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POLE2 silencing inhibits the progression of colorectal carcinoma cells via wnt signaling axis.

ABSTRACT: Colorectal cancer (CRC) is one of the most common malignant carcinoma worldwide. DNA polymerase epsilon 2, accessory subunit (POLE2) participates in DNA replication, repair, and cell cycle control, but its association with CRC development remains unclear. In the present study, the differentially expressed genes (DEGs) in CRC were screened from bioinformatics analysis based on GEO database. RT-qPCR was used to assess mRNA expression. CCK-8 and colony formation assays were applied for the evaluation of cell proliferation. Wound healing and transwell assays were used to detect cell migration and invasion. Protein levels were determined by Western blotting assay. We found that POLE2 was highly expressed in CRC tissues and cell lines. Inhibition of POLE2 suppressed the proliferation, migration and invasion of CRC cells. Mechanistically, Wnt/β-catenin signaling pathway was inactivated by inhibition of POLE2. Activation of Wnt/β-catenin pathway can reverse the function of POLE2 knockdown on CRC cells. In vivo studies demonstrated that POLE2 silencing could notably inhibit the growth of tumors, which was consistent with the results in vitro. In conclusion, we found POLE2 as a novel oncogene in CRC, providing a potential therapeutic or diagnostic target in CRC.

SUBMITTER: Jian W

PROVIDER: S-EPMC11340749 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature

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POLE2 silencing inhibits the progression of colorectal carcinoma cells via wnt signaling axis.

Jian Weihua W Zhang Lei L

Cancer biology & therapy 20240818 1

Colorectal cancer (CRC) is one of the most common malignant carcinoma worldwide. DNA polymerase epsilon 2, accessory subunit (POLE2) participates in DNA replication, repair, and cell cycle control, but its association with CRC development remains unclear. In the present study, the differentially expressed genes (DEGs) in CRC were screened from bioinformatics analysis based on GEO database. RT-qPCR was used to assess mRNA expression. CCK-8 and colony formation assays were applied for the evaluati ...[more]

PMID: 39155507

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Project description:BackgroundIntegrin β6 (ITGB6), a key submonomer of integrin αvβ6, plays an important role in epithelial-to-mesenchymal transition (EMT), wound healing, epithelial-derived tumor growth, fibrosis, and epithelial repair. However, the role of ITGB6 in cervical carcinoma (CC) remains elusive.MethodsThe expression levels of ITGB6 in CC tissues and cell lines were determined using quantitative real-time polymerase chain reaction (qRT-PCR). The cell viability, proliferation, apoptosis, migration, and invasion were evaluated by Cell Counting Kit-8 (CCK-8), colony-forming, flow cytometry, and Transwell assay, respectively. The expression of related proteins, including EMT markers and the Janus kinase/signal transducer and activator of transcription (JAK/STAT3) signaling markers, were detected using western blotting.ResultsThe ITGB6 expression in CC tissues and cells (C-33A, Hela, SiHa, and Caski) was remarkably higher than that in paracarcinoma tissues and ECT1/E6E7 cells. The data from The Cancer Genome Atlas (TCGA) data set suggested that patients with CC with high ITGB6 expression showed poorer overall survival (OS). Compared with the empty transfection group (si-NC), si-ITGB6 restrained the proliferation, migration, and invasion of SiHa and Hela cells, while promoting cell apoptosis. si-ITGB6 suppression decreased the expression of Snail, vimentin, and N-cadherin, while increasing E-cadherin expression. Further research showed that si-ITGB6 reduced p-JAK1/JAK1, p-JAK2/JAK2, and p-STAT3/STAT3 expression in the JAK/STAT3 signaling pathway. Interestingly, proliferation, migration, invasion, and the expressions of the molecular markers of the JAK/STAT3 signaling pathway and EMT pathway induced by ITGB6 were altered by RO8191 (JAK/STAT3 pathway activator). Furthermore, the protein expression levels of Snail, vimentin, N-cadherin, p-STAT3/STAT3, p-JAK1/JAK1, and p-JAK2/JAK2 in tumor tissues were higher than those in adjacent normal tissue, while the expression level of E-cadherin was downregulated in tumor tissues.ConclusionsSilencing of ITGB6 restrains cell proliferation, migration and invasion, and promotes apoptosis in CC by inhibiting JAK/STAT signaling pathways. Thus, ITGB6 may perhaps be a new and useful candidate target for treating CC.

Project description:BackgroundRecent studies have identified that circular RNAs (circRNAs) have an important role in cancer via their well-recognized sponge effect on miRNAs, which regulates a large variety of cancer-related genes. However, only a few circRNAs have been well-studied in renal cell carcinoma (RCC) and their regulatory function remains largely elusive.MethodsBioinformatics approaches were used to characterize the differentially expressed circRNAs in our own circRNA-sequencing dataset, as well as two public circRNA microarray datasets. CircNTNG1 (hsa_circ_0002286) was identified as a potential tumor-suppressing circRNA. Transwell assay and CCK-8 assay were used to assess phenotypic changes. RNA pull-down, luciferase reporter assays and FISH experiment were used to confirm the interactions among circNTNG1, miR-19b-3p, and HOXA5 mRNA. GSEA was performed to explore the downstream pathway regulated by HOXA5. Immunoblotting, chromatin immunoprecipitation, and methylated DNA immunoprecipitation were used to study the mechanism of HOXA5.ResultsIn all three circRNA datasets, circNTNG1, which was frequently deleted in RCC, showed significantly low expression in the tumor group. The basic properties of circNTNG1 were characterized, and phenotype studies also demonstrated the inhibitory effect of circNTNG1 on RCC cell aggressiveness. Clinically, circNTNG1 expression was associated with RCC stage and Fuhrman grade, and it also served as an independent predictive factor for both OS and RFS of RCC patients. Next, the sponge effect of circNTNG1 on miR-19b-3p and the inhibition of HOXA5 by miR-19b-3p were validated. GSEA analysis indicated that HOXA5 could inactivate the epithelial-mesenchymal transition (EMT) process, and this inactivation was mediated by HOXA5-induced SNAI2 (Slug) downregulation. Finally, it was confirmed that the Slug downregulation was caused by HOXA5, along with the DNA methyltransferase DNMT3A, binding to its promoter region and increasing the methylation level.ConclusionsBased on the experimental data, in RCC, circNTNG1/miR-19b-3p/HOXA5 axis can regulate the epigenetic silencing of Slug, thus interfering EMT and metastasis of RCC. Together, our findings provide potential biomarkers and novel therapeutic targets for future study in RCC.

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POLE2 silencing inhibits the progression of colorectal carcinoma cells via wnt signaling axis.

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POLE2 silencing inhibits the progression of colorectal carcinoma cells via wnt signaling axis.

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