, particularly targeting miR-216b . Moreover, inhibition of miR-216b reversed the suppressive effects of CCAT2 knockdown on cell proliferation and metastasis, confirming its functional relevance [ 75 , 76 ]. Through miR-216b sequestration, CCAT2 upregulates the anti-apoptotic gene BCL-2 and activates critical oncogenic signaling pathways, including PTEN/PI3K/AKT and mTOR , thereby enhancing cell proliferation and facilitating tumor progression (Fig. 2 ) [ 77 – 81 ]. In addition to miR-216b , CCAT2 also interacts with miR-143 , a tumor-suppressor microRNA implicated in restraining oncogenes involved in cellular proliferation and therapeutic resistance. The role of miR-143 has been characterized across multiple cancers, including colon, breast, and cervical malignancies [ 82 ]. Notably, miR-143 targets FOSL2 , an oncogene that promotes angiogenesis and metastatic dissemination in lung and breast cancers [ 83 ], suggesting that CCAT2 may modulate multiple microRNA-mediated networks to sustain tumorigenic programs. Clinical studies corroborate the preclinical findings, reinforcing the relevance of CCAT2 in EC pathophysiology [ 80 ]. Seyed Hosseini et al. reported that siRNA-mediated knockdown of CCAT2 in EC cells significantly inhibited cellular growth and survival, further supporting its oncogenic role. Moreover, elevated CCAT2 expression has been correlated with metastasis and poor survival outcomes in gynecologic cancers [ 80 ]. Furthermore, genetic studies have also investigated the contribution of specific CCAT2 polymorphisms to reproductive and cancer-related outcomes [ 84 ]. Two SNPs, rs6983267 and rs3843549 , were examined in a cohort of 248 recurrent miscarriage cases and 392 healthy controls [ 84 ]. Interestingly, the rs6983267 G allele was associated with a reduced risk of recurrent miscarriage. Furthermore, individuals carrying both protective alleles ( rs3843549 AA and rs6983267 TG/GG ) exhibited a lower risk compared to those with one or no protective alleles [ 84 ]. This effect was particularly notable in women under 35 years of age with a history of two to three miscarriages, indicating a potential functional link between these genetic variants and reproductive outcomes [ 84 ]. However, the interpretation of these findings is limited by small sample sizes, population-specific cohorts, and potential confounding from population stratification [ 85 ]. Additionally, these associations may reflect linkage disequilibrium with neighboring loci such as MYC , rather than a direct regulatory effect of CCAT2 [ 86 ]. Replication studies in independent, ethnically diverse cohorts are therefore required, alongside meta-analyses and re-evaluation of GWAS datasets, to validate these associations. Crucially, direct functional studies are necessary to confirm how these variants influence CCAT2 expression and activity [ 87 , 88 ]. Collectively, the available evidence positions CCAT2 as a promising prognostic biomarker and a potential therapeutic target in endometrial cancer (Fig. 2 ; Table 4 ). Its functional roles in regulating apoptosis, proliferation, and metastasis, along with genetic associations, underscore the translational potential of CCAT2. A summary of studies examining CCAT2 in EC is provided in Table 5 Table 4 LncRNA CCAT2 role in endometrial cancer progression Cancer Expression Model Target/pathway Main findings Refs. EC Up regulated EC patients tissue, 30 pairs of EC and matched non-cancerous tissues miR-216b, PTEN/PI3K/AKT and mTOR. significant overexpression of CCAT2 in EC cells [ 75 ] EC Up regulated EC patients miR-216b, PTEN/PI3K/AKT and mTOR. overexpression of CCAT2 in EC cells [ 133 ] EC Up regulated EC patients inhibiting CCAT2 expression using siRNA Correlates with tumor invasion, migration and cell proliferation [ 80 ] EC Up regulated 248 patients with a history of recurrent miscarriage and 392 controls using PCR the rs6983267 G allele in lncRNA CCAT2 was linked to reduce susceptibility to recurrent miscarriage [ 84 ] EC Up regulated EC patients PTEN/PI3K/AKT and mTOR signaling pathways, miR-143, miR-216b, [ 134 ] EC: endometrial cancer, CCAT2: colon cancer associated transcript 2, PCR: Polymerase Chain Reaction, ncRNA: Long Non-Coding RNA, miR : microRNA, PTEN: Phosphatase and tensin homolog deleted on chromosome 10, PI3K: Phosphatidylinositol 3-kinase, AKT: protein kinase B, mTOR: mammalian target of rapamycin, siRNA: Small interfering RNA Table 5 LncRNA CCAT2 as a diagnostic and prognostic biomarker for female-related cancers Diseases Targeted lncRNA and marker Expression Number of cases Refs. BC MEG3,NBAT1,NKILA, GAS5, EPB41L4A-AS2, Z38, andBC040587, H19, SPRY4-IT1, XIST, UCA1, AC026904.1 , CCAT1, CCAT2, ITGB2-AS, andAK058003 downregulated: MEG3, NBAT1, NKILA, GAS5, EPB41L4A-AS2, Z38, andBC040587, upregulated: H19, SPRY4-IT1, XIST, UCA1, AC026904.1 , CCAT1, CCAT2, ITGB2-AS, andAK058003 30 patients 30 healthy normal [ 135 ] CC CCAT2,CA125,SCC upregulated 180, 154 in 5 year survival [ 64 ] CC CCAT2 upregulated Thirty pairs of CC tissues and adjacent normal tissues [ 30 ] BC CCAT2 upregulated 67 female patients [ 136 ] BC CCAT2 upregulated 120 [ 62 ] BC CCAT2 upregulated 60 [ 94 ] BC CCAT2 upregulated - [ 63 ] EOC Ccat2 upregulated Two human EOC cell lines (SKOV3, A2780) [ 105 ] BC CCAT2 downregulated - [ 98 ] BC CCAT2 upregulated 100 female patients [ 93 ] EOC miR-424 upregulated 31 cases of EOC patients at Huai’an First People’s Hospital [ 28 ] CESC CCAT2 upregulated 123 specimens [ 65 ] OC CCAT2 upregulated 109 °C and 45 normal ovarian tissue samples [ 118 ] CESC CCAT2, LINC01133, LINC00511 upregulated 115 cases of CESC, 79 cases of CIN and 101 healthy controls [ 137 ] CESC CCAT2 rs6983267 SNP, MYC upregulated 481patients [ 138 ] BC: breast cancer; CC: cervical carcinoma; EOC: epithelial ovarian carcinoma; OC: Ovarian cancer; CESC: Cervical Squamous Carcinoma; MEG3: Maternally Expressed 3; NBAT1: Neuroblastoma Associated Transcript 1; NKILA: NF-KappaB Interacting lncRNA; GAS5: Growth arrest-specific 5; SPRY4-IT1: SPRY4 Intronic Transcript 1; XIST: X-inactive specific transcript; UCA1: Urothelial cancer associated 1; ITGB2-AS: Integrin Subunit Beta 2; CIN: Cervical intraepithelial neoplasia LncRNA CCAT2 role in endometrial cancer progression EC: endometrial cancer, CCAT2: colon cancer associated transcript 2, PCR: Polymerase Chain Reaction, ncRNA: Long Non-Coding RNA, miR : microRNA, PTEN: Phosphatase and tensin homolog deleted on chromosome 10, PI3K: Phosphatidylinositol 3-kinase, AKT: protein kinase B, mTOR: mammalian target of rapamycin, siRNA: Small interfering RNA LncRNA CCAT2 as a diagnostic and prognostic biomarker for female-related cancers downregulated: MEG3, NBAT1, NKILA, GAS5, EPB41L4A-AS2, Z38, andBC040587, upregulated: H19, SPRY4-IT1, XIST, UCA1, AC026904.1 , CCAT1, CCAT2, ITGB2-AS, andAK058003 30 patients 30 healthy normal BC: breast cancer; CC: cervical carcinoma; EOC: epithelial ovarian carcinoma; OC: Ovarian cancer; CESC: Cervical Squamous Carcinoma; MEG3: Maternally Expressed 3; NBAT1: Neuroblastoma Associated Transcript 1; NKILA: NF-KappaB Interacting lncRNA; GAS5: Growth arrest-specific 5; SPRY4-IT1: SPRY4 Intronic Transcript 1; XIST: X-inactive specific transcript; UCA1: Urothelial cancer associated 1; ITGB2-AS: Integrin Subunit Beta 2; CIN: Cervical intraepithelial neoplasia

Chemotherapy-induced drug resistance remains a critical barrier to achieving optimal therapeutic outcomes. This resistance arises from multiple mechanisms, including genetic mutations, epigenetic alterations, and influences from the tumor microenvironment [ 96 ]. Accumulating evidence indicates that the long non-coding RNA CCAT2 plays a pivotal role in mediating drug resistance in female-related cancers [ 93 ]. Zhou et al. demonstrated that CCAT2 is overexpressed in both malignant and drug-resistant cells, which is associated with elevated IC50 values, enhanced cellular proliferation, S-phase accumulation, and reduced apoptosis. These findings suggest that high CCAT2 expression compromises the efficacy of neoadjuvant therapies. Importantly, silencing CCAT2 or treatment with CCI-77 9 markedly inhibited tumor growth in transplanted models, whereas CCAT2 overexpression promoted tumor progression [ 93 ]. Further studies have shown that CCAT2 knockdown suppresses cell proliferation, invasion, and migration, while enhancing apoptosis and sensitizing cells to 5-FU through upregulation of miR-145 , which is typically downregulated in drug-resistant cells [ 97 ]. Mechanistically, CCAT2 suppresses p53 -mediated activation of miR-145 , thereby enhancing drug resistance in breast cancer (BC), highlighting CCAT2 as a potential therapeutic target to improve chemosensitivity [ 97 ]. Xie et al. demonstrated that cytoplasmic CCAT2 limits cancer stemness in BC, as evidenced by flow cytometry and stem cell marker analyses, which showed a reduction in the BC stem cell population following CCAT2 overexpression. In vivo experiments further confirmed that cytoplasmic CCAT2 suppresses tumor growth via the miR-221-p27 signaling pathway [ 98 ]. Moreover, CCAT2 has been shown to regulate key proteins in the TGF-β signaling pathway, including Smad2 and α-SMA . Downregulation of CCAT2 in BC cells decreased the expression of these proteins, induced cell cycle arrest by shifting cells from the S and G2/M phases to the G0/G1 phase, promoting apoptosis, indicating that CCAT2 influences tumor growth and metastatic potential [ 94 ]. Mechanistic investigations have demonstrated that CCAT2 functions as a competing ceRNA, sequestering miR-493-5p and thereby upregulating CREB1 expression. Overexpression of CREB1 promoted migration and aggressiveness in cervical cancer (CC) cells, while CCAT2 knockdown inhibited malignant behaviors via the miR-493-5p/CREB1 axis, suggesting CCAT2 as a promising therapeutic target in CC [ 30 ]. In BC, tamoxifen (TAM) resistance remains a clinical challenge, particularly in estrogen receptor-positive (ER+) patients, many of whom eventually relapse despite initial responsiveness [ 59 ]. Moradi et al. demonstrated that CCAT2, along with AKT3 and mTOR , is markedly upregulated in tamoxifen-resistant breast cancer cell lines, whereas hsa-miR-145-5p was significantly downregulated. The hsa-miR-145-5p/AKT3/mTOR signaling axis governs apoptosis, migration, and proliferation, and CCAT2 appears to modulate this pathway, indicating that targeting CCAT2 may improve tamoxifen efficacy [ 6 ]. Consistent with these findings, Wu et al. confirmed via flow cytometry that CCAT2 silencing increases apoptosis in HeLa cells, supporting its role in drug resistance [ 99 ]. Collectively, these studies underscore CCAT2 as a critical regulator of chemotherapy resistance and tumor progression in female-related cancers. Targeting CCAT2 may provide a novel therapeutic approach to inhibit cancer cell proliferation, promote apoptosis, and overcome drug resistance, thereby improving treatment outcomes (Fig. 3 ). Fig. 3 lncRNA CCAT2 in female-related cancers. This lncRNA can contribute to female-related cancers by influencing processes such as lymph node metastasis, interfering with apoptosis, and enhancing the invasion of cancer cells. Additionally, it can affect drug resistance in cancer cells and may serve as a biomarker for the early detection of female-related cancers. miR; MicroRNA, mTOR; Mammalian Target of Rapamycin, AKT; Protein Kinase B, TGF-β; Transforming Growth Factor Beta, CREB; cAMP response element-binding protein. lncRNA CCAT2 in female-related cancers. This lncRNA can contribute to female-related cancers by influencing processes such as lymph node metastasis, interfering with apoptosis, and enhancing the invasion of cancer cells. Additionally, it can affect drug resistance in cancer cells and may serve as a biomarker for the early detection of female-related cancers. miR; MicroRNA, mTOR; Mammalian Target of Rapamycin, AKT; Protein Kinase B, TGF-β; Transforming Growth Factor Beta, CREB; cAMP response element-binding protein.

The role of lncRNAs in cancer is profound, as they establish complex regulatory networks through RNA–protein, RNA–RNA, and RNA–DNA interactions. Moreover, these interactions influence both the malignant behavior of tumor cells and the dynamics of the tumor microenvironment. Tumor-suppressive lncRNAs include FER1L4 , GAS5 , MEG3 , and LINC00672 , whereas oncogenic lncRNAs comprise CCAT2 , MALAT1 , BANCR , H19 , NEAT1 , Linc-RoR , TUG1 , TDRG1 , and PCGEM1 . Furthermore, lncRNAs are emerging as reliable biomarkers for early cancer detection due to their stability, presence in tumor tissues and biological fluids, and resistance to degradation. Notably, H19 displays a distinct expression pattern in ECs, suggesting its potential as a therapeutic target for cancers that predominantly affect females. More importantly, our findings highlight the oncogenic role of lncRNA CCAT2, supporting its potential as a diagnostic and prognostic biomarker in female-related cancers. Elevated CCAT2 expression correlates with reduced disease-free survival and promotes cancer cell proliferation, invasion, and progression through the cell cycle. Furthermore, CCAT2 overexpression is associated with decreased miR-216b levels, a regulator of the PI3K/Akt pathway, underscoring its contribution as an oncogene in female-related malignancies. Additionally, given its pivotal role in cancer biology, CCAT2 represents a promising target for therapeutic intervention. Approaches aimed at silencing CCAT2 expression or disrupting its molecular interactions are under exploration. For instance, siRNAs and antisense oligonucleotides (ASOs) targeting CCAT2 have demonstrated potential in preclinical cancer models. Continued research into the molecular mechanisms governing CCAT2 activity will advance our understanding of its function and facilitate the development of innovative diagnostic and therapeutic strategies. Future therapeutic avenues may include CRISPR-Cas–based inhibition of CCAT2, which warrants further investigation. Additionally, miRNA-based therapies offer complementary potential. One approach involves suppressing oncogenic miRNAs using synthetic inhibitors, anti-miRNAs, or locked nucleic acids (LNAs), though further research is needed to evaluate their efficacy and safety. Conversely, miRNA replacement therapy aims to restore downregulated tumor-suppressor miRNAs to physiological levels. The validation of this strategy requires extensive preclinical studies and multiple clinical trials to confirm its therapeutic benefits and limitations.

