代谢性疾病及治疗药物与肝癌的相关性研究进展
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摘要
代谢性疾病与肝癌发病密切相关,其作用机制可能与体内胰岛素抵抗、高血糖、脂肪细胞因子分泌异常、内质网应激、肠道相关菌群失调、血脂异常等因素有关。研究表明治疗代谢性疾病的药物如二甲双胍和阿托伐他汀可以降低肝癌的发病和复发风险。本文就代谢性疾病及治疗药物与肝癌的相关性研究作一综述。
Metabolic diseases are significantly associated with the development of hepatocelluar carcinomas(HCC),and the mechanism may be related to insulin resistance,hyperglycemia,abnormal secretion of adipocyte cytokines,endoplasmic reticulum stress,gut-associated microbiota disorders,dyslipidemia and other factors.Moreover,the therapeutic drugs for metabolic diseases such as metformin and atorvastatin have been reported to reduce the incidence and recurrence risk of HCC.Therefore,we summarizes the research progress in the associations of metabolic diseases and therapeutic drugs with hepatocellular carcinomas.
Metabolic diseases are significantly associated with the development of hepatocelluar carcinomas(HCC),and the mechanism may be related to insulin resistance,hyperglycemia,abnormal secretion of adipocyte cytokines,endoplasmic reticulum stress,gut-associated microbiota disorders,dyslipidemia and other factors.Moreover,the therapeutic drugs for metabolic diseases such as metformin and atorvastatin have been reported to reduce the incidence and recurrence risk of HCC.Therefore,we summarizes the research progress in the associations of metabolic diseases and therapeutic drugs with hepatocellular carcinomas.
引文
[1]Bruix J,Gores GJ,Mazzaferro V.Hepatocellular carcinoma:clinical frontiers and perspectives[J].Gut,2014,63(5):844-855.
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[3]Pais R,Lebray P,Rousseau G,et al.Nonalcoholic fatty liver disease increases the risk of hepatocellular carcinoma in patients with alcohol-associated cirrhosis awaiting liver transplants[J].Clin Gastroenterol Hepatol,2015,13(5):992-999.e2.
[4]Petrick JL,Freedman ND,Demuth J,et al.Obesity,diabetes,serum glucose,and risk of primary liver cancer by birth cohort,race/ethnicity,and sex:multiphasic health checkup study[J].Cancer Epidemiol,2016,42:140-146.
[5]Wang C,Wang X,Gong G,et al.Increased risk of hepatocellular carcinoma in patients with diabetes mellitus:a systematic review and meta-analysis of cohort studies[J].Int J Cancer,2012,130(7):1639-1648.
[6]Simon TG,King LY,Chong DQ,et al.Diabetes,metabolic comorbidities,and risk of hepatocellular carcinoma:results from two prospective cohort studies[J].Hepatology,2018,67(5):1797-1806.
[7]Barth RJ.Insulin resistance,obesity and the metabolic syndrome[J].South Dakota Med J South Dakota Stat Med Assoc,2011,Spec No(22-27):22.
[8]Wang HY,Yang SL,Liang HF,et al.HBx protein promotes oval cell proliferation by up-regulation of cyclin d1 via activation of the MEK/ERK and PI3K/Akt pathways[J].Int J Mol Sci,2014,15(3):3507-3518.
[9]Song MK,Park YK,Ryu JC.Polycyclic aromatic hydrocarbon(PAH)-mediated upregulation of hepatic microRNA-181 family promotes cancer cell migration by targeting MAPK phosphatase-5,regulating the activation of p38 MAPK[J].Toxicol Appl Pharmacol,2013,273(1):130-139.
[10]Ni Z,Wang B,Dai X,et al.HCC cells with high levels of Bcl-2 are resistant to ABT-737 via activation of the ROS-JNK-autophagy pathway[J].Free Rad Biol Med,2014,70(3):194-203.
[11]Samarin J,Laketa V,Malz M,et al.PI3K/AKT/m TOR-dependent stabilization of oncogenic far-upstream element binding proteins in hepatocellular carcinoma cells[J].Hepatology,2016,63(3):813-826.
[12]Zhang CH,Xu GL,Jia WD,et al.Activation of STAT3 signal pathway correlates with twist and E-Cadherin expression in hepatocellular carcinoma and their clinical significance[J].J Surg Res,2010,166(1):236-246.
