Antitumor Effects and Mechanisms of Metabolic Syndrome Medications on Hepatocellular Carcinoma

References

• Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN Estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249. doi:10.3322/caac.21660
   PubMed Web of Science ®Google Scholar
• 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. doi:10.3322/caac.21492
   PubMed Web of Science ®Google Scholar
• Llovet JM, Kelley RK, Villanueva A, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7(1):6. doi:10.1038/s41572-020-00240-3
   PubMed Web of Science ®Google Scholar
• Zhang G, Li R, Deng Y, Zhao L. Conditional survival of patients with hepatocellular carcinoma: results from the surveillance, epidemiology, and end results registry. Expert Rev Gastroenterol Hepatol. 2018;12(5):515–523. doi:10.1080/17474124.2018.1453806
   PubMed Web of Science ®Google Scholar
• Altekruse SF, Henley SJ, Cucinelli JE, McGlynn KA. Changing hepatocellular carcinoma incidence and liver cancer mortality rates in the United States. Am J Gastroenterol. 2014;109(4):542–553. doi:10.1038/ajg.2014.11
   PubMed Web of Science ®Google Scholar
• Xu L, Kim Y, Spolverato G, Gani F, Pawlik TM. Racial disparities in treatment and survival of patients with hepatocellular carcinoma in the United States. Hepatobiliary Surg Nutr. 2016;5(1):43–52. doi:10.3978/j.issn.2304-3881.2015.08.05
   PubMed Web of Science ®Google Scholar
• Tseng TC, Liu CJ, Yang HC, et al. High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load. Gastroenterology. 2012;142(5):1140–1149e3; quiz e13–4. doi:10.1053/j.gastro.2012.02.007
   Web of Science ®Google Scholar
• Ikeda K, Saitoh S, Arase Y, et al. Effect of interferon therapy on hepatocellular carcinogenesis in patients with chronic hepatitis type C: a long-term observation study of 1643 patients using statistical bias correction with proportional hazard analysis. Hepatology. 1999;29(4):1124–1130. doi:10.1002/hep.510290439
   PubMed Web of Science ®Google Scholar
• Carrat F, Fontaine H, Dorival C, et al. Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study. Lancet. 2019;393(10179):1453–1464. doi:10.1016/S0140-6736(18)32111-1
   PubMed Web of Science ®Google Scholar
• Cho HJ, Cheong JY. Role of immune cells in patients with hepatitis B Virus-related hepatocellular carcinoma. Int J Mol Sci. 2021;22(15):1. doi:10.3390/ijms22158011
   Web of Science ®Google Scholar
• Niu ZS, Niu XJ, Wang WH. Genetic alterations in hepatocellular carcinoma: an update. World J Gastroenterol. 2016;22(41):9069–9095. doi:10.3748/wjg.v22.i41.9069
   PubMed Web of Science ®Google Scholar
• Nagaoki Y, Hyogo H, Aikata H, et al. Recent trend of clinical features in patients with hepatocellular carcinoma. Hepatol Res. 2012;42(4):368–375. doi:10.1111/j.1872-034X.2011.00929.x
   PubMed Web of Science ®Google Scholar
• Nishikawa H, Osaki Y. Non-B, non-C hepatocellular carcinoma (review). Int J Oncol. 2013;43(5):1333–1342. doi:10.3892/ijo.2013.2061
   PubMed Web of Science ®Google Scholar
• Zhang W, He H, Zang M, et al. Genetic features of aflatoxin-associated hepatocellular carcinoma. Gastroenterology. 2017;153(1):249–262 e2. doi:10.1053/j.gastro.2017.03.024
   PubMed Web of Science ®Google Scholar
• Huang DQ, Singal AG, Kono Y, Tan DJH, El-Serag HB, Loomba R. Changing global epidemiology of liver cancer from 2010 to 2019: NASH is the fastest growing cause of liver cancer. Cell Metab. 2022;34(7):969–977e2. doi:10.1016/j.cmet.2022.05.003
   PubMed Web of Science ®Google Scholar
• Oura K, Takuma K, Nakahara M, et al. Clinical characteristics of hepatocellular carcinoma for the past 15 years. J Kagawa Phys Assoc. 2021;57:10–19.
   Google Scholar
• Kudo M, Kawamura Y, Hasegawa K, et al. Management of hepatocellular carcinoma in japan: JSH consensus statements and recommendations 2021 update. Liver Cancer. 2021;10(3):181–223. doi:10.1159/000514174
   PubMed Web of Science ®Google Scholar
• European Association for the Study of the Liver. Electronic address eee, European Association for the study of the L. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69(1):182–236. doi:10.1016/j.jhep.2018.03.019
   PubMed Web of Science ®Google Scholar
• Noto H, Goto A, Tsujimoto T, Noda M. Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis. PLoS One. 2012;7(3):e33411. doi:10.1371/journal.pone.0033411
   PubMed Web of Science ®Google Scholar
• Kasuga M, Ueki K, Tajima N, et al. Report of the Japan Diabetes Society/Japanese Cancer Association Joint Committee on diabetes and cancer. Cancer Sci. 2013;104(7):965–976. doi:10.1111/cas.12203
   PubMed Web of Science ®Google Scholar
• Tadic M, Cuspidi C, Belyavskiy E, Grassi G. Intriguing relationship between antihypertensive therapy and cancer. Pharmacol Res. 2019;141:501–511. doi:10.1016/j.phrs.2019.01.037
   PubMed Web of Science ®Google Scholar
• Lee MMY, Docherty KF, Sattar N, et al. Renin-angiotensin system blockers, risk of SARS-CoV-2 infection and outcomes from CoViD-19: systematic review and meta-analysis. Eur Heart J Cardiovasc Pharmacother. 2022;8(2):165–178. doi:10.1093/ehjcvp/pvaa138
   PubMed Web of Science ®Google Scholar
• Morale MG, Tamura RE, Rubio IGS. Metformin and Cancer hallmarks: molecular mechanisms in thyroid, prostate and head and neck cancer models. Biomolecules. 2022;12(3):1. doi:10.3390/biom12030357
   Web of Science ®Google Scholar
• Ye J, Qi L, Chen K, et al. Metformin induces TPC-1 cell apoptosis through endoplasmic reticulum stress-associated pathways in vitro and in vivo. Int J Oncol. 2019;55(1):331–339. doi:10.3892/ijo.2019.4820
   PubMed Web of Science ®Google Scholar
• Amable G, Martinez-Leon E, Picco ME, et al. Metformin inhibits beta-catenin phosphorylation on Ser-552 through an AMPK/PI3K/Akt pathway in colorectal cancer cells. Int J Biochem Cell Biol. 2019;112:88–94. doi:10.1016/j.biocel.2019.05.004
   PubMed Web of Science ®Google Scholar
• Almaimani RA, Aslam A, Ahmad J, et al. In vivo and in vitro enhanced tumoricidal effects of metformin, active vitamin D3, and 5-fluorouracil triple therapy against colon cancer by modulating the PI3K/Akt/PTEN/mTOR network. Cancers. 2022;14(6):1. doi:10.3390/cancers14061538
   Web of Science ®Google Scholar
• Ren D, Qin G, Zhao J, et al. Metformin activates the STING/IRF3/IFN-beta pathway by inhibiting AKT phosphorylation in pancreatic cancer. Am J Cancer Res. 2020;10(9):2851–2864.
