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The Mir-30A-5P/CLCF1 Axis Regulates Sorafenib Resistance and Aerobic Glycolysis in Hepatocellular Carcinoma

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The Mir-30A-5P/CLCF1 Axis Regulates Sorafenib Resistance and Aerobic Glycolysis in Hepatocellular Carcinoma Zhang et al. Cell Death and Disease (2020) 11:902 https://doi.org/10.1038/s41419-020-03123-3 Cell Death & Disease ARTICLE Open Access The miR-30a-5p/CLCF1 axis regulates sorafenib resistance and aerobic glycolysis in hepatocellular carcinoma Zhongqiang Zhang1,2,XiaoTan3,JingLuo1, Hongliang Yao 4, Zhongzhou Si1 and Jing-Shan Tong5 Abstract HCC (hepatocellular carcinoma) is a major health threat for the Chinese population and has poor prognosis because of strong resistance to chemotherapy in patients. For instance, a considerable challenge for the treatment of HCC is sorafenib resistance. The aberrant glucose metabolism in cancer cells aerobic glycolysis is associated with resistance to chemotherapeutic agents. Drug-resistance cells and tumors were exposed to sorafenib to establish sorafenib- resistance cell lines and tumors. Western blotting and real-time PCR or IHC staining were used to analyze the level of CLCF1 in the sorafenib resistance cell lines or tumors. The aerobic glycolysis was analyzed by ECAR assay. The mechanism mediating the high expression of CLCF1 in sorafenib-resistant cells and its relationships with miR-130-5p was determined by bioinformatic analysis, dual luciferase reporter assays, real-time PCR, and western blotting. The in vivo effect was evaluated by xenografted with nude mice. The relation of CLCF1 and miR-30a-5p was determined in patients’ samples. In this study, we report the relationship between sorafenib resistance and increased glycolysis in HCC cells. We also show the vital role of CLCF1 in promoting glycolysis by activating PI3K/AKT signaling and its downstream genes, thus participating in glycolysis in sorafenib-resistant HCC cells. Furthermore, we also show that miR-30a-5p directly targets CLCF1 and that sorafenib-mediated suppression of miR-30a-5p results in the upregulation 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; of CLCF1 in HCC cells resistant to sorafenib. We also found that when a cholesterol modified agomiR-30a-5p was delivered systemically to mice harboring sorafenib-resistant HCC tumors, tumor growth decreased significantly. There is an uncharacterized mechanism of biochemical resistance to hormone therapies orchestrated by the miR-30a-5p/ CLCF1 axis to mediate sorafenib resistance and aerobic glycolysis in HCC. Therefore, this study indicates that targeting the miR-30a-5p/CLCF1 axis may hold promise for therapeutic intervention in HCC sorafenib resistance patients. Introduction including resection, ablation, and transplantation, are only On a global scale, HCC (hepatocellular carcinoma) feasible in patients diagnosed in the early stages1,2. The ranks sixth among cancers and is the third leading cause manifestation of HCC is more frequent in cirrhosis and of death due to cancer1. The incidence of this deadly liver dysfunction patients, which limits the interventions disease is still on the rise, and curative treatments, with systemic cytotoxic drugs3,4. HCC at the advanced stage is not amenable to surgery, and the only treatment strategy is chemotherapy5,6. Correspondence: Zhongzhou Si ([email protected]) or Jing- For HCC treatment, conventional chemotherapeutics Shan Tong ([email protected]) fl fi 1 such as doxorubicin and uorouracil are not ef cacious Department of Liver Transplantation, The Second Xiangya Hospital of Central 7,8 South University, 410011 Changsha, Hunan Province, P.R. China and exhibit potent side effects . Significant progress in 2Department of Surgery, University of Pittsburgh School of Medicine, cancer treatment has been achieved with the advent of University of Pittsburgh Medical Center Presbyterian Hospital, Pittsburgh, PA targeted drug therapy and small molecule kinase inhibi- 15213, USA 9,10 Full list of author information is available at the end of the article tors . The only clinical solution currently available for Edited by I. Amelio © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Cell Death Differentiation Association Zhang et al. Cell Death and Disease (2020) 11:902 Page 2 of 14 the treatment of HCC in patients who cannot undergo anticancer therapies based on miRNA are actively being surgery is sorafenib. As an inhibitor of Raf kinase, sor- developed27,28. Additionally, miRNAs