[13]Ji Y,Wang Z,Li Z,et al.Silencing IGF-II impairs c-myc and N-ras expressions of SMMC-7721 cells via suppressing FAK/PI3K/Akt signaling pathway[J].Cytokine,2017,90:44-53.
[14]Ahmed M.Non-alcoholic fatty liver disease in 2015[J].World J Hepatol,2015,7(11):1450-1459.
[15]Ali Kamkar MM,Ahmad R,Alsmadi O,et al.Insight into the impact of diabetes mellitus on the increased risk of hepatocellular carcinoma:mini-review[J].JDiab Metab Dis,2014,13(1):57.
[16]Wensheng L,Baker SS,Baker RD,et al.Antioxidant mechanisms in nonalcoholic fatty liver disesae[J].Curr Drug Tar,2015,16(12):1301-1314.
[17]Tae YR,Jiyoung P,Philipp ES.Hyperglycemia as a risk factor for cancer progression[J].2014,38(5):330-336.
[18]Singh MK,Das BK,Choudhary S,et al.Diabetes and hepatocellular carcinoma:A pathophysiological link and pharmacological management[J].Biomed Pharma,2018,106:991-1002.
[19]Simone R,Subash CG,Madan MC,et al.Oxidative stress,inflammation,and cancer:How are they linked[J]?Free Rad Biol Med,2010,49(11):1603-1616.
[20]Gan L,Liu Z,Sun C.Obesity linking to hepatocellular carcinoma:a global view[J].Biochim Biophys Acta,2018,1869(2):97-102.
[21]Zhu P,Goh YY,Chin HFA,et al.Angiopoietin-like4:a decade of research[J].Biosci Rep,2012,32(3):211-219.
[22]Polyzos SA,Aronis KN,Kountouras J,et al.Circulating leptin in non-alcoholic fatty liver disease:a systematic review and meta-analysis[J].Diabet,2016,59(1):30.
[23]Nan J,Sun R,Sun Q.Leptin signaling molecular actions and drug target in hepatocellular carcinoma[J].Drug Design Development&Therapy,2014,2014(default):2295-2302.
[24]Nikolaos S,Vassilis P,Yoichi F,et al.Leptin as a critical regulator of hepatocellular carcinoma development through modulation of human telomerase reverse transcriptase[J].BMC Cancer,2010,10(1):442.
[25]Font-Burgada J,Sun B,Karin M.Obesity and cancer:the oil that feeds the flame[J].Cell Metabolism,2016,23(1):48-62.
[26]Polyzos SA,Toulis KA,Goulis DG,et al.Serum total adiponectin in nonalcoholic fatty liver disease:a systematic review and meta-analysis[J].Metab Clin Exp,2011,60(3):313-326.
[27]Sadik NA,Ahmed A,Ahmed S.The significance of serum levels of adiponectin,leptin,and hyaluronic acid in hepatocellular carcinoma of cirrhotic and noncirrhotic patients[J].Hum Exp Toxicol,2012,31(4):311-321.
[28]Adolph TE,Grander C,Grabherr F,et al.Adipokines and non-alcoholic fatty liver disease:multiple interactions[J].Int J Mol Sci,2017,18(8).pii:E1649.
[29]Saxena NK,Fu PP,Nagalingam A,et al.Adiponectin modulates C-jun N-terminal kinase and mammalian target of rapamycin and inhibits hepatocellular carcinoma[J].Gastroenterology,2010,139(5):1762-1773.
[30]Barja-Fernandez S,Moreno-Navarrete JM,Folgueira C,et al.Plasma ANGPTL-4 is associated with obesity and glucose tolerance:cross-sectional and longitudinal findings[J].Mol Nut Food Res,2018,62(10):e1800060.
[31]El-Shal AS,Zidan HE,Rashad NM,et al.Angiopoietin-like protein 3 and 4 expression 4 and their serum levels in hepatocellular carcinoma[J].Cytokine,2017,96(8):75.
[32]La PL,ListìA,Caruso S,et al.Potential role of AN-GPTL4 in the cross talk between metabolism and cancer through PPAR signaling pathway[J].PPAR research,2017,2017(20):8187235.
[33]Wang YX.PPARs:diverse regulators in energy metabolism and metabolic diseases[J].Cell Res,2010,20(2):124-137.