   PubMed Web of Science ®Google Scholar
• Tang G, Guo J, Zhu Y, et al. Metformin inhibits ovarian cancer via decreasing H3K27 trimethylation. Int J Oncol. 2018;52(6):1899–1911. doi:10.3892/ijo.2018.4343
   PubMed Web of Science ®Google Scholar
• Pfister D, Nunez NG, Pinyol R, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature. 2021;592(7854):450–456. doi:10.1038/s41586-021-03362-0
   PubMed Web of Science ®Google Scholar
• Pinter M, Pinato DJ, Ramadori P, Heikenwalder M. NASH and hepatocellular carcinoma: immunology and immunotherapy. Clin Cancer Res. 2022;2022. doi:10.1158/1078-0432.CCR-21-1258
   Google Scholar
• Must A, Spadano J, Coakley EH, Field AE, Colditz G, Dietz WH. The disease burden associated with overweight and obesity. JAMA. 1999;282(16):1523–1529. doi:10.1001/jama.282.16.1523
   PubMed Web of Science ®Google Scholar
• Zunica ERM, Heintz EC, Axelrod CL, Kirwan JP. Obesity Management in the primary prevention of hepatocellular carcinoma. Cancers. 2022;14(16). doi:10.3390/cancers14164051
   PubMed Web of Science ®Google Scholar
• Lauby-Secretan B, Scoccianti C, Loomis D, et al. Body fatness and cancer--viewpoint of the IARC working group. N Engl J Med. 2016;375(8):794–798. doi:10.1056/NEJMsr1606602
   PubMed Web of Science ®Google Scholar
• Godoy-Matos AF, Silva Junior WS, Valerio CM. NAFLD as a continuum: from obesity to metabolic syndrome and diabetes. Diabetol Metab Syndr. 2020;12:60. doi:10.1186/s13098-020-00570-y
   PubMed Web of Science ®Google Scholar
• Ye J, Wu Y, Li F, et al. Effect of orlistat on liver fat content in patients with nonalcoholic fatty liver disease with obesity: assessment using magnetic resonance imaging-derived proton density fat fraction. Therap Adv Gastroenterol. 2019;12:1756284819879047. doi:10.1177/1756284819879047
   Web of Science ®Google Scholar
• Kojima M, Takahashi H, Kuwashiro T, et al. Glucagon-like peptide-1 receptor agonist prevented the progression of hepatocellular carcinoma in a mouse model of nonalcoholic steatohepatitis. Int J Mol Sci. 2020;21(16). doi:10.3390/ijms21165722
   Web of Science ®Google Scholar
• Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Hypertension. 2018;71(6):e13–e115. doi:10.1161/HYP.0000000000000065
   PubMed Web of Science ®Google Scholar
• Zhao YC, Zhao GJ, Chen Z, She ZG, Cai J, Li H. Nonalcoholic fatty liver disease: an emerging driver of hypertension. Hypertension. 2020;75(2):275–284. doi:10.1161/HYPERTENSIONAHA.119.13419
   PubMed Web of Science ®Google Scholar
• Lorbeer R, Bayerl C, Auweter S, et al. Association between MRI-derived hepatic fat fraction and blood pressure in participants without history of cardiovascular disease. J Hypertens. 2017;35(4):737–744. doi:10.1097/HJH.0000000000001245
   PubMed Web of Science ®Google Scholar
• Bonnet F, Gastaldelli A, Pihan-le Bars F, et al. Gamma-glutamyltransferase, fatty liver index and hepatic insulin resistance are associated with incident hypertension in two longitudinal studies. J Hypertens. 2017;35(3):493–500. doi:10.1097/HJH.0000000000001204
   PubMed Web of Science ®Google Scholar
• Zhou K, Cen J. The fatty liver index (FLI) and incident hypertension: a longitudinal study among Chinese population. Lipids Health Dis. 2018;17(1):214. doi:10.1186/s12944-018-0858-6
   PubMed Web of Science ®Google Scholar
• Sung KC, Wild SH, Byrne CD. Development of new fatty liver, or resolution of existing fatty liver, over five years of follow-up, and risk of incident hypertension. J Hepatol. 2014;60(5):1040–1045. doi:10.1016/j.jhep.2014.01.009
   PubMed Web of Science ®Google Scholar
• Lonardo A, Nascimbeni F, Mantovani A, Targher G. Hypertension, diabetes, atherosclerosis and NASH: cause or consequence? J Hepatol. 2018;68(2):335–352. doi:10.1016/j.jhep.2017.09.021
   PubMed Web of Science ®Google Scholar
• Oikonomou D, Georgiopoulos G, Katsi V, et al. Non-alcoholic fatty liver disease and hypertension: coprevalent or correlated? Eur J Gastroenterol Hepatol. 2018;30(9):979–985. doi:10.1097/MEG.0000000000001191
   PubMed Web of Science ®Google Scholar
• Houghton D, Zalewski P, Hallsworth K, et al. The degree of hepatic steatosis associates with impaired cardiac and autonomic function. J Hepatol. 2019;70(6):1203–1213. doi:10.1016/j.jhep.2019.01.035
   PubMed Web of Science ®Google Scholar
• Satou R, Penrose H, Navar LG. Inflammation as a regulator of the renin-angiotensin system and blood pressure. Curr Hypertens Rep. 2018;20(12):100. doi:10.1007/s11906-018-0900-0
   PubMed Web of Science ®Google Scholar
• Meex RCR, Watt MJ. Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance. Nat Rev Endocrinol. 2017;13(9):509–520. doi:10.1038/nrendo.2017.56
   PubMed Web of Science ®Google Scholar
• Nunes KP, de Oliveira AA, Mowry FE, Biancardi VC. Targeting toll-like receptor 4 signalling pathways: can therapeutics pay the toll for hypertension? Br J Pharmacol. 2019;176(12):1864–1879. doi:10.1111/bph.14438
   PubMed Web of Science ®Google Scholar
• Sinn DH, Kang D, Jang HR, et al. Development of chronic kidney disease in patients with non-alcoholic fatty liver disease: a cohort study. J Hepatol. 2017;67(6):1274–1280. doi:10.1016/j.jhep.2017.08.024
   PubMed Web of Science ®Google Scholar
• Cheng JW, Zhu L, Gu MJ, Song ZM. Meta analysis of propranolol effects on gastrointestinal hemorrhage in cirrhotic patients. World J Gastroenterol. 2003;9(8):1836–1839. doi:10.3748/wjg.v9.i8.1836
   PubMed Web of Science ®Google Scholar
• Kim G, Kim J, Lim YL, Kim MY, Baik SK. Renin-angiotensin system inhibitors and fibrosis in chronic liver disease: a systematic review. Hepatol Int. 2016;10(5):819–828. doi:10.1007/s12072-016-9705-x
   PubMed Web of Science ®Google Scholar
• Yokohama S, Yoneda M, Haneda M, et al. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology. 2004;40(5):1222–1225. doi:10.1002/hep.20420
   PubMed Web of Science ®Google Scholar
• Goh GB, Pagadala MR, Dasarathy J, et al. Renin-angiotensin system and fibrosis in non-alcoholic fatty liver disease. Liver Int. 2015;35(3):979–985. doi:10.1111/liv.12611
   PubMed Web of Science ®Google Scholar
• Barone M, Viggiani MT, Losurdo G, Principi M, Leo AD. Systematic review: renin-angiotensin system inhibitors in chemoprevention of hepatocellular carcinoma. World J Gastroenterol. 2019;25(20):2524–2538. doi:10.3748/wjg.v25.i20.2524
   PubMed Web of Science ®Google Scholar
• Kim KM, Roh JH, Lee S, Yoon JH. Do renin-angiotensin system inhibitors reduce risk for hepatocellular carcinoma?: a nationwide nested case-control study. Clin Res Hepatol Gastroenterol. 2021;45(4):101510. doi:10.1016/j.clinre.2020.07.015
