Cancer Susceptibility Candidate 15 Expression Research Articles

Downregulation of CASC15 attenuates the symptoms of polycystic ovary syndrome by affecting granulosa cell proliferation and regulating ovarian follicular development

Polycystic ovary syndrome (PCOS) is a type of follicular dysplasia with an unclear pathogenesis, posing certain challenges in its diagnosis and treatment. Cancer susceptibility candidate 15 (CASC15), a long non-coding RNA closely associated with tumour development, has been implicated in PCOS onset and development. Therefore, this study aimed to investigate the molecular mechanisms underlying PCOS by downregulating CASC15 expression in both in vitro and in vivo models. We explored the potential regulatory relationship between CASC15 expression and PCOS by examining cell proliferation, cell cycle dynamics, cell autophagy, steroid hormone secretion capacity, and overall ovarian function in mice. We found that CASC15 expression in granulosa cells derived from patients with PCOS was significantly higher than those of the normal group (P < 0.001). In vitro experiments revealed that downregulating CASC15 significantly inhibited cell proliferation, promoted apoptosis, induced G1-phase cell cycle arrest, and influenced cellular autophagy levels. Moreover, downregulating CASC15 affected the follicular development process in newborn mouse ovaries. In vivo studies in mice demonstrated that disrupting CASC15 expression improved PCOS-related symptoms such as polycystic changes and hyperandrogenism, and significantly affected ovulation induction and embryo implantation in pregnant mice. Overall, CASC15 was highly expressed in granulosa cells of patients with PCOS and its downregulation improved PCOS-related symptoms by influencing granulosa cell function and follicular development in mice.

Hypoxia-sensitive long noncoding RNA CASC15 promotes lung tumorigenesis by regulating the SOX4/\u03b2-catenin axis

BackgroundAccumulating evidence has demonstrated that long non-coding RNAs (lncRNAs) are involved in the hypoxia-related cancer process and play pivotal roles in enabling malignant cells to survive under hypoxic stress. However, the molecular crosstalk between lncRNAs and hypoxia signaling cascades in non-small cell lung cancer (NSCLC) remains largely elusive.MethodsFirstly, we identified differentially expressed lncRNA cancer susceptibility candidate 15 (CASC15) as associated with NSCLC based on bioinformatic data. The clinical significance of CASC15 in lung cancer was investigated by Kaplan-Meier survival analysis. Then, we modulated CASC15 expression in NSCLC cell lines by RNAi. CCK-8 and transwell assays were carried out to examine the effects of CASC15 on proliferation and migration of NSCLC cells. Upstream activator and downstream targets of CASC15 were validated by luciferase reporter assay, qRT-PCR, Western blotting, and chromatin immunoprecipitation (ChIP). Lastly, RNA in situ hybridization (RNA-ISH) and immunohistochemistry (IHC) were performed to confirm the genetic relationships between CASC15 and related genes in clinical samples.ResultsCASC15 was highly expressed in NSCLC tissues and closely associated with poor prognosis. Loss-of-function analysis demonstrated that CASC15 was essential for NSCLC cell migration and growth. Mechanistic study revealed that CASC15 was transcriptionally activated by hypoxia signaling in NSCLC cells. Further analysis showed that hypoxia-induced CASC15 transactivation was mainly dependent on hypoxia-inducible factor 1α (HIF-1α) and hypoxia response elements (HREs) located in CASC15 promoter. CASC15 promotes the expression of its chromosomally nearby gene, SOX4. Then SOX4 functions to stabilize β-catenin protein, thereby enhancing the proliferation and migration of NSCLC cells. HIF-1α/CASC15/SOX4/β-catenin pathway was activated in a substantial subset of NSCLC patients.ConclusionsHIF-1α/CASC15/SOX4/β-catenin axis plays an essential role in the development and progression of NSCLC. The present work provides new evidence that lncRNA CASC15 holds great promise to be used as novel biomarkers for NSCLC. Blocking the HIF-1α/CASC15/SOX4/β-catenin axis can serve as a potential therapeutic strategy for treating NSCLC.

Long non‑coding RNA CASC15 facilitates esophageal squamous cell carcinoma tumorigenesis via decreasing SIM2 stability via FTO‑mediated demethylation.

Long non-coding RNAs (lncRNAs) are involved in the regulation of esophageal squamous cell carcinoma (ESCC) progression. However, the function and mechanism of lncRNA cancer susceptibility candidate 15 (CASC15) are poorly defined. In the present study, tumor and normal adjacent tissues were collected from 45 patients with ESCC. Expression levels of CASC15, fat mass and obesity-associated (FTO) protein and single-minded 2 (SIM2) were examined via reverse transcription-quantitative PCR and western blot assays. Cell proliferation and apoptosis were evaluated via MTT, flow cytometry and caspase-3 activity assays, respectively. Additionally, an ESCC mouse xenograft model was used to assess the function of CASC15 in vivo. The interaction between FTO and CASC15/SIM2 was analyzed via RNA immunoprecipitation and RNA pull-down assays. The results revealed that CASC15 expression was elevated in ESCC tissues, and patients with ESCC exhibiting high CASC15 expression had a poor prognosis. CASC15-knockdown inhibited ESCC cell proliferation and facilitated apoptosis. Additionally, CASC15-knockdown decreased the growth of ESCC xenograft tumors. CASC15 decreased SIM2 stability via FTO-mediated demethylation. Additionally, FTO loss markedly weakened CASC15-mediated pro-proliferative and anti-apoptotic effects in ESCC cells. SIM2 downregulation weakened the effect of CASC15-knockdown on cell proliferation and inhibited the increase of the apoptotic rate and caspase-3 activity induced by CASC15 depletion in ESCC cells. In conclusion, CASC15 promoted ESCC tumorigenesis by decreasing SIM2 stability via FTO-mediated demethylation.