[34]Yoon JC,Chickering TW,Rosen ED,et al.Peroxisome proliferator-activated receptorγtarget gene encoding a novel angiopoietin-related protein associated with adipose differentiation[J].Mol Cell Biol,2000,20(14):5343.
[35]Cubillosruiz JR,Bettigole SE,Glimcher LH.Tumorigenic and immunosuppressive effects of endoplasmic reticulum stress in cancer[J].Cell,2017,168(4):692-706.
[36]Wu Y,Shan B,Dai J,et al.Dual role for inositol-requiring enzyme 1αin promoting the development of hepatocellular carcinoma during diet-induced obesity[J].Hepatology,2018,68(2):533-546.
[37]Tam AB,Hoffmann A,Niwa M.ER stress activates NF-κB by integrating functions of basal IKK activity,IRE1 and PERK[J].Plos One,2012,7(10):e45078.
[38]Nakagawa H,Umemura A,Taniguchi K,et al.ERstress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development[J].Cancer Cell,2014,26(3):331-343.
[39]Yoshimoto S,Loo TM,Atarashi K,et al.Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome[J].Nature,2014,499(7456):97-101.
[40]Loo TM,Kamachi F,Watanabe Y,et al.Gut microbiota promotes obesity-associated liver cancer through PGE2-mediated suppression of antitumor immunity[J].Cancer Dis,2017,7(5):522-538.
[41]Khan S,Jamal S.A study of serological markers and lipid profile in non-alcoholic liver cirrhosis patients[J].Pak J Pharmaceutical Sci,2018,31(1):89.
[42]Liu D,Chi CW,Fu L,et al.Squalene epoxidase drives NAFLD-induced hepatocellular carcinoma and is a pharmaceutical target[J].Sci Transl Med,2018,10(437):eaap9840.
[43]Kaur P,Mittal A,Nayak SK,et al.Current strategies and drug targets in the management of type 2 diabetes mellitus[J].Curr Drug Targets,2018,19(15):1738-1766.
[44]Singh S,Singh PP,Singh AG,et al.Anti-diabetic medications and the risk of hepatocellular cancer:a systematic review and meta-analysis[J].Am J Gastroenterol,2013,108(6):881-891.
[45]Mei ZB,Zhang ZJ,Liu CY,et al.Survival benefits of metformin for colorectal cancer patients with diabetes:a systematic review and meta-analysis[J].Plos One,2014,9(3):e91818.
[46]Mitsuhashi A,Sato Y,Kiyokawa T,et al.Phase IIstudy of medroxyprogesterone acetate plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer[J].Ann Oncol Off JEuro Soc Med Oncol,2015,27(2):262.
[47]Chan K,Kuo C,Hsu J,et al.Metformin confers risk reduction for developing hepatocellular carcinoma recurrence after liver resection[J].Liver Int,2017,37(3):434.
[48]Zhang R,Yao RR,Li JH,et al.Activated hepatic stellate cells secrete periostin to induce stem cell-like phenotype of residual hepatocellular carcinoma cells after heat treatment[J].Sci Rep,2017,7(1):2164.
[49]Zhou X,Chen J,Chen L,et al.Negative regulation of Sirtuin 1 by AMP-activated protein kinase promotes metformin-induced senescence in hepatocellular carcinoma xenografts[J].Cancer Lett,2017,411:1.
[50]Obara A,Fujita Y,Abudukadier A,et al.DEPTOR-related m TOR suppression is involved in metformin's anti-cancer action in human liver cancer cells[J].Bioche Biophysical Res Commu,2015,460(4):1047-1052.
[51]Sun Y,Tao C,Huang X,et al.Metformin induces apoptosis of human hepatocellular carcinoma Hep G2cells by activating an AMPK/p53/miR-23a/FOXA1pathway[J].Onco Ther,2016,9(Issue 1):2845.
[52]Matusewicz L,Meissner J,Toporkiewicz M,et al.The effect of statins on cancer cells-review[J].Tum Biol J Int Soc Oncodevel Biol Med,2015,36(7):4889-4904.
[53]Kim G,Jang SY,Nam CM,et al.Statin use and the risk of hepatocellular carcinoma in patients at high risk:a nationwide nested case-control study[J].JHepatol,2018,68(3):476-484.
[54]Hung MS,Chen IC,Lee CP,et al.Statin improves survival in patients with EGFR-TKI lung cancer:A nationwide population-based study[J].Plos One,2017,12(2):e0171137.