   PubMed Web of Science ®Google Scholar
• Pinter M, Weinmann A, Worns MA, et al. Use of inhibitors of the renin-angiotensin system is associated with longer survival in patients with hepatocellular carcinoma. United European Gastroenterol J. 2017;5(7):987–996. doi:10.1177/2050640617695698
   PubMed Web of Science ®Google Scholar
• Facciorusso A, Del Prete V, Crucinio N, et al. Angiotensin receptor blockers improve survival outcomes after radiofrequency ablation in hepatocarcinoma patients. J Gastroenterol Hepatol. 2015;30(11):1643–1650. doi:10.1111/jgh.12988
   PubMed Web of Science ®Google Scholar
• Ho CM, Lee CH, Lee MC, et al. Comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in chemoprevention of hepatocellular carcinoma: a nationwide high-risk cohort study. BMC Cancer. 2018;18(1):401. doi:10.1186/s12885-018-4292-y
   PubMed Web of Science ®Google Scholar
• Hagberg KW, Sahasrabuddhe VV, McGlynn KA, Jick SS. Does Angiotensin-converting enzyme inhibitor and beta-blocker use reduce the risk of primary liver cancer? A case-control study using the U.K. clinical practice research datalink. Pharmacotherapy. 2016;36(2):187–195. doi:10.1002/phar.1704
   PubMed Web of Science ®Google Scholar
• Walker AJ, West J, Grainge MJ, Card TR. Angiotensin converting enzyme inhibitors and hepatocellular carcinoma incidence in the general practice research database. Cancer Causes Control. 2011;22(12):1743–1747. doi:10.1007/s10552-011-9837-1
   PubMed Web of Science ®Google Scholar
• Kaibori M, Ishizaki M, Matsui K, Kitade H, Matsui Y, Kwon AH. Evaluation of metabolic factors on the prognosis of patients undergoing resection of hepatocellular carcinoma. J Gastroenterol Hepatol. 2011;26(3):536–543. doi:10.1111/j.1440-1746.2010.06439.x
   PubMed Web of Science ®Google Scholar
• Yoshiji H, Noguchi R, Toyohara M, et al. Combination of vitamin K2 and angiotensin-converting enzyme inhibitor ameliorates cumulative recurrence of hepatocellular carcinoma. J Hepatol. 2009;51(2):315–321. doi:10.1016/j.jhep.2009.04.011
   PubMed Web of Science ®Google Scholar
• Yoshiji H, Noguchi R, Ikenaka Y, et al. Soluble VEGF receptor-2 may be a predictive marker of anti-angiogenic therapy with clinically available safe agents. Oncol Lett. 2011;2(1):69–73. doi:10.3892/ol.2010.196
   PubMed Web of Science ®Google Scholar
• Yoshiji H, Noguchi R, Ikenaka Y, et al. Combination of branched-chain amino acids and angiotensin-converting enzyme inhibitor suppresses the cumulative recurrence of hepatocellular carcinoma: a randomized control trial. Oncol Rep. 2011;26(6):1547–1553. doi:10.3892/or.2011.1433
   PubMed Web of Science ®Google Scholar
• Udumyan R, Montgomery S, Duberg AS, et al. Beta-adrenergic receptor blockers and liver cancer mortality in a national cohort of hepatocellular carcinoma patients. Scand J Gastroenterol. 2020;55(5):597–605. doi:10.1080/00365521.2020.1762919
   PubMed Web of Science ®Google Scholar
• Nkontchou G, Aout M, Mahmoudi A, et al. Effect of long-term propranolol treatment on hepatocellular carcinoma incidence in patients with HCV-associated cirrhosis. Cancer Prev Res. 2012;5(8):1007–1014. doi:10.1158/1940-6207.CAPR-11-0450
   PubMed Web of Science ®Google Scholar
• Suna N, Ozer Etik D, Ocal S, Selcuk H. Effect of propranolol treatment on the incidence of hepatocellular carcinoma in patients waiting for liver transplant with cirrhosis: a retrospective, surveillance study in a tertiary center. Exp Clin Transplant. 2019;17(5):632–637. doi:10.6002/ect.2018.0321
   PubMed Web of Science ®Google Scholar
• Chang PY, Chung CH, Chang WC, et al. The effect of propranolol on the prognosis of hepatocellular carcinoma: a nationwide population-based study. PLoS One. 2019;14(5):e0216828. doi:10.1371/journal.pone.0216828
   PubMed Web of Science ®Google Scholar
• Kim TW, Kim HJ, Chon CU, et al. Is there any vindication for low dose nonselective beta-blocker medication in patients with liver cirrhosis? Clin Mol Hepatol. 2012;18(2):203–212. doi:10.3350/cmh.2012.18.2.203
   PubMedGoogle Scholar
• Oura K, Tadokoro T, Fujihara S, et al. Telmisartan inhibits hepatocellular carcinoma cell proliferation in vitro by inducing cell cycle arrest. Oncol Rep. 2017;38(5):2825–2835. doi:10.3892/or.2017.5977
   PubMed Web of Science ®Google Scholar
• Santhekadur PK, Akiel M, Emdad L, et al. Staphylococcal nuclease domain containing-1 (SND1) promotes migration and invasion via angiotensin II type 1 receptor (AT1R) and TGFbeta signaling. FEBS Open Bio. 2014;4:353–361. doi:10.1016/j.fob.2014.03.012
   PubMed Web of Science ®Google Scholar
• Cook JL, Zhang Z, Re RN. In vitro evidence for an intracellular site of angiotensin action. Circ Res. 2001;89(12):1138–1146. doi:10.1161/hh2401.101270
   PubMed Web of Science ®Google Scholar
• Fan F, Tian C, Tao L, et al. Candesartan attenuates angiogenesis in hepatocellular carcinoma via downregulating AT1R/VEGF pathway. Biomed Pharmacother. 2016;83:704–711. doi:10.1016/j.biopha.2016.07.039
   PubMed Web of Science ®Google Scholar
• Tamaki Y, Nakade Y, Yamauchi T, et al. Angiotensin II type 1 receptor antagonist prevents hepatic carcinoma in rats with nonalcoholic steatohepatitis. J Gastroenterol. 2013;48(4):491–503. doi:10.1007/s00535-012-0651-7
   PubMed Web of Science ®Google Scholar
• Yoshiji H, Yoshii J, Ikenaka Y, et al. Suppression of the renin-angiotensin system attenuates vascular endothelial growth factor-mediated tumor development and angiogenesis in murine hepatocellular carcinoma cells. Int J Oncol. 2002;20(6):1227–1231.
   PubMed Web of Science ®Google Scholar
• Yoshiji H, Kuriyama S, Kawata M, et al. The angiotensin-I-converting enzyme inhibitor perindopril suppresses tumor growth and angiogenesis: possible role of the vascular endothelial growth factor. Clin Cancer Res. 2001;7(4):1073–1078.
   PubMed Web of Science ®Google Scholar
• Yoshiji H, Noguchi R, Kaji K, et al. Attenuation of insulin-resistance-based hepatocarcinogenesis and angiogenesis by combined treatment with branched-chain amino acids and angiotensin-converting enzyme inhibitor in obese diabetic rats. J Gastroenterol. 2010;45(4):443–450. doi:10.1007/s00535-009-0158-z
   PubMed Web of Science ®Google Scholar
• Noguchi R, Yoshiji H, Kuriyama S, et al. Combination of interferon-beta and the angiotensin-converting enzyme inhibitor, perindopril, attenuates murine hepatocellular carcinoma development and angiogenesis. Clin Cancer Res. 2003;9(16 Pt 1):6038–6045.