LncRNA CASC15 Functions As An Unfavorable Predictor Of Ovarian Cancer Prognosis And Inhibits Tumor Progression Through Regulation Of miR-221/ARID1A Axis.

BackgroundLncRNA cancer susceptibility candidate 15 (CASC15) has been demonstrated to act as an oncogene in different cancers; however, its role in ovarian cancer remains elusive.MethodsQuantitative real-time PCR (qRT-PCR) was performed to examine the expression of lncRNA CASC15. Kaplan–Meier survival analysis was performed to evaluate the prognostic significance of lncRNA CASC15. CCK-8, soft-agar colony-formation, flow cytometry, transwell migration and invasion assays were used to analyze the biological behavior of lncRNA CASC5 in ovarian cancer. Furthermore, the potential mechanism of lncRNA CAC15 was investigated by bioinformatics analysis, luciferase reporter assay, and biotin pull-down assay.ResultsIn this study, we found that the expression of CASC15 was lower in ovarian cancer tissues and cells by qRT-PCR. In addition, low expression of CASC15 was closely correlated with advanced TNM stage, moderate/poor differentiation, and larger size. Moreover, Kaplan–Meier survival analysis showed that patients with low CASC15 expression level had poorer overall survival and progression-free survival than those with high CASC15 expression. Meanwhile, ROC analysis found that CASC15 had diagnostic values to distinguish tumor tissues from nontumorous tissues. Overexpression of CASC15 prohibited the malignancy of ovarian cancer cells, including proliferation, colony formation, cell cycle, migration, and invasion, and promoted cell apoptosis. In addition, bioinformatics analysis, luciferase reporter assay, and biotin pull-down assay confirmed that CASC15 straightly interacted with miR-221. We also observed that ARID1A was a downstream target of miR-221 and CASC15 subsequently exerted its tumor-suppressive effects by regulating the expression of ARID1A in ovarian cancer cells.ConclusionOverall, this study firstly elucidated that CASC15 could play a tumor-suppressive role in ovarian cancer by the regulation of CASC15/miR-221/ARID1A axis, which may provide a ponderable prognostic biomarker and promising therapeutic target for treatment of patients with ovarian cancer.

LncRNA CACS15 contributes to oxaliplatin resistance in colorectal cancer by positively regulating ABCC1 through sponging miR-145

Increasing evidence suggests that long non-coding RNAs (lncRNAs) are implicated with chemoresistance of cancers. However, their functional role and molecular mechanisms in colorectal cancer (CRC) chemoresistance are still largely unclear. In this work, we aimed to investigate the functional role of lncRNA cancer susceptibility candidate 15 (CASC15) in oxaliplatin (OXA) resistance of CRC and reveal the underlying molecular mechanism. Our results discovered that CASC15 was up-regulated in OXA-resistant CRC tissues and cells. Patients with high CASC15 expression level had a poor prognosis. CASC15 knockdown re-sensitized HT29/OXA and HCT116/OXA cells to OXA. Moreover, CASC15 could act as a competing endogenous RNA (ceRNA) to de-repress ABCC1 expression through sponging miR-145. miR-145 overexpression or ABCC1 knockdown could mimic the functional role of down-regulated CACS15 in OXA resistance, which was counteracted by CASC15 overexpression. Furthermore, CASC15 knockdown facilitated OXA sensitivity of OXA-resistant CRC cells in vivo. In summary, CASC15 silencing overcame OXA resistance of CRC by regulating miR-145/ABCC1 axis, providing a potential therapeutic target for CRC chemoresistance.

Higher lncRNA CASC15 expression predicts poor prognosis and associates with tumor growth in cervical cancer.