Among lncRNAs involved in female-related cancers, CCAT2 exhibits both overlapping and distinctive oncogenic mechanisms compared with other well-characterized molecules such as MALAT1 and H19 [ 100 , 101 ]. Additionally, like many cancer-associated lncRNAs, CCAT2 contributes to tumor progression through transcriptional modulation, chromatin remodeling, and miRNA sponging, processes that represent general hallmarks of lncRNA function in oncogenesis [ 70 ]. Beyond these shared molecular strategies, lncRNAs regulate critical cellular behaviors, including proliferation, invasion, and metastasis, by influencing gene expression across multiple regulatory levels [ 102 ]. However, despite these mechanistic similarities, CCAT2 possesses unique molecular signatures and clinical implications that distinguish it as a non-redundant oncogenic regulator in gynecologic malignancies [ 102 ]. Above all, its ability to integrate transcriptional regulation with structural genomic functions sets it apart from other well-studied lncRNAs, emphasizing its multifaceted role in cancer biology. Although MALAT1 has been reported to suppress metastasis in breast cancer models, its knockout leading to increased metastatic potential in both mouse and human cells, CCAT2 acts conversely as a facilitator of tumor progression [ 103 , 104 ]. Furthermore, MALAT1 exerts its function through interaction with the transcription factor TEAD , thereby preventing TEAD–YAP association, a process essential for metastasis [ 103 , 104 ]. Moreover, the loss of MALAT1 alters gene expression and splicing patterns that favor tumor dissemination and metastasis [ 103 , 104 ]. In contrast, CCAT2 directly activates the Wnt/β-catenin signaling pathway and upregulates downstream oncogenic effectors such as c-MYC and MMP7 , providing a mechanistic link between molecular regulation and aggressive clinical behavior [ 105 ]. Additionally, CCAT2’s involvement in chromosomal instability and allelic imbalance at the 8q24 locus introduces a structural genomic role not observed in MALAT1 or H19 , highlighting its ability to integrate transcriptional control with chromosomal maintenance [ 102 ]. These molecular distinctions underscore that CCAT2 contributes to cancer progression through mechanisms extending beyond the general regulatory patterns typical of other oncogenic lncRNAs [ 102 ]. More importantly, from a clinical standpoint, CCAT2 demonstrates superior prognostic reliability and consistency compared with MALAT1 and H19 in gynecologic malignancies [ 70 ]. In OC cohorts, elevated CCAT2 expression is significantly associated with advanced FIGO stage, higher tumor grade, and distant metastasis, with explicit survival statistics confirming its prognostic value (OS P = 0.006; DFS P = 0.001) [ 70 ]. Moreover, data from a pancancer TCGA-based meta-analysis demonstrated uniform CCAT2 upregulation across various tumor types, with its elevated expression significantly associated with increased tumor size, advanced disease stage, and reduced overall survival [ 102 ]. These findings indicate that CCAT2 not only acts as a molecular driver of tumor aggressiveness but also serves as a reliable prognostic biomarker across multiple female-related cancers. By contrast, MALAT1 and H19 show less consistent and quantifiable prognostic associations [ 103 , 104 ]. Although MALAT1 is frequently overexpressed in gynecologic cancers and associated with tumor size, invasion, and survival in cervical cancer cohorts [ 103 , 104 ], most studies lack standardized hazard ratios or C-index values, limiting direct comparison. Similarly, H19 is linked to shorter progression-free survival and enhanced invasion in ovarian cancer models [ 106 ]; however, its context-dependent dual role, acting as either an oncogene or tumor suppressor across different female cancers, reduces its reliability as a universal prognostic biomarker [ 107 ]. Taken together, the evidence demonstrates that while CCAT2 retains certain common oncogenic attributes of lncRNAs, its specific molecular mechanisms and consistent clinical relevance distinguish it from MALAT1 and H19 [ 70 ]. Above all, its direct activation of Wnt/β-catenin signaling, involvement in chromosomal instability, and consistent prognostic association across gynecologic cancers emphasize its unique mechanistic and clinical relevance, establishing CCAT2 as a critical target for future research and therapeutic development. Recent studies have increasingly highlighted the critical role of the TME in cancer progression, emphasizing that tumor growth and metastasis do not depend exclusively on cancer cell-intrinsic factors but are profoundly modulated by the surrounding stromal and immune components [ 108 ]. Within this context, the lncRNA CCAT2 has emerged as a pivotal regulator of intercellular communication, particularly through its packaging in exosomes and subsequent transfer to recipient cells ([ 108 , 109 ]. Exosomal CCAT2 has been shown to effectively modulate angiogenesis, a hallmark of cancer progression, by promoting the proliferation, migration, and tube formation of endothelial cells ([ 108 , 109 ]. For example, studies on nasopharyngeal carcinoma (NPC) have demonstrated that human umbilical vein endothelial cells (HUVECs) cocultured with supernatant or exosomes derived from CNE2 tumor cells exhibit increased CCAT2 expression, enhanced proliferation, higher migration rates, and greater formation of capillary-like structures compared to controls [ 108 , 109 ]. Knockdown of CCAT2 in either tumor cells or