
FGF21 increases the sensitivity of sorafenib to hepatocellular carcinoma under hypoxia
Ting Zhang, Huiling Shi, Shihui Zhang, Qin Zhu, Mengyuan Qiu, Ashleigh T. Chitakunye, Hanyu Hong, Liaoxin Luo, Yujing Li, Qiuyu Sun, Xiaokun Li, Lin Cai
Malignancy Spectrum ›› 2024, Vol. 1 ›› Issue (2) : 99-112.
FGF21 increases the sensitivity of sorafenib to hepatocellular carcinoma under hypoxia
Background: Hepatocellular carcinoma (HCC) is a common disease in human history and one of the main causes of cancer-related death. Insufficient oxygen supply in the tumor microenvironment forces cancer cells to survive in a mild hypoxia environment. Fibroblast growth factor 21 (FGF21), a member of the FGF family, has become the focus of public attention due to its outstanding achievements in diabetes and lipid lowering. However, the mechanism of FGF21 in HCC remains unclear.
Objective: The aims of this study were to clarify whether or not FGF21 could increase the sensitivity of sorafenib (SORA) to HCC under hypoxia and explore the possible mechanism.
Methods: In this study, by using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide cell viability test, plate clone formation test, western blot analysis, Hoechst/propidium iodide double staining experiment, flow cytometry, quantitative reverse transcription polymerase chain reaction, and subcutaneous tumor transplantation in mice, we studied the effects of recombinant human FGF21 combined with SORA on hepatoma cells in vitro and in vivo. FGF21 could enhance the phosphorylation of mothers against decapentaplegic homolog 3 (Smad3) under anaerobic conditions. When combined with SORA, FGF21 could increase the sensitivity of hepatoma cells to SORA and inhibit the growth and migration of hepatoma cells.
Results: FGF21 may increase the sensitivity of HCC to SORA by enhancing the phosphorylation of Smad3 through the phosphatidylinositol 3-kinase/protein kinase B pathway under hypoxia.
Conclusion: Our study suggested the possibility of combination therapy for SORA and FGF21 on HCC.
FGF21 / sorafenib / drug resistance / hypoxia / Smad3
[1] |
Villanueva A. Hepatocellular carcinoma. N Engl J Med. 2019;380(15):1450-1462.
CrossRef
Google scholar
|
[2] |
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424.
CrossRef
Google scholar
|
[3] |
Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019;16(10):589-604.
CrossRef
Google scholar
|
[4] |
Pawlotsky JM. Pathophysiology of hepatitis C virus infection and related liver disease. Trends Microbiol. 2004;12(2):96-102.
CrossRef
Google scholar
|
[5] |
Trépo C, Chan HLY, Lok A. Hepatitis B virus infection. Lancet. 2014;384(9959):2053-2063.
CrossRef
Google scholar
|
[6] |
Llovet JM, Bruix J. Molecular targeted therapies in hepato-cellular carcinoma. Hepatology. 2008;48(4):1312-1327.
CrossRef
Google scholar
|
[7] |
Guan DX, Shi J, Zhang Y, et al. Sorafenib enriches epithelial cell adhesion molecule-positive tumor initiating cells and exacerbates a subtype of hepatocellular carcinoma through TSC2-AKT cascade. Hepatology. 2015;62(6):1791-1803.
CrossRef
Google scholar
|
[8] |
Negri FV, Dal Bello B, Porta C, et al. Expression of pERK and VEGFR-2 in advanced hepatocellular carcinoma and resistance to sorafenib treatment. Liver Int. 2015;35(8):2001-2008.
CrossRef
Google scholar
|
[9] |
Abdel-Rahman O, Lamarca A. Development of sorafenibrelated side effects in patients diagnosed with advanced hepatocellular carcinoma treated with sorafenib: a systematic-review and meta-analysis of the impact on survival. Expert Rev Gastroenterol Hepatol. 2017;11(1):75-83.
CrossRef
Google scholar
|
[10] |
Mazzoccoli G, Miele L, Oben J, Grieco A, Vinciguerra M. Biology, epidemiology, clinical aspects of hepatocellular carcinoma and the role of sorafenib. Curr Drug Targets. 2016;17(7):783-799.
CrossRef
Google scholar
|
[11] |
Tovar V, Cornella H, Moeini A, et al. Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma. Gut. 2017;66(3):530-540.
CrossRef
Google scholar
|
[12] |
Chen J, Jin R, Zhao J, et al. Potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma. Cancer Lett. 2015;367(1):1-11.
CrossRef
Google scholar
|
[13] |
Kohga K, Takehara T, Tatsumi T, et al. Sorafenib inhibits the shedding of major histocompatibility complex class I-related chain a on hepatocellular carcinoma cells by down-regulating a disintegrin and metalloproteinase. Hepatology. 2010;51(4):1264-1273.
CrossRef
Google scholar
|
[14] |
Chen S, Cao Q, Wen W, Wang H. Targeted therapy for hepatocellular carcinoma: challenges and opportunities. Cancer Lett. 2019;460:1-9.
CrossRef
Google scholar
|
[15] |
Yuen VWH, Wong CCL. Hypoxia-inducible factors and innate immunity in liver cancer. J Clin Invest. 2020;130(10):5052-5062.
CrossRef
Google scholar
|
[16] |
Jungermann K, Kietzmann T. Oxygen: modulator of metabolic zonation and disease of the liver. Hepatology. 2000;31(2):255-260.
CrossRef
Google scholar
|
[17] |
Vaupel P, Höckel M, Mayer A. Detection and characterization of tumor hypoxia using pO2 histography. Antioxid Redox Signal. 2007;9(8):1221-1236.
