YAP inhibits autophagy and promotes progression of colorectal cancer via upregulating Bcl-2 expression.
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ABSTRACT:
SUBMITTER: Jin L
PROVIDER: S-EPMC8105309 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The present study aimed to illustrate the role of LINC00565 in aggravating colorectal cancer (CRC) by targeting enhancer of zeste homolog 2 (EZH2). The relative levels of LINC00565 and EZH2 in CRC tissues, based on their Tumor-Node-Metastasis stage and tumor size, were detected by reverse transcription-quantitative polymerase chain reaction. The diagnostic value of LINC00565 in CRC was assessed by depicting receiver operating characteristic curves. Pearson's correlation test was applied to analyze the expression correlation between LINC00565 and EZH2 in CRC tissues. The transfection efficacy of three LINC00565 small interfering RNAs was examined in CRC HCT116 and SW480 cell lines. After knockdown of LINC00565, the proliferative and migratory abilities of CRC cells were detected by Cell Counting Kit-8 and Transwell assays, respectively. The subcellular distribution of LINC00565 was analyzed, and the interaction between LINC00565 and EZH2 was determined by RNA immunoprecipitation. Finally, co-regulation of LINC00565 and EZH2 on CRC cell functions was explored by performing rescue experiments. Results showed that LINC00565 was upregulated in CRC tissues, especially in patients with stage III+IV and in those with large tumor sizes, suggesting its diagnostic value in CRC. EZH2 was also upregulated in CRC tissues, showing a positive correlation with LINC00565. LINC00565 was mainly expressed in the cytoplasm and was found to bind with EZH2. Validation was performed by overexpressing EZH2, which abolished the role of silenced LINC00565 in regulating proliferative and migratory abilities in CRC. Therefore, the upregulation of LINC00565 in CRC tissues was found to stimulate the aggravation of CRC by upregulating EZH2.
| S-EPMC7709565 | biostudies-literature
Project description:BackgroundForkhead box S1 (FOXS1) is a member of the forkhead box (FOX) transcriptional factor superfamily. The biological roles and underlying regulatory mechanism of FOXS1 in CRC remain unclear.MethodsBioinformatics analysis, Western blotting, real-time PCR, and immunohistochemistry (IHC) were used to detect the expression FOXS1 in CRC. MTT assay, transwell assay, human umbilical vein endothelial cell tube formation assay, and chicken chorioallantoic membrane assay were performed to investigate the effects of FOXS1 on proliferation, invasion, and angiogenesis. Additionally, tumor formation assay and orthotopic implantation assay were used to investigate the effects of FOXS1 on tumor growth and metastasis in vivo. Furthermore, gene set enrichment analysis (GSEA) was used to analyze the correlation between FOXS1 and EMT or angiogenesis. The correlation between FOXS1 and CXCL8 expression was analyzed in clinical CRC samples using IHC.ResultsThe results showed that FOXS1 expression was upregulated in CRC tissues compared with adjacent normal intestine tissues. A high FOXS1 expression is positively correlated with poor survival. FOXS1 promoted the malignant behavior of CRC cancer cells in vitro, including proliferation, invasion, and angiogenesis. In addition, FOXS1 promoted tumor growth and metastasis in nude mice. Mechanistically, FOXS1 upregulated the expression of C-X-C motif chemokine ligand 8 (CXCL8) at the transcriptional level. Knockdown of CXCL8 blocked FOXS1 induced the enhancement of the EMT and angiogenesis. GSEAs in public CRC datasets revealed strong correlations between FOXS1 expression and EMT marker and angiogenesis markers. IHC showed that FOXS1 expression was positively correlated with CXCL8 expression and CD31 expression in clinical CRC samples.ConclusionThe results suggest that FOXS1 promotes angiogenesis and metastasis by upregulating CXCL8 in CRC. Interference with the FOXS1/CXCL8 axis may serve as a potential therapeutic target for the treatment of metastatic CRC.