their exosomes led to a marked reduction in these angiogenic activities, confirming the functional role of exosomal CCAT2 in endothelial cell activation [ 108 ]. These findings suggest that CCAT2 acts as a critical paracrine effector, bridging tumor cell-intrinsic oncogenic signals with stromal remodeling ([ 108 , 109 ]. Beyond its angiogenic function, CCAT2 is likely to influence immune regulation within the TME, particularly through macrophage polarization and immune checkpoint modulation. Tumor-derived exosomes are well-established mediators of immune crosstalk, capable of reprogramming macrophages toward a pro-tumorigenic M2 phenotype, which supports tumor growth, angiogenesis, and immunosuppression [ 110 , 111 ]. By analogy with other exosomal lncRNAs, CCAT2 may facilitate this polarization, either directly through uptake by macrophages or indirectly via modulation of endothelial cells and fibroblasts, creating a permissive microenvironment for tumor expansion [ 110 , 111 ]. Additionally, exosomal CCAT2 could influence the expression of immune checkpoints such as PD-L1, thereby contributing to immune evasion and resistance to immunotherapy. This perspective aligns with the growing recognition that exosomal cargoes are not merely byproducts of tumor metabolism but functionally active mediators that orchestrate both stromal and immune components in a coordinated manner [ 110 , 111 ]. Integrating these mechanistic insights, CCAT2-mediated exosomal signaling represents a convergence point linking molecular pathways with clinically relevant tumor behaviors [ 108 ]. By promoting angiogenesis, potentially modulating macrophage polarization, and affecting immune checkpoint regulation, CCAT2 not only drives local tumor progression but also prepares distant niches for metastatic colonization ([ 108 , 109 ]. Consequently, targeting exosomal CCAT2 may offer a dual therapeutic advantage: inhibiting angiogenesis and remodeling the TME toward an anti-tumorigenic state [ 110 , 111 ]. Future studies should aim to delineate the precise molecular interactions between CCAT2-containing exosomes and specific stromal or immune cell populations, thereby providing a comprehensive understanding of how this lncRNA integrates signaling networks within the TME [ 110 , 111 ]. Such an approach would substantially enrich current discussions of CCAT2 in cancer biology and highlight its potential as both a biomarker and therapeutic target [ 108 ]. Although CCAT2 demonstrates consistent overexpression in breast, ovarian, cervical, and endometrial cancers, its diagnostic performance, including sensitivity, specificity, and area under the curve (AUC), has not yet been clearly established for these malignancies [ 112 ]. In OC, pooled analyses of circulating lncRNAs, which included CCAT2 among other candidates, demonstrated a pooled sensitivity of 81%, specificity of 78%, and an AUC of approximately 0.86 across 1,732 patients and 3,958 controls, indicating moderate diagnostic utility; however, these findings do not allow conclusions regarding the diagnostic performance of CCAT2 alone [ 112 ]. Similarly, in CC, serum CCAT2 levels were significantly elevated in primary cervical cancer patients compared to individuals with CIN and healthy controls, and they correlated with FIGO stage and squamous cell carcinoma antigen (SCC-Ag) levels. Notably, CCAT2 expression decreased following surgical resection, and the combination of CCAT2 with CA125 and SCC improved overall diagnostic efficiency, though no standalone sensitivity, specificity, or AUC values were reported [ 64 ]. Similarly, research on breast and endometrial cancers has demonstrated differential expression and functional significance of CCAT2, although ROC-based diagnostic metrics were not reported [ 113 , 114 ]. Furthermore, when compared with established biomarkers, such as CA-125 in OC and SCC-Ag in CC, CCAT2 emerges as a promising but still investigational alternative. CA-125 , although widely employed, has limited specificity because its levels can also rise in benign gynecological conditions, including endometriosis and pelvic inflammatory disease, thereby reducing its utility for early detection [ 115 , 116 ]. Similarly, SCC-Ag demonstrates moderate sensitivity and is prone to false-positive results in inflammatory conditions [ 115 , 117 ]. In contrast, CCAT2 is consistently overexpressed in both tumor tissues and circulating serum of patients with ovarian and cervical cancers, and it exhibits strong correlations with FIGO stage, lymph node metastasis, and poor survival outcomes [ 114 , 118 ]. In particular, a study by Cao et al. demonstrated that CCAT2 achieved 73.3% sensitivity and 87.0% specificity in cervical cancer patients, outperforming CA-125 , which had 81.7% sensitivity but only 46% specificity in the same cohort [ 64 ]. Nevertheless, head-to-head prospective validation studies and comprehensive ROC analyses remain lacking for CCAT2, and no evidence currently confirms its superiority over conventional markers in routine clinical practice. Consequently, future investigations should focus on determining whether combining CCAT2 with CA-125 or SCC-Ag can enhance diagnostic accuracy, particularly in early-stage disease, and should also evaluate its independent prognostic value in large, well-characterized cohorts. Regarding therapeutic applications, CCAT2 knockdown strategies employing siRNA or antisense oligonucleotides face substantial obstacles, including the need for efficient and tumor-specific delivery, rapid degradation in