   PubMed Web of Science ®Google Scholar
• Noguchi R, Yoshiji H, Ikenaka Y, et al. Dual blockade of angiotensin-II and aldosterone suppresses the progression of a non-diabetic rat model of steatohepatitis. Hepatol Res. 2013;43(7):765–774. doi:10.1111/hepr.12008
   PubMed Web of Science ®Google Scholar
• Saber S, Mahmoud AAA, Goda R, Helal NS, El-Ahwany E, Abdelghany RH. Perindopril, fosinopril and losartan inhibited the progression of diethylnitrosamine-induced hepatocellular carcinoma in mice via the inactivation of nuclear transcription factor kappa-B. Toxicol Lett. 2018;295:32–40. doi:10.1016/j.toxlet.2018.05.036
   PubMed Web of Science ®Google Scholar
• Saber S, Mahmoud A, Helal N, El-Ahwany E, Abdelghany R. Liver protective effects of renin-angiotensin system inhibition have no survival benefits in hepatocellular carcinoma induced by repetitive administration of diethylnitrosamine in mice. Open Access Maced J Med Sci. 2018;6(6):955–960. doi:10.3889/oamjms.2018.167
   PubMedGoogle Scholar
• Mansour MA, Al-Ismaeel H, Al-Rikabi AC, Al-Shabanah OA. Comparison of angiotensin converting enzyme inhibitors and angiotensin II type 1 receptor blockade for the prevention of premalignant changes in the liver. Life Sci. 2011;89(5–6):188–194. doi:10.1016/j.lfs.2011.06.002
   PubMed Web of Science ®Google Scholar
• Nasr M, Selima E, Hamed O, Kazem A. Targeting different angiogenic pathways with combination of curcumin, leflunomide and perindopril inhibits diethylnitrosamine-induced hepatocellular carcinoma in mice. Eur J Pharmacol. 2014;723:267–275. doi:10.1016/j.ejphar.2013.11.022
   PubMed Web of Science ®Google Scholar
• Yanase K, Yoshiji H, Ikenaka Y, et al. Synergistic inhibition of hepatocellular carcinoma growth and hepatocarcinogenesis by combination of 5-fluorouracil and angiotensin-converting enzyme inhibitor via anti-angiogenic activities. Oncol Rep. 2007;17(2):441–446.
   PubMed Web of Science ®Google Scholar
• Otsuka M, Kato N, Shao RX, et al. Vitamin K2 inhibits the growth and invasiveness of hepatocellular carcinoma cells via protein kinase A activation. Hepatology. 2004;40(1):243–251. doi:10.1002/hep.20260
   PubMed Web of Science ®Google Scholar
• Kakizaki S, Sohara N, Sato K, et al. Preventive effects of vitamin K on recurrent disease in patients with hepatocellular carcinoma arising from hepatitis C viral infection. J Gastroenterol Hepatol. 2007;22(4):518–522. doi:10.1111/j.1440-1746.2007.04844.x
   PubMed Web of Science ®Google Scholar
• Yoshiji H, Kuriyama S, Noguchi R, et al. Amelioration of carcinogenesis and tumor growth in the rat liver by combination of vitamin K2 and angiotensin-converting enzyme inhibitor via anti-angiogenic activities. Oncol Rep. 2006;15(1):155–159.
   PubMed Web of Science ®Google Scholar
• Yoshiji H, Kuriyama S, Noguchi R, et al. Combination of vitamin K2 and the angiotensin-converting enzyme inhibitor, perindopril, attenuates the liver enzyme-altered preneoplastic lesions in rats via angiogenesis suppression. J Hepatol. 2005;42(5):687–693. doi:10.1016/j.jhep.2004.12.025
   PubMed Web of Science ®Google Scholar
• Yoshiji H, Noguchi R, Kuriyama S, Yoshii J, Ikenaka Y. Combination of interferon and angiotensin-converting enzyme inhibitor, perindopril, suppresses liver carcinogenesis and angiogenesis in mice. Oncol Rep. 2005;13(3):491–495.
   PubMed Web of Science ®Google Scholar
• Srivastava SP, Goodwin JE. Cancer biology and prevention in diabetes. Cells. 2020;9(6). doi:10.3390/cells9061380
   Web of Science ®Google Scholar
• Tanase DM, Gosav EM, Costea CF, et al. The Intricate relationship between Type 2 Diabetes Mellitus (T2DM), Insulin Resistance (IR), and Nonalcoholic Fatty Liver Disease (NAFLD). J Diabetes Res. 2020;2020:3920196. doi:10.1155/2020/3920196
   PubMed Web of Science ®Google Scholar
• Jarvis H, Craig D, Barker R, et al. Metabolic risk factors and incident advanced liver disease in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of population-based observational studies. PLoS Med. 2020;17(4):e1003100. doi:10.1371/journal.pmed.1003100
   PubMed Web of Science ®Google Scholar
• Pitisuttithum P, Chan WK, Piyachaturawat P, et al. Predictors of advanced fibrosis in elderly patients with biopsy-confirmed nonalcoholic fatty liver disease: the GOASIA study. BMC Gastroenterol. 2020;20(1):88. doi:10.1186/s12876-020-01240-z
   PubMed Web of Science ®Google Scholar
• Ballestri S, Zona S, Targher G, et al. Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis. J Gastroenterol Hepatol. 2016;31(5):936–944. doi:10.1111/jgh.13264
   PubMed Web of Science ®Google Scholar
• Brouwers M, Simons N, Stehouwer CDA, Isaacs A. Non-alcoholic fatty liver disease and cardiovascular disease: assessing the evidence for causality. Diabetologia. 2020;63(2):253–260. doi:10.1007/s00125-019-05024-3
   PubMed Web of Science ®Google Scholar
• Koo BK, Allison MA, Criqui MH, Denenberg JO, Wright CM. The association between liver fat and systemic calcified atherosclerosis. J Vasc Surg. 2020;71(1):204–211 e4. doi:10.1016/j.jvs.2019.03.044
   PubMed Web of Science ®Google Scholar
• Fujiwara N, Qian T, Koneru B, Hoshida Y. Omics-derived hepatocellular carcinoma risk biomarkers for precision care of chronic liver diseases. Hepatol Res. 2020;50(7):817–830. doi:10.1111/hepr.13506
   PubMed Web of Science ®Google Scholar
• Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R. Diabetes and cancer. Endocr Relat Cancer. 2009;16(4):1103–1123. doi:10.1677/ERC-09-0087
   PubMed Web of Science ®Google Scholar
• Abudawood M. Diabetes and cancer: a comprehensive review. J Res Med Sci. 2019;24:94. doi:10.4103/jrms.JRMS_242_19
   PubMed Web of Science ®Google Scholar
• Shebl FM, Andreotti G, Rashid A, et al. Diabetes in relation to biliary tract cancer and stones: a population-based study in Shanghai, China. Br J Cancer. 2010;103(1):115–119. doi:10.1038/sj.bjc.6605706
   PubMed Web of Science ®Google Scholar
• Waters KM, Henderson BE, Stram DO, Wan P, Kolonel LN, Haiman CA. Association of diabetes with prostate cancer risk in the multiethnic cohort. Am J Epidemiol. 2009;169(8):937–945. doi:10.1093/aje/kwp003
   PubMed Web of Science ®Google Scholar
• Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348(17):1625–1638. doi:10.1056/NEJMoa021423
   PubMed Web of Science ®Google Scholar
• Garcia-Jimenez C, Gutierrez-Salmeron M, Chocarro-Calvo A, Garcia-Martinez JM, Castano A, De la Vieja A. From obesity to diabetes and cancer: epidemiological links and role of therapies. Br J Cancer. 2016;114(7):716–722. doi:10.1038/bjc.2016.37
   PubMed Web of Science ®Google Scholar
• Gutierrez-Salmeron M, Chocarro-Calvo A, Garcia-Martinez JM, de la Vieja A, Garcia-Jimenez C. Epidemiological bases and molecular mechanisms linking obesity, diabetes, and cancer. Endocrinol Diabetes Nutr. 2017;64(2):109–117. doi:10.1016/j.endinu.2016.10.005