To investigate the role of long non-coding RNA Cancer Susceptibility Candidate 15 (CASC15) in cervical cancer and its potential molecular mechanism. The CASC15 expression was measured in cervical cancer tissues and cell lines by using quantitative Real-time polymerase chain reaction (qRT-PCR) analysis. Cell counting kit-8 (CCK8), flow cytometry analysis and transwell cell invasion assays were employed to detect the capacities of cell proliferation and cell invasion. Furthermore, Western blot analysis was applied to detected the E-cadherin and N-cadherin expression in EMT pathway. We demonstrated that lncRNA CASC15 expression was higher in cervical cancer tissues compared to adjacent normal tissues. Higher lncRNA CASC15 expression associated with lymph node metastasis and FIGO stage. Moreover, our results showed that higher lncRNA CASC15 expression predicted poor prognosis of cervical cancer. Functional assays showed that knockdown of lncRNA CASC15 suppressed cell proliferation and cell cycle progression in cervical cancer. Moreover, we also found that knockdown of lncRNA CASC15 inhibited cell invasion ability and Epithelial-Mesenchymal Transition (EMT) signaling pathway by upregulating E-cadherin and downregulating N-cadherin expression in cervical cancer. These results indicated that lncRNA CASC15 expression may be a prognostic biomarker and contributed to cell proliferation and invasion in cervical cancer.

Long non-coding RNA CASC15 promotes melanoma progression by epigenetically regulating PDCD4

BackgroundLong non-coding RNAs (LncRNAs) have been identified as critical regulators in a variety of cancer types. Cancer susceptibility candidate 15 (CASC15), a lncRNA located at chromosome 6p22.3, has been discovered to participate in melanoma progression and phenotype switching. Nevertheless, the roles and molecular mechanisms of CASC15 in melanoma are far from being understood.ResultsWe found that CASC15 expression was up-regulated in melanoma tissues and associated with advanced pathological stages. Function experiments displayed that CASC15 knockdown hindered proliferation, facilitated apoptosis and suppressed invasion, while CASC15 overexpression facilitated proliferation and invasion in melanoma cells. Further mechanistic analysis showed that CASC15 epigenetically silenced the expression of programmed cell death 4 (PDCD4) by recruiting EZH2 and increasing H3K27me3 level at the promoter region of PDCD4. Additionally, PDCD4 overexpression inhibited proliferation, enhanced apoptosis and decreased invasion of melanoma cells. Moreover, CASC15-knockdown-induced anti-cancer effects were abated by PDCD4 down-regulation. Furthermore, depletion of CASC15 blocked tumor growth of melanoma by up-regulating PDCD4 in vivo.ConclusionsCASC15 acts as an oncogene by negatively regulating PDCD4 expression via recruiting EZH2 and subsequently increasing H3K27me3 level. Together, our study indicates that CASC15/EZH2/PDCD4 may serve as a promising therapeutic target for melanoma intervention.

Long non-coding RNA CASC15 promotes tongue squamous carcinoma progression through targeting miR-33a-5p.

Long non-coding RNAs (lncRNAs) have gained a lot of attention because they participate in several human disorders, including tumors. This study determined the role of LncRNA CASC15 (cancer susceptibility candidate 15) in the development of tongue squamous cell carcinoma (TSCC). Here, we identified that CASC15 expression was upregulated in TSCC samples and cell lines. We showed that overexpression of CASC15 promoted cell proliferation, cycle, and migration in TSCC. In addition, we revealed that miR-33a-5p expression was downregulated in TSCC tissues and cell lines. Moreover, we showed that the expression of CASC15 was negatively related with miR-33a-5p expression in TSCC tissues. Ectopic expression of miR-33a-5p suppressed cell proliferation, cycle, and migration in TSCC. Elevated expression of CASC15 suppressed miR-33a-5p expression and promoted ZEB1 expression in SCC4 cell. Ectopic expression of CASC15 promoted TSCC cell proliferation, cycle, and migration through targeting miR-33a-5p. These results suggested that lncRNA CASC15 and miR-33a-5p might be exploited as new markers of TSCC and were potential treatment targets for TSCC patients.

Long non-coding RNA CASC15 is upregulated in hepatocellular carcinoma and facilitates hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, accounting for one-sixth of all malignant tumors, and the mortality rate of HCC ranks second among all cancer-related deaths. Increasing evidence has recently shown that long non-coding RNAs (lncRNAs) play an important role in cancer occurrence and progression, including HCC. Cancer susceptibility candidate 15 (CASC15), a lncRNA, has been reported to be involved in melanoma progression and phenotype switching. However, the function of CASC15 in human HCC is still unknown. In the present study, we evaluated expression of CASC15 and its potential functions in HCC. The expression of CASC15 in HCC tissues was quantitated by the reverse-transcription quantitative polymerase chain reaction, which showed that CASC15 was overexpressed in 59% (48/82) of HCC tissues compared with corresponding adjacent normal tissues, and the CASC15 expression level was significantly correlated with metastasis (P=0.012), tumor size (P=0.037), and TNM stage (P=0.013). Kaplan-Meier survival curves showed that high CASC15 expression was associated with poor prognosis in HCC patients (P<0.05). Moreover, a knockdown model of CASC15 was established, which showed that CASC15 significantly impaired HCC cell proliferation, migration, and invasion. CASC15 knockdown also induced cell apoptosis in vitro and impaired tumor growth in vivo. In conclusion, CASC15 plays an important role in the progression of HCC, acting as an oncogene. High expression of CASC15 is correlated with a poor prognosis, suggesting that CASC15 may be a predictive biomarker of HCC.