systemic circulation, immune activation, and off-target effects that could induce unintended gene silencing or toxicity [ 119 , 120 ]. Addressing these challenges will necessitate the development of optimized delivery systems, such as lipid nanoparticles or exosome-based carriers, along with rigorous validation of safety and efficacy in early-phase clinical trials before CCAT2 can be reliably considered as a therapeutic target in female-related cancers [ 119 , 120 ]. Therefore, although CCAT2 holds promise as both a biomarker and a therapeutic target, dedicated clinical trials with well-defined patient cohorts are essential to establish its utility, and its translation into routine clinical practice remains limited [ 113 ]. Although this review primarily focuses on CCAT2 biology within female-related primary tumors, whether CCAT2 also contributes to metastatic adaptation within the bone niche remains an open question. At present, direct evidence connecting CCAT2 to osteotropism, osteoclast–osteoblast coupling, bone turnover markers, or response to bone-modifying agents is limited. Nevertheless, studies in other tumor contexts demonstrate that tumor-derived exosomal lncRNAs can directly modulate osteoclast differentiation and osteolytic bone metastasis through defined signaling axes in osteoclasts, supporting the broader concept that lncRNA cargo can shape bone niche remodeling [ 121 – 123 ]. In diagnostically challenging scenarios such as skeletal metastases of unknown primary, systematic profiling of CCAT2 (e.g., in circulating and/or extracellular vesicle fractions) could be evaluated for incremental diagnostic or prognostic value, but dedicated studies are currently lacking. Accordingly, future work should map CCAT2 expression across tumor and stromal/immune compartments in bone lesions and prospectively test associations with bone turnover markers and clinical outcomes; until such data are available, this topic should be considered hypothesis-generating rather than established. More broadly, renal cell carcinoma frequently develops osteolytic bone metastases, and tumor–bone crosstalk in this setting has been linked to mTOR signaling and metabolic remodeling. Preclinical data suggest that combined targeting of mTOR and bone-resorptive pathways (e.g., zoledronic acid or denosumab) may disrupt this vicious cycle [ 124 ], while transcriptome-wide, machine-learning–based pan-RCC analyses have identified prognostic mitochondrial gene signatures beyond histopathologic boundaries [ 125 ]. In this wider oncologic context, lncRNA-driven regulation of metabolic and co-stimulatory immune pathways, including CD40 signaling, may represent cross-tumor axes worth interrogating in bone metastatic niches, and CCAT2 could be included as a candidate lncRNA in such multi-omic and spatially resolved studies [ 126 ]. Despite the substantial evidence implicating CCAT2 in female-related cancers, several limitations warrant consideration. Most available studies are constrained by relatively small sample sizes and the absence of validation across independent, large-scale cohorts, thereby limiting the reproducibility and generalizability of findings [ 46 , 47 ]. Moreover, many investigations rely primarily on qRT-PCR analyses or single cell line knockdown experiments, which, although informative, fail to fully reflect the molecular heterogeneity and biological complexity of human tumors [ 46 , 47 ]. Technical inconsistencies in RNA extraction, quantification, and normalization further contribute to experimental bias and variability in reported outcomes [ 46 , 47 ]. Future studies should prioritize rigorous, multicenter validation of CCAT2 as a biomarker across ethnically diverse cohorts to enhance the robustness, reproducibility, and clinical generalizability of the findings [ 46 , 47 ]. The integration of multi-omics approaches, encompassing transcriptomics, epigenomics, and proteomics, will be crucial for elucidating the comprehensive regulatory networks governed by CCAT2 and their context-specific roles across diverse cancer types [ 46 , 47 ] Additionally, employing advanced preclinical models, such as patient-derived organoids and xenograft systems, will enable a more accurate recapitulation of the TME and facilitate the evaluation of CCAT2-targeted therapies in clinically relevant conditions [ 108 ]. These strategies will collectively accelerate the translation of CCAT2-based diagnostics and therapeutics from bench to bedside, offering novel opportunities for personalized cancer management [ 63 , 93 , 94 , 98 , 105 ]. Future studies should prioritize rigorous, multicenter validation of CCAT2 as a biomarker across ethnically diverse cohorts to enhance the robustness, reproducibility, and clinical generalizability of the findings [ 45 , 46 ]. The integration of multi-omics approaches, encompassing transcriptomics, epigenomics, and proteomics, will be crucial for elucidating the comprehensive regulatory networks governed by CCAT2 and their context-specific roles across diverse cancer types [ 45 , 46 ] Additionally, employing advanced preclinical models, such as patient-derived organoids and xenograft systems, will enable a more accurate recapitulation of the TME and facilitate the evaluation of CCAT2-targeted therapies in clinically relevant conditions [ 107 ]. These strategies will collectively accelerate the translation of CCAT2-based diagnostics and therapeutics from bench to bedside, offering novel opportunities for personalized cancer management [ 92 , 93 , 97 , 104 , 126 ].