[55]Van RW,Rahal OM,Woodward WA.Effect of statins on breast cancer recurrence and mortality:a review[J].Breast Cancer Targets Ther,2017,9:559.
[56]Nishio T,Taura K,Nakamura N,et al.Impact of statin use on the prognosis of patients with hepatocellular carcinoma undergoing liver resection:a subgroup analysis of patients without chronic hepatitis viral infection[J].Surgery,2017,163(2):264-269.
[57]Ridruejo E,Romero-Caími G,Obregón MJ,et al.Potential molecular targets of statins in the prevention of hepatocarcinogenesis[J].Ann Hepatol,2018,17(3):490.
[58]Ghalali A,Martinrenedo J,Hogberg J,et al.Atorvastatin decreases HBx-induced phospho-Akt in hepatocytes via P2X receptors[J].Mol Cancer Res Mcr,2017,15(6):molcanres.0373.2016.
[59]Li Y,Yu L,Na J,et al.Survival of cancer patients in northeast china:analysis of sampled cancers from population-based cancer registries[J].Cancer Res Treatment Off J Kor Cancer Assoc,2017,49(4):1106-1113.
[60]刘双勇,吴德全.肝癌术后复发转移原因及治疗现状[J].疑难病杂志,2018,17(3):100-103.
[61]Yoshida N,Takayama T,Midorikawa Y,et al.Surgical outcomes in patients with hepatocellular carcinoma associated with metabolic syndrome[J].World J Sur,2015,39(2):471-477.
[62]Gupta A,Das A,Majumder K,et al.Obesity is independently associated with increased risk of hepatocellular cancer-related mortality:A systematic review and meta-analysis[J].Am J Clin Oncol,2018,41(9):874-881.
[63]Su YW,Liu PH,Hsu CY,et al.Prognostic impact of diabetes mellitus on hepatocellular carcinoma:Special emphasis from the BCLC perspective[J].Plos One,2017,12(3):e0174333.
[64]Gao XH,Zhang SS,Chen H,et al.Systemic hepaticdamage index for predicting the prognosis of hepatocellular carcinoma after curative resection[J].Front Physiol,2017,8:480.
[2]Torre LA,Bray F,Siegel RL,et al.Global cancer statistics,2012[J].Ca A Cancer J Clinic,2015,65(2):69-90.
[3]Pais R,Lebray P,Rousseau G,et al.Nonalcoholic fatty liver disease increases the risk of hepatocellular carcinoma in patients with alcohol-associated cirrhosis awaiting liver transplants[J].Clin Gastroenterol Hepatol,2015,13(5):992-999.e2.
[4]Petrick JL,Freedman ND,Demuth J,et al.Obesity,diabetes,serum glucose,and risk of primary liver cancer by birth cohort,race/ethnicity,and sex:multiphasic health checkup study[J].Cancer Epidemiol,2016,42:140-146.
[5]Wang C,Wang X,Gong G,et al.Increased risk of hepatocellular carcinoma in patients with diabetes mellitus:a systematic review and meta-analysis of cohort studies[J].Int J Cancer,2012,130(7):1639-1648.
[6]Simon TG,King LY,Chong DQ,et al.Diabetes,metabolic comorbidities,and risk of hepatocellular carcinoma:results from two prospective cohort studies[J].Hepatology,2018,67(5):1797-1806.
[7]Barth RJ.Insulin resistance,obesity and the metabolic syndrome[J].South Dakota Med J South Dakota Stat Med Assoc,2011,Spec No(22-27):22.
[8]Wang HY,Yang SL,Liang HF,et al.HBx protein promotes oval cell proliferation by up-regulation of cyclin d1 via activation of the MEK/ERK and PI3K/Akt pathways[J].Int J Mol Sci,2014,15(3):3507-3518.
[9]Song MK,Park YK,Ryu JC.Polycyclic aromatic hydrocarbon(PAH)-mediated upregulation of hepatic microRNA-181 family promotes cancer cell migration by targeting MAPK phosphatase-5,regulating the activation of p38 MAPK[J].Toxicol Appl Pharmacol,2013,273(1):130-139.
[10]Ni Z,Wang B,Dai X,et al.HCC cells with high levels of Bcl-2 are resistant to ABT-737 via activation of the ROS-JNK-autophagy pathway[J].Free Rad Biol Med,2014,70(3):194-203.