   PubMed Web of Science ®Google Scholar
• Ohkuma T, Peters SAE, Woodward M. Sex differences in the association between diabetes and cancer: a systematic review and meta-analysis of 121 cohorts including 20 million individuals and one million events. Diabetologia. 2018;61(10):2140–2154. doi:10.1007/s00125-018-4664-5
   PubMed Web of Science ®Google Scholar
• El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology. 2004;126(2):460–468. doi:10.1053/j.gastro.2003.10.065
   PubMed Web of Science ®Google Scholar
• Shi T, Kobara H, Oura K, Masaki T. Mechanisms underlying hepatocellular carcinoma progression in patients with type 2 diabetes. J Hepatocell Carcinoma. 2021;8:45–55. doi:10.2147/JHC.S274933
   PubMed Web of Science ®Google Scholar
• Streba LA, Vere CC, Rogoveanu I, Streba CT. Nonalcoholic fatty liver disease, metabolic risk factors, and hepatocellular carcinoma: an open question. World J Gastroenterol. 2015;21(14):4103–4110. doi:10.3748/wjg.v21.i14.4103
   PubMed Web of Science ®Google Scholar
• Hamouda HA, Mansour SM, Elyamany MF. Vitamin D combined with pioglitazone mitigates type-2 diabetes-induced hepatic injury through targeting inflammation, apoptosis, and oxidative stress. Inflammation. 2022;45(1):156–171. doi:10.1007/s10753-021-01535-7
   PubMed Web of Science ®Google Scholar
• Zhang Y, Wang H, Zhang L, Yuan Y, Yu D. Codonopsis lanceolata polysaccharide CLPS alleviates high fat/high sucrose diet-induced insulin resistance via anti-oxidative stress. Int J Biol Macromol. 2020;145:944–949. doi:10.1016/j.ijbiomac.2019.09.185
   PubMed Web of Science ®Google Scholar
• Ponziani FR, Bhoori S, Castelli C, et al. Hepatocellular carcinoma is associated with gut microbiota profile and inflammation in nonalcoholic fatty liver disease. Hepatology. 2019;69(1):107–120. doi:10.1002/hep.30036
   PubMed Web of Science ®Google Scholar
• Gurung M, Li Z, You H, et al. Role of gut microbiota in type 2 diabetes pathophysiology. EBioMedicine. 2020;51:102590. doi:10.1016/j.ebiom.2019.11.051
   PubMed Web of Science ®Google Scholar
• Kawaguchi T, Nakano D, Okamura S, et al. Spontaneous regression of hepatocellular carcinoma with reduction in angiogenesis-related cytokines after treatment with sodium-glucose cotransporter 2 inhibitor in a cirrhotic patient with diabetes mellitus. Hepatol Res. 2019;49(4):479–486. doi:10.1111/hepr.13247
   PubMed Web of Science ®Google Scholar
• Yoo J, Jeong IK, Ahn KJ, Chung HY, Hwang YC. Fenofibrate, a PPARalpha agonist, reduces hepatic fat accumulation through the upregulation of TFEB-mediated lipophagy. Metabolism. 2021;120:154798. doi:10.1016/j.metabol.2021.154798
   PubMed Web of Science ®Google Scholar
• Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia. 2009;52(9):1766–1777. doi:10.1007/s00125-009-1440-6
   PubMed Web of Science ®Google Scholar
• Hsieh MC, Lee TC, Cheng SM, Tu ST, Yen MH, Tseng CH. The influence of type 2 diabetes and glucose-lowering therapies on cancer risk in the Taiwanese. Exp Diabetes Res. 2012;2012:413782. doi:10.1155/2012/413782
   PubMedGoogle Scholar
• Hemkens LG, Grouven U, Bender R, et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia. 2009;52(9):1732–1744. doi:10.1007/s00125-009-1418-4
   PubMed Web of Science ®Google Scholar
• Jonasson JM, Ljung R, Talback M, Haglund B, Gudbjornsdottir S, Steineck G. Insulin glargine use and short-term incidence of malignancies-a population-based follow-up study in Sweden. Diabetologia. 2009;52(9):1745–1754. doi:10.1007/s00125-009-1444-2
   PubMed Web of Science ®Google Scholar
• Fagot JP, Blotiere PO, Ricordeau P, Weill A, Alla F, Allemand H. Does insulin glargine increase the risk of cancer compared with other basal insulins?: a French nationwide cohort study based on national administrative databases. Diabetes Care. 2013;36(2):294–301. doi:10.2337/dc12-0506
   PubMed Web of Science ®Google Scholar
• But A, De Bruin ML, Bazelier MT, et al. Cancer risk among insulin users: comparing analogues with human insulin in the CARING five-country cohort study. Diabetologia. 2017;60(9):1691–1703. doi:10.1007/s00125-017-4312-5
   PubMed Web of Science ®Google Scholar
• Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330(7503):1304–1305. doi:10.1136/bmj.38415.708634.F7
   PubMed Web of Science ®Google Scholar
• Donadon V, Balbi M, Mas MD, Casarin P, Zanette G. Metformin and reduced risk of hepatocellular carcinoma in diabetic patients with chronic liver disease. Liver Int. 2010;30(5):750–758. doi:10.1111/j.1478-3231.2010.02223.x
   PubMed Web of Science ®Google Scholar
• Hassan MM, Curley SA, Li D, et al. Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma. Cancer. 2010;116(8):1938–1946. doi:10.1002/cncr.24982
   PubMed Web of Science ®Google Scholar
• Lai SW, Chen PC, Liao KF, Muo CH, Lin CC, Sung FC. Risk of hepatocellular carcinoma in diabetic patients and risk reduction associated with anti-diabetic therapy: a population-based cohort study. Am J Gastroenterol. 2012;107(1):46–52. doi:10.1038/ajg.2011.384
   PubMed Web of Science ®Google Scholar
• Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Anti-diabetic medications and the risk of hepatocellular cancer: a systematic review and meta-analysis. Am J Gastroenterol. 2013;108(6):881–91; quiz 892. doi:10.1038/ajg.2013.5
   PubMed Web of Science ®Google Scholar
• Zhou YY, Zhu GQ, Wang Y, et al. Systematic review with network meta-analysis: statins and risk of hepatocellular carcinoma. Oncotarget. 2016;7(16):21753–21762. doi:10.18632/oncotarget.7832
   PubMed Web of Science ®Google Scholar
• Tsilidis KK, Capothanassi D, Allen NE, et al. Metformin does not affect cancer risk: a cohort study in the U.K. Clinical practice research datalink analyzed like an intention-to-treat trial. Diabetes Care. 2014;37(9):2522–2532. doi:10.2337/dc14-0584
   PubMed Web of Science ®Google Scholar
• Florentin M, Kostapanos MS, Papazafiropoulou AK. Role of dipeptidyl peptidase 4 inhibitors in the new era of antidiabetic treatment. World J Diabetes. 2022;13(2):85–96. doi:10.4239/wjd.v13.i2.85
   PubMed Web of Science ®Google Scholar
• Yin R, Xu Y, Wang X, Yang L, Zhao D. Role of dipeptidyl peptidase 4 inhibitors in antidiabetic treatment. Molecules. 2022;27(10). doi:10.3390/molecules27103055
   Web of Science ®Google Scholar
• Nagel AK, Ahmed-Sarwar N, Werner PM, Cipriano GC, Van Manen RP, Brown JE. Dipeptidyl peptidase-4 inhibitor-associated pancreatic carcinoma: a review of the FAERS database. Ann Pharmacother. 2016;50(1):27–31. doi:10.1177/1060028015610123
   PubMed Web of Science ®Google Scholar
• Zhao M, Chen J, Yuan Y, et al. Dipeptidyl peptidase-4 inhibitors and cancer risk in patients with type 2 diabetes: a meta-analysis of randomized clinical trials. Sci Rep. 2017;7(1):8273. doi:10.1038/s41598-017-07921-2
   PubMed Web of Science ®Google Scholar
