Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Molecular Diagnostics

Low miR-10b-3p associated with sorafenib resistance in hepatocellular carcinoma

British Journal of Cancer volume 126, pages 1806–1814 (2022)Cite this article

Subjects

Abstract

Background

Sorafenib is one of the standard first-line therapies for advanced hepatocellular carcinoma (HCC). Unfortunately, there are currently no appropriate biomarkers to predict the clinical efficacy of sorafenib in HCC patients. MicroRNAs (miRNAs) have been studied for their biological functions and clinical applications in human cancers.

Methods

In this study, we found that miR-10b-3p expression was suppressed in sorafenib-resistant HCC cell lines through miRNA microarray analysis.

Results

Sorafenib-induced apoptosis in HCC cells was significantly enhanced by miR-10b-3p overexpression and partially abrogated by miR-10b-3p depletion. Among 45 patients who received sorafenib for advanced HCC, those with high miR-10b-3p levels, compared to those with low levels, exhibited significantly longer overall survival (OS) (median, 13.9 vs. 3.5 months, p = 0.021), suggesting that high serum miR-10b-3p level in patients treated with sorafenib for advanced HCC serves as a biomarker for predicting sorafenib efficacy. Furthermore, we confirmed that cyclin E1, a known promoter of sorafenib resistance reported by our previous study, is the downstream target for miR-10b-3p in HCC cells.

Conclusions

This study not only identified the molecular target for miR-10b-3p, but also provided evidence that circulating miR-10b-3p may be used as a biomarker for predicting sorafenib sensitivity in patients with HCC.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: miR-10b-3p as a predictive biomarker of response to sorafenib treatment in HCC cell lines in vitro and in vivo.
Fig. 2: Expression of miR-10b-3p was induced by sorafenib in HCC cells.
Fig. 3: Expression of miR-10b-3p was associated with better prognosis of HCC patients.
Fig. 4: Expression of miR-10b-3p sensitizes HCC cells in response to sorafenib treatment.
Fig. 5: miR-10b-3p was a possible mediator of sorafenib efficacy through down-regulation of cyclin E1 in HCC cell lines.

Similar content being viewed by others

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Zhang PF, Wei CY, Huang XY, Peng R, Yang X, Lu JC, et al. Circular RNA circTRIM33-12 acts as the sponge of MicroRNA-191 to suppress hepatocellular carcinoma progression. Mol Cancer. 2019;18:105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Liu X, Chen D, Chen H, Wang W, Liu Y, Wang Y, et al. YB1 regulates miR-205/200b-ZEB1 axis by inhibiting microRNA maturation in hepatocellular carcinoma. Cancer Commun. 2021. https://doi.org/10.1002/cac2.12164

    Article  Google Scholar 

  3. Komoll RM, Hu Q, Olarewaju O, von Dohlen L, Yuan Q, Xie Y, et al. MicroRNA-342-3p is a potent tumour suppressor in hepatocellular carcinoma. J Hepatol. 2021;74:122–34.

    Article  CAS  PubMed  Google Scholar 

  4. Chen Y, Buyel JJ, Hanssen MJ, Siegel F, Pan R, Naumann J, et al. Exosomal microRNA miR-92a concentration in serum reflects human brown fat activity. Nat Commun. 2016;7:11420.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Matsumura T, Sugimachi K, Iinuma H, Takahashi Y, Kurashige J, Sawada G, et al. Exosomal microRNA in serum is a novel biomarker of recurrence in human colorectal cancer. Br J Cancer. 2015;113:275–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Xu L, Beckebaum S, Iacob S, Wu G, Kaiser GM, Radtke A, et al. MicroRNA-101 inhibits human hepatocellular carcinoma progression through EZH2 downregulation and increased cytostatic drug sensitivity. J Hepatol. 2014;60:590–8.

    Article  CAS  PubMed  Google Scholar 

  7. Chen X, Liang H, Zhang J, Zen K, Zhang CY. Secreted microRNAs: a new form of intercellular communication. Trends Cell Biol. 2012;22:125–32.