LncRNA CCAT2 is located on chromosome 8q24, a genomic locus that is recurrently amplified in several human malignancies, including colorectal and gynecologic cancers [ 31 ]. This region encompasses the rs6983267 single-nucleotide polymorphism (SNP) and the oncogene MYC , indicating a potential regulatory relationship between the two [ 12 ]. Furthermore, CCAT2 is a single-exon transcript of approximately 340 nucleotides with no protein-coding capacity [ 32 ]. Structural analyses have revealed that CCAT2 adopts a defined secondary configuration consisting of stem regions and hairpin loops, which enhance molecular stability and enable selective interactions with RNA-binding proteins and components of the transcriptional and splicing machinery [ 13 ]. Moreover, high-throughput sequencing and RNA immunoprecipitation (RIP-seq) approaches have been instrumental in mapping these interactions and delineating the structural elements essential for CCAT2 function [ 14 , 15 ]. Functionally, CCAT2 acts as a transcriptional enhancer of TCF7L2 , a critical activator of MYC , thereby amplifying the Wnt/β-catenin signaling pathway, a major driver of tumor initiation and progression [ 16 – 18 ]. Above all, activation of this pathway results in elevated expression of MYC and Cyclin D1, promoting uncontrolled proliferation and tumor persistence. In addition, CCAT2 interacts with WISP1 , which facilitates epithelial-to-mesenchymal transition (EMT) and angiogenesis, both fundamental processes in metastasis [ 35 – 37 ]. Beyond its role in Wnt signaling, CCAT2 contributes to chromosomal instability (CIN) through the BOP1–AURKB signaling axis. This interaction disrupts the fidelity of mitotic spindle assembly and chromosome segregation, ultimately fostering aneuploidy and genomic instability, hallmarks of malignant transformation [ 19 , 20 ]. The expression pattern of CCAT2 is highly cell- and tissue-specific, with predominant nuclear localization [ 21 ]. Within the nucleus, CCAT2 modulates chromatin architecture and transcriptional regulation by recruiting or sequestering regulatory proteins. This nuclear presence allows CCAT2 to influence gene expression programs associated with tumor progression and cellular stress responses. Additionally, dysregulation of CCAT2 has been observed in diverse pathological conditions. For instance, in myocardial ischemia, CCAT2 protects cardiomyocytes from apoptosis by modulating BMI1 expression [ 22 ]. Above all, it is also upregulated in autism spectrum disorder [ 23 ] and linked to wound healing through the regulation of fibroblast proliferation and extracellular-matrix remodeling [ 24 ]. Furthermore, evidence suggests that CCAT2 may contribute to cellular senescence and inflammation, implicating it in age-related physiological decline [ 25 ]. More importantly, at the post-transcriptional level, CCAT2 functions as a competitive endogenous RNA (ceRNA), binding and sequestering tumor-suppressive microRNAs (miRNAs) to prevent them from inhibiting oncogenic targets [ 26 ]. Notably, CCAT2 can sponge miR-221/222 , miR-205 , and miR-424 through sequence complementarity, enhancing tumorigenicity and maintaining cancer-stem-cell properties [ 27 – 29 ]. Although ceRNA activity facilitates the deregulation of multiple signaling cascades involved in proliferation, invasion, and resistance to apoptosis. In cervical carcinoma (CC), CCAT2 was shown to regulate the miR-493-5p/CREB1 axis, which promotes cell proliferation and EMT; silencing CCAT2 suppressed these oncogenic effects both in vitro and in xenograft models [ 30 ]. Collectively, these findings demonstrate that CCAT2 exerts oncogenic effects through multiple mechanisms, including transcriptional activation of MYC , regulation of chromosomal stability, and miRNA-mediated post-transcriptional control. In summary, CCAT2 operates as a multifunctional molecular hub that integrates chromatin remodeling, transcriptional regulation, and post-transcriptional control [ 13 , 31 ]. Its localization at the 8q24 region positions it at the crossroads of MYC -driven oncogenic signaling, while its ability to modulate both nuclear and cytoplasmic processes underscores its versatility in cancer biology. Through the activation of Wnt/β-catenin and BOP1–AURKB pathways, CCAT2 promotes genomic instability and malignant progression. Simultaneously, its ceRNA function enhances tumor cell survival and metastatic potential. Together, these structural and functional characteristics identify CCAT2 as a key regulator of tumorigenesis and a promising target for diagnostic and therapeutic exploration in female-related cancers.