| S-EPMC9309265 | biostudies-literature
Project description:Colorectal cancer (CRC) is a highly malignant tumor associated with poor prognosis, yet the molecular mechanisms are not fully understood. In this study, we showed that LYAR, a nucleolar protein, is expressed at a higher level in CRC tissue than in adjacent normal tissue and that LYAR expression is closely associated with distant CRC metastasis. LYAR not only significantly promotes the migration and invasion of CRC cells in vitro, but knockdown (KD) of LYAR in CRC cells also inhibits xenograft tumor metastasis in vivo. Microarray analysis of LYAR KD cells combined with a chromatin immunoprecipitation (ChIP) assay, gene reporter assay, and rescue experiment indicated that FSCN1 (encoding fascin actin-bundling protein 1 (Fascin-1)) serves as a novel key regulator of LYAR-promoted migration and invasion of CRC cells. Knockdown of FSCN1 significantly inhibits subcutaneous tumorigenesis of CRC cells and leads to the downregulation of FASN and SCD, genes encoding key enzymes in fatty acid synthesis. In summary, this study reveals a novel mechanism by which LYAR promotes tumor cell migration and invasion by upregulating FSCN1 expression and affecting fatty acid metabolism in CRC.
| S-EPMC8769847 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is a common malignancy in human. CD44 is a transmembrane glycoprotein which is frequently overexpressed in cancer of various origins. The function and mechanism of CD44 in HCC remains elusive. In this study, we reported that CD44 was overexpressed in HCC to promote the proliferation and migration of HCC cells via oncogenic YAP, which is the key downstream regulator in Hippo pathway. These findings suggest that CD44-YAP is a probable important axis in pathogenesis of HCC, providing an insight in to HCC pathogenesis as well as potential targets for the intervention of HCC.
| S-EPMC8603576 | biostudies-literature
Project description:Background: Cancer stem cells (CSCs) have been recognized as an important drug target, however, the underlying mechanisms have not been fully understood. SKP1 is a traditional drug target for cancer therapy, while, whether SKP1 promotes colorectal cancer (CRC) stem cells (CRC-SCs) and the underlying mechanisms have remained elusive.Methods: Human CRC cell lines and primary human CRC cells were used in this study. Gene manipulation was performed by lentivirus system. The mRNA and protein levels of target genes were examined by qRT-PCR and western blot. The sphere-forming and in vitro migration capacities were determined by sphere formation and transwell assay. The self-renewal was determined by limiting dilution assay. The tumorigenicity and metastasis of cancer cells were examined by xenograft model. The promoter activity was examined by luciferase reporter assay. Nuclear run-on and Chromatin immunoprecipitation-PCR (ChIP-PCR) assay were employed to examine the transcription and protein-DNA interaction. Co-immunoprecipitation assay was used to test protein-protein interaction. The relationship between gene expression and survival was analyzed by Kaplan-meier analysis. The correlation between two genes was analyzed by Spearman analysis. Data are represented as mean?±?SD and the significance was determined by Student's t test.Results: SKP1 was upregulated in CRC-SCs and predicted poor prognosis of colon cancer patients. Overexpression of SKP1 promoted the stemness of CRC cells reflected by increased sphere-forming, migration and self-renewal capacities as well as the expression of CSCs markers. In contrast, SKP1 depletion produced the opposite effects. SKP1 strengthened YAP activity and knockdown of YAP abolished the effect of SKP1 on the stemness of CRC cells. SKP1 suppressed RASSF1 at both mRNA and protein level. Overexpression of RASSF1 abolished the effect of SKP1 on YAP activity and CRC stemness.Conclusion: Our results demonstrated that SKP1 suppresses RASSF1 at both mRNA and protein level, attenuates Hippo signaling, activates YAP, and thereby promoting the stemness of CRC cells.
| S-EPMC7713163 | biostudies-literature
Project description:Distant metastasis is the main cause of death in patients with colorectal cancer (CRC). A better understanding of the mechanisms of metastasis can greatly improve the outcome of patients with CRC. Accumulating evidence suggests that circRNA plays pivotal roles in cancer progression and metastasis, especially acting as a miRNA sponge to regulate the expression of the target gene. Public database bioinformatics analysis found that miR-1825 was highly expressed in CRC tissues. In this study, miR-1825 was highly expressed in CRC tissues, which was positively correlated with lymph node metastasis and distant metastasis. In vitro and in vivo experiments confirmed that miR-1825 was positively correlated with the proliferation and migration of CRC cells. This event can be inhibited by circTBC1D22A. CircTBC1D22A can directly interact with miR-1825 and subsequently act as a miRNA sponge to regulate the expression of target gene ATG14, which collectively advances the autophagy-mediated progression and metastasis of CRC.