    Article  CAS  PubMed  Google Scholar 

  8. Bai X, Liu Z, Shao X, Wang D, Dong E, Wang Y, et al. The heterogeneity of plasma miRNA profiles in hepatocellular carcinoma patients and the exploration of diagnostic circulating miRNAs for hepatocellular carcinoma. PLoS One. 2019;14:e0211581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Brase JC, Wuttig D, Kuner R, Sultmann H. Serum microRNAs as non-invasive biomarkers for cancer. Mol Cancer. 2010;9:306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Shi Y, Zhang DD, Liu JB, Yang XL, Xin R, Jia CY, et al. Comprehensive analysis to identify DLEU2L/TAOK1 axis as a prognostic biomarker in hepatocellular carcinoma. Mol Ther Nucleic Acids. 2021;23:702–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hung CH, Hu TH, Lu SN, Kuo FY, Chen CH, Wang JH, et al. Circulating microRNAs as biomarkers for diagnosis of early hepatocellular carcinoma associated with hepatitis B virus. Int J Cancer. 2016;138:714–20.

    Article  CAS  PubMed  Google Scholar 

  12. Lin XJ, Chong Y, Guo ZW, Xie C, Yang XJ, Zhang Q, et al. A serum microRNA classifier for early detection of hepatocellular carcinoma: a multicentre, retrospective, longitudinal biomarker identification study with a nested case-control study. Lancet Oncol. 2015;16:804–15.

    Article  CAS  PubMed  Google Scholar 

  13. Parpart S, Roessler S, Dong F, Rao V, Takai A, Ji J, et al. Modulation of miR-29 expression by alpha-fetoprotein is linked to the hepatocellular carcinoma epigenome. Hepatology. 2014;60:872–83.

    Article  CAS  PubMed  Google Scholar 

  14. Zanutto S, Ciniselli CM, Belfiore A, Lecchi M, Masci E, Delconte G, et al. Plasma miRNA-based signatures in CRC screening programs. Int J Cancer. 2020;146:1164–73.

    Article  CAS  PubMed  Google Scholar 

  15. Lu X, Lu J, Wang S, Zhang Y, Ding Y, Shen X, et al. Circulating serum exosomal miR-92a-3p as a novel biomarker for early diagnosis of gastric cancer. Future Oncol. 2021;17:907–19.

    Article  CAS  PubMed  Google Scholar 

  16. Hu Z, Chen X, Zhao Y, Tian T, Jin G, Shu Y, et al. Serum microRNA signatures identified in a genome-wide serum microRNA expression profiling predict survival of non-small-cell lung cancer. J Clin Oncol. 2010;28:1721–6.

    Article  PubMed  Google Scholar 

  17. Kleivi Sahlberg K, Bottai G, Naume B, Burwinkel B, Calin GA, Borresen-Dale AL, et al. A serum microRNA signature predicts tumor relapse and survival in triple-negative breast cancer patients. Clin Cancer Res. 2015;21:1207–14.

    Article  CAS  PubMed  Google Scholar 

  18. Sheedy P, Medarova Z. The fundamental role of miR-10b in metastatic cancer. Am J cancer Res. 2018;8:1674–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Guan L, Ji D, Liang N, Li S, Sun B. Up-regulation of miR-10b-3p promotes the progression of hepatocellular carcinoma cells via targeting CMTM5. J Cell Mol Med. 2018;22:3434–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhou J, Yu L, Gao X, Hu J, Wang J, Dai Z, et al. Plasma microRNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma. J Clin Oncol. 2011;29:4781–8.

    Article  CAS  PubMed  Google Scholar 

  21. Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Prim. 2021;7:6.

    Article  PubMed  Google Scholar 

  22. Kanthaje S, Makol A, Chakraborti A. Sorafenib response in hepatocellular carcinoma: MicroRNAs as tuning forks. Hepatol Res. 2018;48:5–14.