• Overbeek JA, Bakker M, van der Heijden A, van Herk-sukel MPP, Herings RMC, Nijpels G. Risk of dipeptidyl peptidase-4 (DPP-4) inhibitors on site-specific cancer: a systematic review and meta-analysis. Diabetes Metab Res Rev. 2018;34(5):e3004. doi:10.1002/dmrr.3004
   PubMed Web of Science ®Google Scholar
• Hsu WH, Sue SP, Liang HL, et al. Dipeptidyl peptidase 4 inhibitors decrease the risk of hepatocellular carcinoma in patients with chronic hepatitis c infection and type 2 diabetes mellitus: a nationwide study in Taiwan. Front Public Health. 2021;9:711723. doi:10.3389/fpubh.2021.711723
   PubMed Web of Science ®Google Scholar
• Yen FS, Wei JC, Yip HT, Hwu CM, Hou MC, Hsu CC. Dipeptidyl peptidase-4 inhibitors may accelerate cirrhosis decompensation in patients with diabetes and liver cirrhosis: a nationwide population-based cohort study in Taiwan. Hepatol Int. 2021;15(1):179–190. doi:10.1007/s12072-020-10122-1
   PubMed Web of Science ®Google Scholar
• Zou H, Zhou B, Xu G. SGLT2 inhibitors: a novel choice for the combination therapy in diabetic kidney disease. Cardiovasc Diabetol. 2017;16(1):65. doi:10.1186/s12933-017-0547-1
   PubMed Web of Science ®Google Scholar
• Ferrannini E, Solini A. SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects. Nat Rev Endocrinol. 2012;8(8):495–502. doi:10.1038/nrendo.2011.243
   PubMed Web of Science ®Google Scholar
• Tang H, Dai Q, Shi W, Zhai S, Song Y, Han J. SGLT2 inhibitors and risk of cancer in type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials. Diabetologia. 2017;60(10):1862–1872. doi:10.1007/s00125-017-4370-8
   PubMed Web of Science ®Google Scholar
• Dicembrini I, Nreu B, Mannucci E, Monami M. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors and cancer: a meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2019;21(8):1871–1877. doi:10.1111/dom.13745
   PubMed Web of Science ®Google Scholar
• Kuchay MS, Krishan S, Mishra SK, et al. Effect of empagliflozin on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease: a randomized controlled trial (E-LIFT trial). Diabetes Care. 2018;41(8):1801–1808. doi:10.2337/dc18-0165
   PubMed Web of Science ®Google Scholar
• Ito D, Shimizu S, Inoue K, et al. Comparison of ipragliflozin and pioglitazone effects on nonalcoholic fatty liver disease in patients with type 2 diabetes: a randomized, 24-week, open-label, active-controlled Trial. Diabetes Care. 2017;40(10):1364–1372. doi:10.2337/dc17-0518
   PubMed Web of Science ®Google Scholar
• Shibuya T, Fushimi N, Kawai M, et al. Luseogliflozin improves liver fat deposition compared to metformin in type 2 diabetes patients with non-alcoholic fatty liver disease: a prospective randomized controlled pilot study. Diabetes Obes Metab. 2018;20(2):438–442. doi:10.1111/dom.13061
   PubMed Web of Science ®Google Scholar
• Abd El-Fattah EE, Zakaria AY. Metformin modulate immune fitness in hepatocellular carcinoma: molecular and cellular approach. Int Immunopharmacol. 2022;109:108889. doi:10.1016/j.intimp.2022.108889
   PubMed Web of Science ®Google Scholar
• Vacante F, Senesi P, Montesano A, Paini S, Luzi L, Terruzzi I. Metformin counteracts HCC progression and metastasis enhancing KLF6/p21 expression and downregulating the IGF axis. Int J Endocrinol. 2019;2019:7570146. doi:10.1155/2019/7570146
   PubMed Web of Science ®Google Scholar
• Sun R, Zhai R, Ma C, Miao W. Combination of aloin and metformin enhances the antitumor effect by inhibiting the growth and invasion and inducing apoptosis and autophagy in hepatocellular carcinoma through PI3K/AKT/mTOR pathway. Cancer Med. 2020;9(3):1141–1151. doi:10.1002/cam4.2723
   PubMed Web of Science ®Google Scholar
• Bhat M, Yanagiya A, Graber T, et al. Metformin requires 4E-BPs to induce apoptosis and repress translation of Mcl-1 in hepatocellular carcinoma cells. Oncotarget. 2017;8(31):50542–50556. doi:10.18632/oncotarget.10671
   PubMedGoogle Scholar
• Sun Y, Tao C, Huang X, et al. Metformin induces apoptosis of human hepatocellular carcinoma HepG2 cells by activating an AMPK/p53/miR-23a/FOXA1 pathway. Onco Targets Ther. 2016;9:2845–2853. doi:10.2147/OTT.S99770
   PubMed Web of Science ®Google Scholar
• Miyoshi H, Kato K, Iwama H, et al. Effect of the anti-diabetic drug metformin in hepatocellular carcinoma in vitro and in vivo. Int J Oncol. 2014;45(1):322–332. doi:10.3892/ijo.2014.2419
   PubMed Web of Science ®Google Scholar
• Fujita K, Iwama H, Miyoshi H, et al. Diabetes mellitus and metformin in hepatocellular carcinoma. World J Gastroenterol. 2016;22(27):6100–6113. doi:10.3748/wjg.v22.i27.6100
   PubMed Web of Science ®Google Scholar
• Wabitsch S, McCallen JD, Kamenyeva O, et al. Metformin treatment rescues CD8(+) T-cell response to immune checkpoint inhibitor therapy in mice with NAFLD. J Hepatol. 2022;77(3):748–760. doi:10.1016/j.jhep.2022.03.010
   PubMed Web of Science ®Google Scholar
• Nishina S, Yamauchi A, Kawaguchi T, et al. Dipeptidyl peptidase 4 inhibitors reduce hepatocellular carcinoma by activating lymphocyte chemotaxis in mice. Cell Mol Gastroenterol Hepatol. 2019;7(1):115–134. doi:10.1016/j.jcmgh.2018.08.008
   PubMed Web of Science ®Google Scholar
• Huang XY, Zhang PF, Wei CY, et al. Circular RNA circMET drives immunosuppression and anti-PD1 therapy resistance in hepatocellular carcinoma via the miR-30-5p/snail/DPP4 axis. Mol Cancer. 2020;19(1):92. doi:10.1186/s12943-020-01213-6
   PubMed Web of Science ®Google Scholar
• Zhong J, Sun P, Xu N, et al. Canagliflozin inhibits p-gp function and early autophagy and improves the sensitivity to the antitumor effect of doxorubicin. Biochem Pharmacol. 2020;175:113856. doi:10.1016/j.bcp.2020.113856
   PubMed Web of Science ®Google Scholar
• Luo J, Sun P, Zhang X, et al. Canagliflozin modulates hypoxia-induced metastasis, angiogenesis and glycolysis by decreasing HIF-1alpha protein synthesis via AKT/mTOR pathway. Int J Mol Sci. 2021;22(24). doi:10.3390/ijms222413336
   Web of Science ®Google Scholar
• Abdel-Rafei MK, Thabet NM, Rashed LA, Moustafa EM. Canagliflozin, a SGLT-2 inhibitor, relieves ER stress, modulates autophagy and induces apoptosis in irradiated HepG2 cells: signal transduction between PI3K/AKT/GSK-3beta/mTOR and Wnt/beta-catenin pathways; in vitro. J Cancer Res Ther. 2021;17(6):1404–1418. doi:10.4103/jcrt.JCRT_963_19
   PubMed Web of Science ®Google Scholar
• Carr RM, Ahima RS. Pathophysiology of lipid droplet proteins in liver diseases. Exp Cell Res. 2016;340(2):187–192. doi:10.1016/j.yexcr.2015.10.021
   PubMed Web of Science ®Google Scholar
• Mashek DG, Khan SA, Sathyanarayan A, Ploeger JM, Franklin MP. Hepatic lipid droplet biology: getting to the root of fatty liver. Hepatology. 2015;62(3):964–967. doi:10.1002/hep.27839
   PubMed Web of Science ®Google Scholar
• Almeda-Valdes P, Altamirano-Barrera A, Mendez-Sanchez N. Insights in non-alcoholic fatty liver disease pathophysiology with lipidomic analyses. Ann Hepatol. 2015;14(4):567–569.