2024-01-11 | GSE252689 | GEO
Project description:To explore the effect of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) on colorectal cancer (CRC) by recognizing the m6A modification of YAP mRNA thus activating ErbB2 expression. High expressions of IGF2BP2, YAP, and ErbB2 promoted the proliferation, migration and invasion of CRC cells and reduced their apoptosis. IGF2BP2 recognized the m6A on YAP mRNA and promoted the translation of mRNA. YAP regulated ErbB2 expression by promoting TEAD4 enrichment in ErbB2 promoter region. Therefore, IGF2BP2 promoted the expression of ErbB2 to enhance the proliferation, invasion and migration of CRC cells, to repress cell apoptosis, and to promote solid tumor formation in nude mice. IGF2BP2 activates the expression of ErbB2 by recognizing the m6A of YAP, thus affecting the cell cycle of CRC, inhibiting cell apoptosis, and promoting proliferation.
| S-EPMC8486198 | biostudies-literature
Project description:BackgroundMulti-drug resistance is the major cause of chemotherapy failure in hepatocellular carcinoma (HCC). YAP, a critical effector of the Hippo pathway, has been shown to contribute to the progression, metastasis and invasion of cancers. However, the potential role of YAP in mediating drug resistance remains obscure.MethodsRT-qPCR and western blot were used to assess YAP expression in HCC cell lines. CCK-8 assays, flow cytometry, a xenograft tumour model, immunochemistry and GFP-mRFP-LC3 fusion proteins were utilized to evaluate the effect of YAP on multi-drug resistance, intracellular ROS production and the autophagy of HCC cells in vitro and in vivo. Autophagy inhibitor and rescue experiments were carried out to elucidate the mechanism by which YAP promotes chemoresistance in HCC cells.ResultsWe found that BEL/FU, a typical HCC cell line with chemoresistance, exhibited overexpression of YAP. Moreover, the inhibition of YAP by shRNA or verteporfin conferred the sensitivity of BEL/FU cells to chemotherapeutic agents through autophagy-related cell death in vitro and in vivo. Mechanistically, YAP silencing significantly enhanced autophagic flux by increasing RAC1-driven ROS, which contributed to the inactivation of mTOR in HCC cells. In addition, the antagonist of autophagy reversed the enhanced effect of YAP silencing on cell death under treatment with chemotherapeutic agents.ConclusionOur findings suggested that YAP upregulation endowed HCC cells with multi-drug resistance via the RAC1-ROS-mTOR pathway, resulting in the repression of autophagy-related cell death. The blockade of YAP may serve as a promising novel therapeutic strategy for overcoming chemoresistance in HCC.
| S-EPMC6626386 | biostudies-literature
Project description: Not available
| S-EPMC11341911 | biostudies-literature
Project description:SETDB1, a histone H3K9 methyltransferase, has been reported to be upregulated in a variety of tumors and promotes cancer development. However, the exact pathogenesis of SETDB1 in human colorectal cancer (CRC) is hitherto unknown. Here, we showed that SETDB1 expression was highly amplified in CRC. Functionally, SETDB1 downregulation in SW480 and HCT116 cells reduced cell proliferation, migration, invasion, and increased CRC cells apoptosis. In contrast, SETDB1 overexpression promoted CRC cells proliferation, migration, and invasion. High expression of SETDB1 was associated with a more aggressive phenotype in vitro. Flow cytometry showed that cell cycle was arrested in G1 phase after SETDB1 silencing. Furthermore, depletion of SETDB1 in vivo suppressed CRC cells proliferation. Mechanistically, p21 was identified as the target of SETDB1. After transfected with siSETDB1, expression of p21 was distinctly increased. In contrast, expression of p21 was significantly decreased after overexpression SETDB1. We also showed that SETDB1 could be involved in the regulation of epithelial-mesenchymal transition (EMT) in HCT116 cells. Moreover, we confirmed that SETDB1 could regulate the activity of p21 promoter by dual-luciferase repoter assay, and proved that SETDB1 could bind to the promoter of p21 and regulate its H3K9me3 enrichment level by ChIP-PCR experiment. Finally, we verified that silencing of SETDB1 inhibited CRC tumorigenesis in vivo. In conclusion, our results indicate that SETDB1 is a major driver of CRC development and might provide a new therapeutic target for the clinical treatment of CRC.
| S-EPMC7214465 | biostudies-literature