    Article  CAS  PubMed  Google Scholar 

  23. Azumi J, Tsubota T, Sakabe T, Shiota G. miR-181a induces sorafenib resistance of hepatocellular carcinoma cells through downregulation of RASSF1 expression. Cancer Sci. 2016;107:1256–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Fornari F, Pollutri D, Patrizi C, La Bella T, Marinelli S, Casadei Gardini A, et al. In hepatocellular carcinoma miR-221 modulates sorafenib resistance through inhibition of caspase-3-mediated apoptosis. Clin Cancer Res. 2017;23:3953–65.

    Article  CAS  PubMed  Google Scholar 

  25. Gramantieri L, Pollutri D, Gagliardi M, Giovannini C, Quarta S, Ferracin M, et al. MiR-30e-3p influences tumor phenotype through MDM2/TP53 axis and predicts sorafenib resistance in hepatocellular carcinoma. Cancer Res. 2020;80:1720–34.

    Article  CAS  PubMed  Google Scholar 

  26. He C, Dong X, Zhai B, Jiang X, Dong D, Li B, et al. MiR-21 mediates sorafenib resistance of hepatocellular carcinoma cells by inhibiting autophagy via the PTEN/Akt pathway. Oncotarget. 2015;6:28867–81.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Nishida N, Arizumi T, Hagiwara S, Ida H, Sakurai T, Kudo M. MicroRNAs for the prediction of early response to sorafenib treatment in human hepatocellular carcinoma. Liver Cancer. 2017;6:113–25.

    Article  CAS  PubMed  Google Scholar 

  28. Tan W, Lin Z, Chen X, Li W, Zhu S, Wei Y, et al. miR-126-3p contributes to sorafenib resistance in hepatocellular carcinoma via downregulating SPRED1. Ann Transl Med. 2021;9:38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Weng H, Zeng L, Cao L, Chen T, Li Y, Xu Y, et al. circFOXM1 contributes to sorafenib resistance of hepatocellular carcinoma cells by regulating MECP2 via miR-1324. Mol Ther Nucleic Acids. 2021;23:811–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Xu Y, Huang J, Ma L, Shan J, Shen J, Yang Z, et al. MicroRNA-122 confers sorafenib resistance to hepatocellular carcinoma cells by targeting IGF-1R to regulate RAS/RAF/ERK signaling pathways. Cancer Lett. 2016;371:171–81.

    Article  CAS  PubMed  Google Scholar 

  31. Zhao W, Ma B, Tian Z, Han H, Tang J, Dong B, et al. Inhibiting CBX4 efficiently protects hepatocellular carcinoma cells against sorafenib resistance. Br J Cancer. 2021;124:1237–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ouyang H, Gore J, Deitz S, Korc M. microRNA-10b enhances pancreatic cancer cell invasion by suppressing TIP30 expression and promoting EGF and TGF-beta actions. Oncogene. 2014;33:4664–74.

    Article  CAS  PubMed  Google Scholar 

  33. Zhang P, Hong H, Sun X, Jiang H, Ma S, Zhao S, et al. MicroRNA-10b regulates epithelial-mesenchymal transition by modulating KLF4/Notch1/E-cadherin in cisplatin-resistant nasopharyngeal carcinoma cells. Am J Cancer Res. 2016;6:141–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Monroig-Bosque PdC, Shah MY, Fu X, Fuentes-Mattei E, Ling H, Ivan C, et al. OncomiR-10b hijacks the small molecule inhibitor linifanib in human cancers. Sci Rep. 2018;8:13106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Khalighfard S, Alizadeh AM, Irani S, Omranipour R. Plasma miR-21, miR-155, miR-10b, and Let-7a as the potential biomarkers for the monitoring of breast cancer patients. Sci Rep. 2018;8:17981.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhu Q, Gong L, Wang J, Tu Q, Yao L, Zhang J-R, et al. miR-10b exerts oncogenic activity in human hepatocellular carcinoma cells by targeting expression of CUB and sushi multiple domains 1 (CSMD1). BMC Cancer. 2016;16:806–806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hsu C, Lin LI, Cheng YC, Feng ZR, Shao YY, Cheng AL, et al. Cyclin E1 inhibition can overcome sorafenib resistance in hepatocellular carcinoma cells through Mcl-1 suppression. Clin Cancer Res. 2016;22:2555–64.