also act as impor- afenib inhibits tumor growth by decreasing the activities tant regulators in the Warburg effect (reprogramming of of the B-RAF serine/threonine kinase and RAF-111,12; cellular energy metabolism) and in drug resistance in concurrently, sorafenib can also inhibit tumor growth by cancers29,30. Therefore, miRNA targeting may be a pro- decreasing tumor angiogenesis via the tyrosine kinase mising treatment strategy to interrupt aerobic glycolysis activities of platelet-derived growth factor (PDGF), FMS- in cancer cells as well as in sorafenib-resistant HCC. like tyrosine kinase 3 (FLT-3), Vascular Endothelial In the present study, we identified CLCF1 as a novel Growth Factor 2 (VEGF-2), and -3 receptors13,14. Never- regulator in sustaining sorafenib resistance in HCC theless, HCC exhibits notable resistance to sorafenib, and cells. We further found that CLCF1 acts as a key only one-third of patients with HCC at an advanced stage mediator to orchestrate sorafenib resistance and aero- respond to treatment11,15. Furthermore, the results of bic glycolysis in HCC cells. Mechanistically, upregula- multiple random clinical cases were systematically ana- tion of CLCF1 boosted PI3K/AKT signaling and thus lyzed and revealed an increase in the survival time by only activated its downstream glycolytic genes in sorafenib- 3 months, indicating the urgent need to discover more resistant HCC cells. We further identified CLCF1 as a robust molecular targeted drugs against drug-resistant direct target of miR-30a-5p and revealed that sorafenib tumors and to further conduct in-depth evaluation of the upregulated CLCF1 by downregulating miR-30a-5p. HCC resistance mechanism and improve the sensitivity of Functional studies showed that the miR-30a-5p/CLCF1 HCC to sorafenib. axis plays an important role in regulating both sorafenib Cardiotrophin-like cytokine factor 1 (CLCF1, also resistance and aerobic glycolysis in sorafenib-resistant referred to as BSF-3 or NNT-1) is a cytokine of the IL-6 cells. Taken together, our findings reveal that the miR- family that is secreted in the form of a soluble CRLF1 30a-5p/CLCF1/PI3K/AKT regulatory cascade is part of (cytokine receptor cytokine-like factor 1) complex16,17. an important mechanism of sorafenib resistance and CLCF1 activates the tripartite CNTFR (ciliary neuro- aerobic glycolysis in HCC cells, suggesting that miR- trophic factor receptor), which consists of LIFRβ, gp130, 30a-5p is a promising therapeutic target to reverse and CNTFRα18. The common signaling pathways shared sorafenib resistance in HCC. by CLCF1 and CNTF indicate that the exhaustive eva- luations conducted preclinically and clinically on CNTF Materials and methods may pave a way for the curative ability of CLCF119.In Cell culture vitro studies and animal models of neurodegenerative The human HCC cell lines HepG2 and Huh7 were diseases have demonstrated the significant neurotrophic obtained from American Type Culture Collection (ATCC, activities of CNTF and have encouraged clinical trials in Manassas, VA, USA) and maintained in DMEM (Dul- patients with amyotrophic lateral sclerosis, Huntington’s becco’s modified Eagle’s medium) with streptomycin/ disease, and cases of retinal degeneration20. In addition, penicillin (1%) and fetal bovine serum (FBS, 10%) in a when administered systemically, CNTF leads to remark- humidified atmosphere of 5% CO2 at 37 °C. HepG2-S-R able, unexpected weight loss, thus leading to preclinical and Huh7-S-R, the sorafenib-resistant sublines, were assessments of CNTF in metabolic syndrome models21,22. derived from HepG2 and Huh7 cells as previously When injections of CNTF were given daily, persistent described31. anorexic effects were observed in leptin-deficient, diet- induced obese mice23. The conditions of hyper- HCC specimens and Immunohistochemistry insulinemia and hyperglycemia were reduced due to HCC tumor specimens and paired normal adjacent CNTF, indicating that type II diabetes could benefit and tissues were obtained from Proteo Genex (CA, USA). that leptin resistance could be overcome in obese indivi- EnVision™ Flex target retrieval solution was employed to duals24,25. CNTF is believed to exert both systemic and deparaffinize and unmask epitopes in the samples. central effects because CNTFR is expressed in the region Endogenous peroxidase was blocked by adding 0.3% H2O2 of the brain directing energy balance, in skeletal muscle or hydrogen peroxide for 5 min. This was followed by the and in adipose
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