CrossRef
Google scholar
|
[18] |
Roth KJ, Copple BL. Role of hypoxia-inducible factors in the development of liver fibrosis. Cell Mol Gastroenterol Hepatol. 2015;1(6):589-597.
CrossRef
Google scholar
|
[19] |
Hagiwara S, Kudo M, Nagai T, et al. Activation of JNK and high expression level of CD133 predict a poor response to sorafenib in hepatocellular carcinoma. Br J Cancer. 2012;106(12):1997-2003.
CrossRef
Google scholar
|
[20] |
Lackner MR, Wilson TR, Settleman J. Mechanisms of acquired resistance to targeted cancer therapies. Future Oncol. 2012;8(8):999-1014.
CrossRef
Google scholar
|
[21] |
Bagrodia S, Smeal T, Abraham RT. Mechanisms of intrinsic and acquired resistance to kinase-targeted therapies. Pigm Cell Melanoma Res. 2012;25(6):819-831.
CrossRef
Google scholar
|
[22] |
Bottsford-Miller JN, Coleman RL, Sood AK. Resistance and escape from antiangiogenesis therapy: clinical implications and future strategies. J Clin Oncol. 2012;30(32):4026-4034.
CrossRef
Google scholar
|
[23] |
Chen W, Xiao W, Zhang K, et al. Activation of c-Jun predicts a poor response to sorafenib in hepatocellular carcinoma: preliminary clinical evidence. Sci Rep. 2016;6:22976.
CrossRef
Google scholar
|
[24] |
Zhang X, Yeung DCY, Karpisek M, et al. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes. 2008;57(5):1246-1253.
CrossRef
Google scholar
|
[25] |
Mraz M, Bartlova M, Lacinova Z, et al. Serum concentrations and tissue expression of a novel endocrine regulator fibroblast growth factor-21 in patients with type 2 diabetes and obesity. Clin Endocrinol. 2009;71(3):369-375.
CrossRef
Google scholar
|
[26] |
Singhal G, Kumar G, Chan S, et al. Deficiency of fibroblast growth factor 21 (FGF21) promotes hepatocellular carcinoma (HCC) in mice on a long term obesogenic diet. Mol Metab. 2018;13:56-66.
CrossRef
Google scholar
|
[27] |
Wang H, Xiao Y, Fu L, et al. High-level expression and purification of soluble recombinant FGF21 protein by SUMO fusion in Escherichia coli. BMC Biotechnol. 2010;10:14.
CrossRef
Google scholar
|
[28] |
Prasad S, Gupta SC, Tyagi AK. Reactive oxygen species (ROS) and cancer: role of antioxidative nutraceuticals. Cancer Lett. 2017;387:95-105.
CrossRef
Google scholar
|
[29] |
Millet C, Zhang YE. Roles of Smad3 in TGF-β signaling during carcinogenesis. Crit Rev Eukaryot Gene Expr. 2007;17(4):281-293.
CrossRef
Google scholar
|
[30] |
Xie Y, Shi X, Sheng K, et al. PI3K/Akt signaling transduction pathway, erythropoiesis and glycolysis in hypoxia. Mol Med Rep. 2018;19(2):783-791.
|
[31] |
Liu CY, Chen KF, Chen PJ. Treatment of liver cancer. Cold Spring Harbor Perspect Med. 2015;5(9):a021535.
CrossRef
Google scholar
|
[32] |
Xia S, Pan Y, Liang Y, Xu J, Cai X. The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma. EBioMedicine. 2020;51:102610.
CrossRef
Google scholar
|
[33] |
Cabral LKD, Tiribelli C, Sukowati CHC. Sorafenib resistance in hepatocellular carcinoma: the relevance of genetic heterogeneity. Cancers. 2020;12(6):1576.
CrossRef
Google scholar
|
[34] |
Geng L, Lam KSL, Xu A. The therapeutic potential of FGF21 in metabolic diseases: from bench to clinic. Nat Rev Endocrinol. 2020;16(11):654-667.
CrossRef
Google scholar
|
[35] |
Lin Z, Tian H, Lam KSL, et al. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab. 2013;17(5):779-789.
CrossRef
Google scholar
|
[36] |
Huang X, Yu C, Jin C, et al. Forced expression of hepatocyte-specific fibroblast growth factor 21 delays initiation of chemically induced hepatocarcinogenesis. Mol Carcinog. 2006;45(12):934-942.
CrossRef
Google scholar
|
[37] |
Chen J, Gingold JA, Su X. Immunomodulatory TGF-β signaling in hepatocellular carcinoma. Trends Mol Med. 2019;25(11):1010-1023.
CrossRef
Google scholar
|
[38] |
Zhao Y, Ma J, Fan Y, et al. TGF-β transactivates EGFR and facilitates breast cancer migration and invasion through canonical Smad3 and ERK/Sp1 signaling pathways. Mol Oncol. 2018;12(3):305-321.
CrossRef
Google scholar
|
[39] |
Zhai B, Jiang X, He C, et al. Arsenic trioxide potentiates the anti-cancer activities of sorafenib against hepatocellular carcinoma by inhibiting Akt activation. Tumor Biol. 2015;36(4):2323-2334.
CrossRef
Google scholar
|
[40] |
Schmitz KJ, Wohlschlaeger J, Lang H, et al. Activation of the ERK and AKT signalling pathway predicts poor prognosis in hepatocellular carcinoma and ERK activation in cancer tissue is associated with hepatitis C virus infection. J Hepatol. 2008;48(1):83-90.
CrossRef
Google scholar
|
/
〈 |
|
〉 |