    Article  CAS  PubMed  Google Scholar 

  38. Lai HH, Li CW, Hong CC, Sun HY, Chiu CF, Ou DL, et al. TARBP2-mediated destabilization of Nanog overcomes sorafenib resistance in hepatocellular carcinoma. Mol Oncol. 2019;13:928–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ou DL, Shen YC, Yu SL, Chen KF, Yeh PY, Fan HH, et al. Induction of DNA damage-inducible gene GADD45beta contributes to sorafenib-induced apoptosis in hepatocellular carcinoma cells. Cancer Res. 2010;70:9309–18.

    Article  CAS  PubMed  Google Scholar 

  40. Marrero JA, Kulik LM, Sirlin CB, Zhu AX, Finn RS, Abecassis MM, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018;68:723–50.

    Article  PubMed  Google Scholar 

  41. Ma L. Role of miR-10b in breast cancer metastasis. Breast Cancer Res. 2010;12:210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Li QJ, Zhou L, Yang F, Wang GX, Zheng H, Wang DS, et al. MicroRNA-10b promotes migration and invasion through CADM1 in human hepatocellular carcinoma cells. Tumour Biol. 2012;33:1455–65.

    Article  CAS  PubMed  Google Scholar 

  43. Biagioni F, Bossel Ben-Moshe N, Fontemaggi G, Canu V, Mori F, Antoniani B, et al. miR-10b*, a master inhibitor of the cell cycle, is down-regulated in human breast tumours. EMBO Mol Med. 2012;4:1214–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Calkins KL, Thamotharan S, Ghosh S, Dai Y, Devaskar SU. MicroRNA 122 reflects liver injury in children with intestinal failure-associated liver disease treated with intravenous fish oil. J Nutr. 2020;150:1144–50.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Yang N, Ekanem NR, Sakyi CA, Ray SD. Hepatocellular carcinoma and microRNA: new perspectives on therapeutics and diagnostics. Adv Drug Deliv Rev. 2015;81:62–74.

    Article  CAS  PubMed  Google Scholar 

  46. Vasuri F, Visani M, Acquaviva G, Brand T, Fiorentino M, Pession A, et al. Role of microRNAs in the main molecular pathways of hepatocellular carcinoma. World J Gastroenterol. 2018;24:2647–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Marisi G, Cucchetti A, Ulivi P, Canale M, Cabibbo G, Solaini L, et al. Ten years of sorafenib in hepatocellular carcinoma: Are there any predictive and/or prognostic markers? World J Gastroenterol. 2018;24:4152–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lu JW, Ho YJ, Yang YJ, Liao HA, Ciou SC, Lin LI, et al. Zebrafish as a disease model for studying human hepatocellular carcinoma. World J Gastroenterol. 2015;21:12042–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Li LM, Hu ZB, Zhou ZX, Chen X, Liu FY, Zhang JF, et al. Serum microRNA profiles serve as novel biomarkers for HBV infection and diagnosis of HBV-positive hepatocarcinoma. Cancer Res. 2010;70:9798–807.

    Article  CAS  PubMed  Google Scholar 

  50. Xiang M, Zeng Y, Yang R, Xu H, Chen Z, Zhong J, et al. U6 is not a suitable endogenous control for the quantification of circulating microRNAs. Biochem Biophys Res Commun. 2014;454:210–4.

    Article  CAS  PubMed  Google Scholar 

  51. Nagy Á, Lánczky A, Menyhárt O, Győrffy B. Validation of miRNA prognostic power in hepatocellular carcinoma using expression data of independent datasets. Sci Rep. 2018;8:9227.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was financially supported by the Cancer Biology Research Group, Center of Precision Medicine, National Taiwan University, Taipei, Taiwan. The authors thank the National Center for High-performance Computing for computer time and facilities as well as the second Core Lab, Department of Medical Research, National Taiwan University Hospital for providing laboratory facilities. D-LO was supported by National Taiwan University YongLin Institute of Health Scholar.

