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Hepatology
Original research
miR-541 potentiates the response of human hepatocellular carcinoma to sorafenib treatment by inhibiting autophagy
  1. Wen-Ping Xu1,
  2. Jin-Pei Liu1,
  3. Ji-Feng Feng1,
  4. Chang-Peng Zhu1,
  5. Yuan Yang2,
  6. Wei-Ping Zhou2,
  7. Jin Ding3,
  8. Chen-Kai Huang4,
  9. Ya-Lu Cui1,
  10. Chen-Hong Ding1,
  11. Xin Zhang1,
  12. Bin Lu5,
  13. Wei-Fen Xie1
  1. 1 Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
  2. 2 Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
  3. 3 The International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Institute, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
  4. 4 Department of Gastroenterology, First Affiliated Hospital of Nanchang University, Nanchang, China
  5. 5 Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, China
  1. Correspondence to Professor Wei-Fen Xie, Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 20003, China; weifenxie{at}medmail.com.cn; Professor Xin Zhang, Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China; zhang68{at}hotmail.com; Professor Bin Lu, Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai 200433, China; binlu{at}smmu.edu.cn

Abstract

Objective Autophagy participates in the progression of hepatocellular carcinoma (HCC) and the resistance of HCC cells to sorafenib. We investigated the feasibility of sensitising HCC cells to sorafenib by modulating miR-541-initiated microRNA-autophagy axis.

Design Gain- and loss-of-function assays were performed to evaluate the effects of miR-541 on the malignant properties and autophagy of human HCC cells. Autophagy was quantified by western blotting of LC3, transmission electron microscopy analyses and confocal microscopy scanning of mRFP-GFP-LC3 reporter construct. Luciferase reporter assays were conducted to confirm the targets of miR-541. HCC xenograft tumours were established to analyse the role of miR-541 in sorafenib-induced lethality.

Results The expression of miR-541 was downregulated in human HCC tissues and was associated with malignant clinicopathologic phenotypes, recurrence and survival of patients with HCC. miR-541 inhibited the growth, metastasis and autophagy of HCC cells both in vitro and in vivo. Prediction software and luciferase reporter assays identified autophagy-related gene 2A (ATG2A) and Ras-related protein Rab-1B (RAB1B) as the direct targets of miR-541. Consistent with the effects of the miR-541 mimic, inhibition of ATG2A or RAB1B suppressed the malignant phenotypes and autophagy of HCC cells. Furthermore, siATG2A and siRAB1B partially reversed the enhancement of the malignant properties and autophagy in HCC cells mediated by the miR-541 inhibitor. More interestingly, higher miR-541 expression predicted a better response to sorafenib treatment, and the combination of miR-541 and sorafenib further suppressed the growth of HCC cells in vivo compared with the single treatment.

Conclusions Dysregulation of miR-541-ATG2A/RAB1B axis plays a critical role in patients’ responses to sorafenib treatment. Manipulation of this axis might benefit survival of patients with HCC, especially in the context of the highly pursued strategies to eliminate drug resistance.

  • hepatocellular carcinoma
  • drug resistance
  • molecular carcinogenesis

https://doi.org/10.1136/gutjnl-2019-318830

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    Footnotes

    • W-PX, J-PL, J-FF and C-PZ are joint first authors.

    • W-PX, J-PL, J-FF and C-PZ contributed equally.

    • Contributors W-PX, XZ, BL and W-FX obtained funding and contributed to the study concept and design; W-PX, J-PL, J-FF, C-KH, Y-LC and C-HD contributed to the acquisition of data; W-PX and C-PZ contributed to analysis and interpretation of data; W-PX performed statistical analysis; W-PX, XZ, and W-FX contributed to drafting of the manuscript; YY and W-PZ provided material support; JD provided critical revision of the manuscript for important intellectual content; XZ, BL and W-FX supervised the study.

    • Funding This work was supported by the National Natural Science Foundation of China (81502077 to W-PX, 81530019 to W-FX, 81572377 to XZ and 81472283 to BL); the Shanghai Science and Technology Committee (15431907100 to W-FX); “Chen Guang” projects (15CG41) from Shanghai Municipal Education Commission and Shanghai Education Development Foundation.

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Ethics approval All human experiments were approved by the Ethics Committee of the Second Military Medical University (Shanghai, China). All animal experiments were performed according to protocols approved by the Institutional Animal Care and Use Committee at the Second Military Medical University.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement No data are available.