ARID1A regulates colorectal cancer metastasis through the AKT/mTOR/p70S6K pathway

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BACKGROUND: Colorectal cancer (CRC) is the most common malignant tumor of the digestive system. Exploring effective diagnostic markers and therapeutic targets has great significance for the diagnosis and treatment of CRC. ARID1A is frequently mutated in CRC, but its prognostic value for this disease remains controversial. Therefore, our aim was to explore the biological role of ARID1A in CRC and the underlying molecular mechanisms. METHODS: The clinical relevance of ARID1A in CRC was evaluated using integrating multiple biological databases and a clinical cohort. In vitro and in vivo functional assays (CCK-8, colony formation, transwell, and xenograft models) assessed its tumor-modulating effects. Autophagy was examined via transmission electron microscopy and immunofluorescence, while western blotting quantified epithelial-mesenchymal transition, autophagy-related, and signaling pathway proteins. RESULTS: Based on CRC mutation data from TCGA-COAD and cBioPortal, the ARID1A mutation frequency was 14% and 16%, respectively. Survival analysis showed that the low-ARID1A-expression group had a poorer prognosis than the high-expression group. In vitro and in vivo studies showed that downregulation of ARID1A promotes various malignant biological behaviors of CRC cells, including proliferation, invasion, and metastasis. These phenotypic changes were accompanied by alterations in autophagy-related markers (such as decreased Beclin1 and LC3B, and increased p62) and activation of the AKT/mTOR/p70S6K signaling pathway. In addition, analyses of clinical samples indicated that low ARID1A expression is an independent risk factor for CRC recurrence and metastasis. CONCLUSION: In summary, ARID1A has a tumor-suppressive role in CRC. These data suggest that ARID1A expression is a potential biomarker for CRC, which could lead to novel clinical diagnostic and treatment approaches.

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