Funding

This study was supported by the following research grants: NTU-109L901403, NTU- 110L901404 (from Ministry of Education, Taiwan), MOST 106-2314-B-002-229-MY3, MOST 107-3017-F-002-002, MOST 107-2314-B-002-210-MY3, MOST 108-2314-B-002-075-MY3, MOST 108-3017-F-002-004, MOST 109-2634-F-002-043, 109-2314-B-002 -229 -MY3, MOST 110-2634-F-002-044 (from Ministry of Science and Technology, Taiwan), YongLin Chair Grant S-01, (from National Taiwan University), UN108-010, UN109-051 (from National Taiwan University Hospital).

Author information

Author notes

  1. These authors contributed equally: Yu-Yun Shao, Pai-Sheng Chen.

Authors and Affiliations

  1. Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei City, 10055, Taiwan

    Yu-Yun Shao, Bin-Shyun Lee, Ann-Lii Cheng, Chiun Hsu & Da-Liang Ou

  2. Department of Oncology, National Taiwan University Hospital, Taipei City, 10048, Taiwan

    Yu-Yun Shao, Ann-Lii Cheng & Chiun Hsu

  3. National Taiwan University Cancer Center, Taipei City, 10672, Taiwan

    Yu-Yun Shao, Ann-Lii Cheng & Chiun Hsu

  4. Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Tainan City, 70101, Taiwan

    Pai-Sheng Chen

  5. Graduate Institute of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei City, 10048, Taiwan

    Liang-In Lin

  6. Columbia University Vagelos College of Physicians and Surgeons, New York, NY, 10032, USA

    Andrew Ling

  7. Department of Internal Medicine, National Taiwan University Hospital, Taipei City, 10048, Taiwan

    Ann-Lii Cheng

  8. YongLin Institute of Health, National Taiwan University, Taipei City, 10672, Taiwan

    Da-Liang Ou

Authors
  1. Yu-Yun Shao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pai-Sheng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liang-In Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bin-Shyun Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Andrew Ling
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ann-Lii Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chiun Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Da-Liang Ou
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Y-YS and P-SC contributed equally to this work. Study concept and design: D-LO, CH; Methodology and technical support: Y-YS, P-SC, B-SL, and D-LO; Analysis and interpretation of data: Y-YS, P-SC, LL, AL, CH, and D-LO; Writing, review, and/or revision of the manuscript: Y-YS, P-SC, and D-LO; Study supervision: A-LC and CH.

Corresponding author

Correspondence to Da-Liang Ou.

Ethics declarations

Competing interests

A-LC is a consultant for and a member of the speaker’s bureau of Bayer-Schering Pharma. A-LC is a consultant of Novartis, Merck Serono, Eisai, Merck Sharp & Dohme (MSD) Corp., ONXEO, Bayer HealthCare Pharmaceuticals Inc., Bristol-Myers Squibb (BMS) Company, and Ono Pharmaceutical Co., Ltd. A-LC is an Associate Editor of Liver Cancer. CH received research grants from BMS/ONO, Roche, and Ipsen and received honorarium from the following pharmaceutical companies: AstraZeneca, Bayer, BMS/ONO, Eisai, Eli Lilly, Ipsen, Merck Serono, MSD, Novartis, Roche, TTY Biopharm.

Ethics approval and consent to participate

The protocol for the in vivo studies was approved by the Institutional Animal Care and Use Committee of the College of Medicine, National Taiwan University (No. 20130360). All the animal studies were performed according to the criteria outlined in the Guide for the Care and Use of Laboratory Animals prepared by the National Academy of Sciences and published by the National Institutes of Health. We enrolled patients who received sorafenib as the first-line therapy for advanced HCC at NTUH. This study was approved by the Institute Research Ethical Committee of NTUH (No. 201401040RIND).

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shao, YY., Chen, PS., Lin, LI. et al. Low miR-10b-3p associated with sorafenib resistance in hepatocellular carcinoma. Br J Cancer 126, 1806–1814 (2022). https://doi.org/10.1038/s41416-022-01759-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41416-022-01759-w

This article is cited by

Search

Advanced search

Quick links