Department of Vascular Surgery, Xinzhou People's Hospital, Xinzhou hospital affiliated to Shanxi Medical University, The Tenth Clinical Medical College of Shanxi Medical University, Xinzhou, Shanxi.
People's Republic of China, Department of Radiotherapy and Oncology, Wuhan Sixth Hospital and Affiliated Hospital of Jianghan University, Wuhan, People's Republic of China;, Email:
Pharmazie. 2022 Sep 1;77(7):224-229. doi: 10.1691/ph.2022.1881.
Pancreatic cancer is one of the most common malignancies with very poor prognosis due to its broad resistance to chemotherapy. ARID1A, a subunit of SWI/SNF complex, is involved in pancreatic carcinogenesis through epigenetic silencing of oncogenes. In this study, we aimed to explore whether ARID1A was implicated in the gemcitabine resistance in pancreatic cancer patients via regulating RRM2. We examined the effect of ARID1A depletion on the gemcitabine sensitivity in pancreatic cancer cells and explored the role of RRM2 in ARID1A-mediated pancreatic cancer cells chemosensitivity to gemcitabine. We found that Knockout of ARID1A led to gemcitabine resistance in pancreatic cancer cells, effect of which could be reversed by RRM2, a gemcitabine resistance related gene. ARID1A decreased the transcription of RRM2, and directly bound to the promoter of RRM2. Moreover, expression of RRM2 was negatively correlated with ARID1A in pancreatic cancer tissues. Thus, ARID1A-mediated RRM2 epigenetic suppression is crucial for enhancement of pancreatic cancer chemosensitivity to gemcitabine, and ARID1A could be used as a biomarker to guide the gemcitabine chemotherapy of pancreatic cancer.
胰腺癌是最常见的恶性肿瘤之一，由于其对化疗的广泛耐药性，预后极差。ARID1A 是 SWI/SNF 复合物的一个亚基，通过表观遗传沉默癌基因参与胰腺癌的发生。在本研究中，我们旨在通过调节 RRM2 来探讨 ARID1A 是否参与胰腺癌患者对吉西他滨的耐药性。我们研究了 ARID1A 缺失对胰腺癌细胞对吉西他滨敏感性的影响，并探讨了 RRM2 在 ARID1A 介导的胰腺癌细胞对吉西他滨化疗敏感性中的作用。我们发现 ARID1A 的敲除导致胰腺癌细胞对吉西他滨产生耐药性，而 RRM2（一种与吉西他滨耐药相关的基因）可逆转这种耐药性。ARID1A 降低了 RRM2 的转录水平，并直接与 RRM2 的启动子结合。此外，在胰腺癌组织中，RRM2 的表达与 ARID1A 呈负相关。因此，ARID1A 介导的 RRM2 表观遗传抑制对于增强胰腺癌细胞对吉西他滨的化疗敏感性至关重要，ARID1A 可以作为指导胰腺癌吉西他滨化疗的生物标志物。