   PubMed Web of Science ®Google Scholar
• Ress C, Kaser S. Mechanisms of intrahepatic triglyceride accumulation. World J Gastroenterol. 2016;22(4):1664–1673. doi:10.3748/wjg.v22.i4.1664
   PubMed Web of Science ®Google Scholar
• Polyzos SA, Kountouras J, Mantzoros CS. Adipokines in nonalcoholic fatty liver disease. Metabolism. 2016;65(8):1062–1079. doi:10.1016/j.metabol.2015.11.006
   PubMed Web of Science ®Google Scholar
• Polyzos SA, Aronis KN, Kountouras J, Raptis DD, Vasiloglou MF, Mantzoros CS. Circulating leptin in non-alcoholic fatty liver disease: a systematic review and meta-analysis. Diabetologia. 2016;59(1):30–43. doi:10.1007/s00125-015-3769-3
   PubMed Web of Science ®Google Scholar
• Haggstrom C, Jonsson H, Bjorge T, et al. Linear age-course effects on the associations between body mass index, triglycerides, and female breast and male liver cancer risk: an internal replication study of 800,000 individuals. Int J Cancer. 2020;146(1):58–67. doi:10.1002/ijc.32240
   PubMed Web of Science ®Google Scholar
• Cho Y, Cho EJ, Yoo JJ, et al. Association between lipid profiles and the incidence of hepatocellular carcinoma: a nationwide population-based study. Cancers. 2021;13(7). doi:10.3390/cancers13071599
   Web of Science ®Google Scholar
• Yi SW, Kim SH, Han KJ, Yi JJ, Ohrr H. Higher cholesterol levels, not statin use, are associated with a lower risk of hepatocellular carcinoma. Br J Cancer. 2020;122(5):630–633. doi:10.1038/s41416-019-0691-3
   PubMed Web of Science ®Google Scholar
• Sinn DH, Kang D, Cho SJ, et al. Risk of hepatocellular carcinoma in individuals without traditional risk factors: development and validation of a novel risk score. Int J Epidemiol. 2020;49(5):1562–1571. doi:10.1093/ije/dyaa089
   PubMed Web of Science ®Google Scholar
• Nderitu P, Bosco C, Garmo H, et al. The association between individual metabolic syndrome components, primary liver cancer and cirrhosis: a study in the Swedish AMORIS cohort. Int J Cancer. 2017;141(6):1148–1160. doi:10.1002/ijc.30818
   PubMed Web of Science ®Google Scholar
• Lee TY, Wu JC, Yu SH, Lin JT, Wu MS, Wu CY. The occurrence of hepatocellular carcinoma in different risk stratifications of clinically noncirrhotic nonalcoholic fatty liver disease. Int J Cancer. 2017;141(7):1307–1314. doi:10.1002/ijc.30784
   PubMed Web of Science ®Google Scholar
• Goh MJ, Sinn DH, Kim S, et al. Statin use and the risk of hepatocellular carcinoma in patients with chronic hepatitis B. Hepatology. 2020;71(6):2023–2032. doi:10.1002/hep.30973
   PubMed Web of Science ®Google Scholar
• Wu CY, Lin JT, Ho HJ, et al. Association of nucleos(t)ide analogue therapy with reduced risk of hepatocellular carcinoma in patients with chronic hepatitis B: a nationwide cohort study. Gastroenterology. 2014;147(1):143–151 e5. doi:10.1053/j.gastro.2014.03.048
   PubMed Web of Science ®Google Scholar
• Tan Y, Zhang X, Zhang W, et al. The influence of metabolic syndrome on the risk of hepatocellular carcinoma in patients with chronic hepatitis B infection in Mainland China. Cancer Epidemiol Biomarkers Prev. 2019;28(12):2038–2046. doi:10.1158/1055-9965.EPI-19-0303
   PubMed Web of Science ®Google Scholar
• Arain SQ, Talpur FN, Channa NA, Ali MS, Afridi HI. Serum lipid profile as a marker of liver impairment in hepatitis B cirrhosis patients. Lipids Health Dis. 2017;16(1):51. doi:10.1186/s12944-017-0437-2
   PubMed Web of Science ®Google Scholar
• Chrostek L, Supronowicz L, Panasiuk A, Cylwik B, Gruszewska E, Flisiak R. The effect of the severity of liver cirrhosis on the level of lipids and lipoproteins. Clin Exp Med. 2014;14(4):417–421. doi:10.1007/s10238-013-0262-5
   PubMed Web of Science ®Google Scholar
• Bassani L, Fernandes SA, Raimundo FV, Harter DL, Gonzalez MC, Marroni CA. LIPID PROFILE OF CIRRHOTIC PATIENTS AND ITS ASSOCIATION WITH PROGNOSTIC SCORES: a cross-sectional study. Arq Gastroenterol. 2015;52(3):210–215. doi:10.1590/S0004-28032015000300011
   PubMedGoogle Scholar
• Tauseef A, Zafar M, Rashid B, et al. Correlation of fasting lipid profile in patients with chronic liver disease: a descriptive cross-sectional study in tertiary care hospital. Cureus. 2020;12(10):e11019. doi:10.7759/cureus.11019
   PubMed Web of Science ®Google Scholar
• Nielsen SF, Nordestgaard BG, Bojesen SE. Statin use and reduced cancer-related mortality. N Engl J Med. 2012;367(19):1792–1802. doi:10.1056/NEJMoa1201735
   PubMed Web of Science ®Google Scholar
• Tsan YT, Lee CH, Wang JD, Chen PC. Statins and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection. J Clin Oncol. 2012;30(6):623–630. doi:10.1200/JCO.2011.36.0917
   PubMed Web of Science ®Google Scholar
• Hsiang JC, Wong GL, Tse YK, Wong VW, Yip TC, Chan HL. Statin and the risk of hepatocellular carcinoma and death in a hospital-based hepatitis B-infected population: a propensity score landmark analysis. J Hepatol. 2015;63(5):1190–1197. doi:10.1016/j.jhep.2015.07.009
   PubMed Web of Science ®Google Scholar
• Tsan YT, Lee CH, Ho WC, Lin MH, Wang JD, Chen PC. Statins and the risk of hepatocellular carcinoma in patients with hepatitis C virus infection. J Clin Oncol. 2013;31(12):1514–1521. doi:10.1200/JCO.2012.44.6831
   PubMed Web of Science ®Google Scholar
• Butt AA, Yan P, Bonilla H, et al. Effect of addition of statins to antiviral therapy in hepatitis C virus-infected persons: results from ERCHIVES. Hepatology. 2015;62(2):365–374. doi:10.1002/hep.27835
