Int J Med Sci 2022; 19(2):257-266. doi:10.7150/ijms.67352 This issue

Research Paper

MiR-25 enhances autophagy and promotes sorafenib resistance of hepatocellular carcinoma via targeting FBXW7

Xiaoning Feng1*, Bei Zou1*, Tianhao Nan2*, Xiaoxiao Zheng3, Li Zheng3, Jiahua Lan3, Wei Chen3✉, Jun Yu1✉

1. Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
2. College of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
3. Cancer Institute of Integrated Traditional Chinese and Western Medicine, Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine of Zhejiang Province, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang, China.
* These authors contributed equally to this work.

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Citation:
Feng X, Zou B, Nan T, Zheng X, Zheng L, Lan J, Chen W, Yu J. MiR-25 enhances autophagy and promotes sorafenib resistance of hepatocellular carcinoma via targeting FBXW7. Int J Med Sci 2022; 19(2):257-266. doi:10.7150/ijms.67352. Available from https://www.medsci.org/v19p0257.htm

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Abstract

Graphic abstract

Sorafenib resistance is a major challenge in the treatment of patients with advanced hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) are a large family of non-coding RNA molecules, which is an important mechanism of drug resistance. We previously found that knockdown of miR-25 increased the sensitivity of TRAIL-induced apoptosis in liver cancer stem cells. We aimed to study the effects of miR-25 on sorafenib resistance of HCC and the underlying mechanisms. In the present study, we analyzed the expression of miR-25 between HCC and normal tissues and predicted miR-25 target genes through databases. After transfecting miR-25 mimics, inhibitor or FBXW7 Plasmid, CCK-8 and flow cytometry assay was performed to determine the sorafenib resistance. We performed LC3-dual-fluorescence assay and Western blotting to detect the autophagy levels. The expression of miR-25 was upregulated in human HCC tissues and was associated with tumor pathological grade, clinic staging, and lymphatic metastasis. MiR-25 enhanced sorafenib resistance of HCC cells and autophagy. FBXW7 is the direct target of miR-25. Overexpression of FBXW7 could reverse the increase of sorafenib resistance caused by miR-25 mimics. Our results suggested that miR-25 increased the sorafenib resistance of HCC via inducing autophagy. In addition, miR-25 decreases the expression of FBXW7 protein to regulate autophagy. Therefore, miR-25 may represent a novel therapeutic target for the treatment of HCC.

Keywords: Hepatocellular carcinoma (HCC), MicroRNAs (miRNAs), FBXW7, Autophagy