Female-related cancers, including breast, ovarian, cervical, and endometrial malignancies, remain among the most significant causes of disease and death in women worldwide [ 1 , 2 ]. As indicated by studies provided by Torre et al. and Sung et al., the global burden continues to rise despite remarkable advances in screening and therapy, with the highest mortality rates still observed in developing regions [ 1 , 2 ]. Although current diagnostic and therapeutic strategies have improved survival in some cases, many women continue to face late-stage diagnoses and therapy resistance [ 3 ]. Therefore, identifying novel molecular targets and biomarkers is essential for earlier detection and more effective treatment [ 3 ]. Additionally, the pathogenesis of gynecologic cancers is complex and multifactorial, shaped by genetic, hormonal, reproductive, and environmental influences, while mutations in tumor-suppressor genes such as BRCA1 , BRCA2 , TP53 , and PTEN further increase susceptibility [ 4 ]. Moreover, prolonged exposure to estrogen or progesterone, often due to hormonal therapies or reproductive factors, has been closely associated with cancer initiation [ 5 ]. Additionally, viral agents such as human papillomavirus (HPV) and Epstein–Barr virus (EBV) can induce oncogenic transformation [ 6 ]. Moreover, lifestyle factors, including obesity, smoking, diet, and physical inactivity, also modulate risk and influence tumor progression [ 7 ]. Collectively, these determinants demonstrate the intricate biological and environmental framework that governs female-related cancers. In recent years, attention has shifted toward understanding the regulatory potential of non-coding genomic regions, which account for the majority of the human genome. lncRNAs, transcripts longer than 200 nucleotides that lack protein-coding capacity, have emerged as crucial regulators of gene expression [ 8 , 9 ]. Through interactions with DNA, RNA, and proteins, lncRNAs orchestrate chromatin remodeling, transcriptional activation, splicing, and post-transcriptional modifications [ 10 ]. Consequently, dysregulated lncRNA expression contributes to several hallmarks of cancer, including uncontrolled proliferation, evasion of apoptosis, metastasis, and angiogenesis [ 11 ]. However, despite its growing recognition, integrated analyses of CCAT2 across female-related cancers remain scarce. Most available reports focus on individual cancer types or single molecular pathways, leaving their broader clinical and mechanistic implications poorly understood. Hence, understanding CCAT2’s multifaceted role could provide a more unified framework for elucidating lncRNA-driven oncogenesis. The present review, therefore, aims to consolidate current knowledge on the biological and clinical significance of CCAT2 in female-related malignancies. By integrating data from molecular, preclinical, and clinical studies, it explores how CCAT2 regulates tumor growth, metastasis, and therapy resistance through key oncogenic pathways, including Wnt/β-catenin , PI3K/AKT/mTOR , and TGF-β .

A comprehensive literature search was conducted in PubMed/MEDLINE, Scopus, and Web of Science to identify relevant English-language studies published between 1 January 2010 and 31 July 2025. The search strategy combined Medical Subject Headings (MeSH) and free-text terms, including (long non-coding RNA’ OR ‘lncRNA’) AND (‘CCAT2’ OR ‘colon cancer-associated transcript 2’) AND (‘breast’ OR ‘ovarian’ OR ‘cervical’ OR ‘endometrial’ OR ‘gynecologic’ OR ‘female’). Titles and abstracts were screened to select original research articles and reviews reporting on CCAT2 biology, expression, mechanistic roles, diagnostic or prognostic performance, or therapeutic relevance in female-related cancers. Studies were excluded if they involved non-human species without translational relevance, non-gynecologic malignancies without broadly applicable mechanistic insights, or lacked primary experimental or clinical data. Search queries were designed to capture CCAT2-related evidence in female-related cancers; bone metastasis-, bone remodeling-, and bone-targeted therapy-specific terms (e.g., osteolysis, RANKL, bisphosphonates/denosumab) were not systematically queried, and any comments on skeletal dissemination are presented as hypothesis-generating future directions rather than a systematically reviewed evidence base. Original research articles investigating the role of lncRNA CCAT2 in female-related cancers, including breast, ovarian, cervical, and endometrial cancers. Studies examining the association of CCAT2 expression with cancer progression, invasion, metastasis, prognosis, or diagnostic potential. Both preclinical studies (in vitro and in vivo) and clinical studies (including cohort, case-control, and patient-derived tissue analyses). Articles published in English. Studies published up to 31 July 2025 (search cutoff date). Original research articles investigating the role of lncRNA CCAT2 in female-related cancers, including breast, ovarian, cervical, and endometrial cancers. Studies examining the association of CCAT2 expression with cancer progression, invasion, metastasis, prognosis, or diagnostic potential. Both preclinical studies (in vitro and in vivo) and clinical studies (including cohort, case-control, and patient-derived tissue analyses). Articles published in English. Studies published up to 31 July 2025 (search cutoff date). Articles focusing on lncRNAs other than CCAT2. Studies exclusively conducted in female-related cancers (e.g., lung, colorectal, prostate). Reviews, editorials, commentaries, conference abstracts, or case reports. Articles lacking original experimental or clinical data. Non-English publications. Articles focusing on lncRNAs other than CCAT2. Studies exclusively conducted in female-related cancers (e.g., lung, colorectal, prostate). Reviews, editorials, commentaries, conference abstracts, or case reports. Articles lacking original experimental or clinical data. Non-English publications.