MiR-6511b-5p suppresses metastasis of pMMR colorectal cancer through methylation of CD44 by directly targeting BRG1

• JinMing Sun ^[2] ; Ling Ye ^[2] ; Yuan Shi ^[2] ; XingWei Wang ^[2] ; XiaFei Zhao ^[2] ; ShengYong Ren ^[2] ; JunWei Fan ^[1] ; HuanZhang Shao ^[2] ; BingYu Qin ^[2]
  1. [1] Shanghai Jiao Tong University

     Shanghai Jiao Tong University

     China

     
  2. [2] Department of Critical Care Medicine, Henan Key Laboratory for Critical Care Medicine, Zhengzhou Key Laboratory for Critical Care Medicine, Henan Provincial People’s Hospital, Zhengzhou, 450003, Henan, China
• Localización: Clinical & translational oncology, ISSN 1699-048X, Vol. 24, Nº. 10 (October), 2022, págs. 1940-1953
• Idioma: inglés
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• Resumen

  • Purpose Distal metastases are a major cause of poor prognosis in colorectal cancer patients. Approximately 95% of metastatic colorectal cancers are defined as DNA mismatch repair proficient (pMMR). Our previous study found that miR-6511b-5p was downregulated in pMMR colorectal cancer. However, the mechanism of miR-6511b-5p in pMMR colorectal cancer metastases remain unclear.

    Methods We first used quantitative real-time PCR to evaluate the role of miR-6511b-5p in colorectal cancer. Second, we conducted invasion assays and wound healing assays to investigate the role of miR-6511b-5p and CD44 in colorectal cancer cells metastases. Third, luciferase reporter assay, in situ hybridization (ISH), and immunohistochemistry assays were performed to study the relationship between miR-6511b-5p and BRG1. Finally, real-time quantitative PCR, immunohistochemistry, and chromatin immunoprecipitation (ChIP) assays were performed to analyze the relationship between BRG1 and CD44 in colorectal cancer.

    Results We found that lower expression of miR-6511b-5p appeared more often in pMMR colorectal cancer patients compared with dMMR (mismatch repair deficient) cases, and was positively correlated with metastases. In vitro, overexpression of miR-6511b-5p inhibited metastasis by decreasing CD44 expression via directly targeting BRG1 in colorectal cancer. Furthermore, BRG1 knockdown decreased the expression of CD44 by promoting CD44 methylation in colorectal cancer cells.

    Conclusion Our data suggest that miR-6511b-5p may act as a promising biomarker and treatment target for pMMR colorectal cancer, particularly in metastatic patients. Mechanistically, miR-6511b-5p suppresses invasion and migration of colorectal cancer cells through methylation of CD44 via directly targeting BRG1.