   PubMed Web of Science ®Google Scholar
• Mohanty A, Tate JP, Garcia-Tsao G. Statins are associated with a decreased risk of decompensation and death in veterans with hepatitis C-related compensated cirrhosis. Gastroenterology. 2016;150(2):430–40 e1. doi:10.1053/j.gastro.2015.10.007
   PubMed Web of Science ®Google Scholar
• Li X, Sheng L, Liu L, Hu Y, Chen Y, Lou L. Statin and the risk of hepatocellular carcinoma in patients with hepatitis B virus or hepatitis C virus infection: a meta-analysis. BMC Gastroenterol. 2020;20(1):98. doi:10.1186/s12876-020-01222-1
   PubMed Web of Science ®Google Scholar
• Wong YJ, Qiu TY, Ng GK, Zheng Q, Teo EK. Efficacy and safety of statin for hepatocellular carcinoma prevention among chronic liver disease patients: a systematic review and meta-analysis. J Clin Gastroenterol. 2021;55(7):615–623. doi:10.1097/MCG.0000000000001478
   PubMed Web of Science ®Google Scholar
• Friedman GD, Achacoso N, Fireman B, Habel LA. Statins and reduced risk of liver cancer: evidence for confounding. J Natl Cancer Inst. 2016;108(10). doi:10.1093/jnci/djw109
   Google Scholar
• Jeong GH, Lee KH, Kim JY, et al. Effect of statin on cancer incidence: an umbrella systematic review and meta-analysis. J Clin Med. 2019;8(6). doi:10.3390/jcm8060819
   Web of Science ®Google Scholar
• Emberson JR, Kearney PM; Cholesterol Treatment Trialists C. Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy. PLoS One. 2012;7(1):e29849. doi:10.1371/journal.pone.0029849
   PubMed Web of Science ®Google Scholar
• Konstantinopoulos PA, Karamouzis MV, Papavassiliou AG. Post-translational modifications and regulation of the RAS superfamily of GTPases as anticancer targets. Nat Rev Drug Discov. 2007;6(7):541–555. doi:10.1038/nrd2221
   PubMed Web of Science ®Google Scholar
• Alipour Talesh G, Trezeguet V, Merched A. Hepatocellular carcinoma and statins. Biochemistry. 2020;59(37):3393–3400. doi:10.1021/acs.biochem.0c00476
   PubMed Web of Science ®Google Scholar
• Sassano A, Katsoulidis E, Antico G, et al. Suppressive effects of statins on acute promyelocytic leukemia cells. Cancer Res. 2007;67(9):4524–4532. doi:10.1158/0008-5472.CAN-06-3686
   PubMed Web of Science ®Google Scholar
• Rao S, Porter DC, Chen X, Herliczek T, Lowe M, Keyomarsi K. Lovastatin-mediated G1 arrest is through inhibition of the proteasome, independent of hydroxymethyl glutaryl-CoA reductase. Proc Natl Acad Sci USA. 1999;96(14):7797–7802. doi:10.1073/pnas.96.14.7797
   PubMed Web of Science ®Google Scholar
• Rombouts K, Kisanga E, Hellemans K, Wielant A, Schuppan D, Geerts A. Effect of HMG-CoA reductase inhibitors on proliferation and protein synthesis by rat hepatic stellate cells. J Hepatol. 2003;38(5):564–572. doi:10.1016/s0168-8278(03
   PubMed Web of Science ®Google Scholar
• Tatsuta M, Iishi H, Baba M, et al. Suppression by pravastatin, an inhibitor of p21ras isoprenylation, of hepatocarcinogenesis induced by N-nitrosomorpholine in Sprague-Dawley rats. Br J Cancer. 1998;77(4):581–587. doi:10.1038/bjc.1998.94
   PubMed Web of Science ®Google Scholar
• Spampanato C, De Maria S, Sarnataro M, et al. Simvastatin inhibits cancer cell growth by inducing apoptosis correlated to activation of Bax and down-regulation of BCL-2 gene expression. Int J Oncol. 2012;40(4):935–941. doi:10.3892/ijo.2011.1273
   PubMed Web of Science ®Google Scholar
• Kah J, Wustenberg A, Keller AD, et al. Selective induction of apoptosis by HMG-CoA reductase inhibitors in hepatoma cells and dependence on p53 expression. Oncol Rep. 2012;28(3):1077–1083. doi:10.3892/or.2012.1860
   PubMed Web of Science ®Google Scholar
• Weis M, Heeschen C, Glassford AJ, Cooke JP. Statins have biphasic effects on angiogenesis. Circulation. 2002;105(6):739–745. doi:10.1161/hc0602.103393
   PubMed Web of Science ®Google Scholar
• Bayat N, Izadpanah R, Ebrahimi-Barough S, et al. The Anti-angiogenic effect of atorvastatin in glioblastoma spheroids tumor cultured in fibrin gel: in 3D in vitro model. Asian Pac J Cancer Prev. 2018;19(9):2553–2560. doi:10.22034/APJCP.2018.19.9.2553
   PubMedGoogle Scholar
• Relja B, Meder F, Wang M, et al. Simvastatin modulates the adhesion and growth of hepatocellular carcinoma cells via decrease of integrin expression and ROCK. Int J Oncol. 2011;38(3):879–885. doi:10.3892/ijo.2010.892
   PubMed Web of Science ®Google Scholar
• Ridruejo E, Romero-Caimi G, Obregon MJ, Kleiman de Pisarev D, Alvarez L. Potential molecular targets of statins in the prevention of hepatocarcinogenesis. Ann Hepatol. 2018;17(3):490–500. doi:10.5604/01.3001.0011.7394
   PubMed Web of Science ®Google Scholar
• Feng J, Dai W, Mao Y, et al. Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1alpha/PPAR-gamma/PKM2-mediated glycolysis. J Exp Clin Cancer Res. 2020;39(1):24. doi:10.1186/s13046-020-1528-x
   PubMed Web of Science ®Google Scholar
• Zhou TY, Zhuang LH, Hu Y, et al. Inactivation of hypoxia-induced YAP by statins overcomes hypoxic resistance tosorafenib in hepatocellular carcinoma cells. Sci Rep. 2016;6:30483. doi:10.1038/srep30483
   PubMed Web of Science ®Google Scholar
• Chamoto K, Chowdhury PS, Kumar A, et al. Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity. Proc Natl Acad Sci USA. 2017;114(5):E761–E770. doi:10.1073/pnas.1620433114
   PubMed Web of Science ®Google Scholar