[11]Samarin J,Laketa V,Malz M,et al.PI3K/AKT/m TOR-dependent stabilization of oncogenic far-upstream element binding proteins in hepatocellular carcinoma cells[J].Hepatology,2016,63(3):813-826.
[12]Zhang CH,Xu GL,Jia WD,et al.Activation of STAT3 signal pathway correlates with twist and E-Cadherin expression in hepatocellular carcinoma and their clinical significance[J].J Surg Res,2010,166(1):236-246.
[13]Ji Y,Wang Z,Li Z,et al.Silencing IGF-II impairs c-myc and N-ras expressions of SMMC-7721 cells via suppressing FAK/PI3K/Akt signaling pathway[J].Cytokine,2017,90:44-53.
[14]Ahmed M.Non-alcoholic fatty liver disease in 2015[J].World J Hepatol,2015,7(11):1450-1459.
[15]Ali Kamkar MM,Ahmad R,Alsmadi O,et al.Insight into the impact of diabetes mellitus on the increased risk of hepatocellular carcinoma:mini-review[J].JDiab Metab Dis,2014,13(1):57.
[16]Wensheng L,Baker SS,Baker RD,et al.Antioxidant mechanisms in nonalcoholic fatty liver disesae[J].Curr Drug Tar,2015,16(12):1301-1314.
[17]Tae YR,Jiyoung P,Philipp ES.Hyperglycemia as a risk factor for cancer progression[J].2014,38(5):330-336.
[18]Singh MK,Das BK,Choudhary S,et al.Diabetes and hepatocellular carcinoma:A pathophysiological link and pharmacological management[J].Biomed Pharma,2018,106:991-1002.
[19]Simone R,Subash CG,Madan MC,et al.Oxidative stress,inflammation,and cancer:How are they linked[J]?Free Rad Biol Med,2010,49(11):1603-1616.
[20]Gan L,Liu Z,Sun C.Obesity linking to hepatocellular carcinoma:a global view[J].Biochim Biophys Acta,2018,1869(2):97-102.
[21]Zhu P,Goh YY,Chin HFA,et al.Angiopoietin-like4:a decade of research[J].Biosci Rep,2012,32(3):211-219.
[22]Polyzos SA,Aronis KN,Kountouras J,et al.Circulating leptin in non-alcoholic fatty liver disease:a systematic review and meta-analysis[J].Diabet,2016,59(1):30.
[23]Nan J,Sun R,Sun Q.Leptin signaling molecular actions and drug target in hepatocellular carcinoma[J].Drug Design Development&Therapy,2014,2014(default):2295-2302.
[24]Nikolaos S,Vassilis P,Yoichi F,et al.Leptin as a critical regulator of hepatocellular carcinoma development through modulation of human telomerase reverse transcriptase[J].BMC Cancer,2010,10(1):442.
[25]Font-Burgada J,Sun B,Karin M.Obesity and cancer:the oil that feeds the flame[J].Cell Metabolism,2016,23(1):48-62.
[26]Polyzos SA,Toulis KA,Goulis DG,et al.Serum total adiponectin in nonalcoholic fatty liver disease:a systematic review and meta-analysis[J].Metab Clin Exp,2011,60(3):313-326.
[27]Sadik NA,Ahmed A,Ahmed S.The significance of serum levels of adiponectin,leptin,and hyaluronic acid in hepatocellular carcinoma of cirrhotic and noncirrhotic patients[J].Hum Exp Toxicol,2012,31(4):311-321.
[28]Adolph TE,Grander C,Grabherr F,et al.Adipokines and non-alcoholic fatty liver disease:multiple interactions[J].Int J Mol Sci,2017,18(8).pii:E1649.
[29]Saxena NK,Fu PP,Nagalingam A,et al.Adiponectin modulates C-jun N-terminal kinase and mammalian target of rapamycin and inhibits hepatocellular carcinoma[J].Gastroenterology,2010,139(5):1762-1773.
[30]Barja-Fernandez S,Moreno-Navarrete JM,Folgueira C,et al.Plasma ANGPTL-4 is associated with obesity and glucose tolerance:cross-sectional and longitudinal findings[J].Mol Nut Food Res,2018,62(10):e1800060.
[31]El-Shal AS,Zidan HE,Rashad NM,et al.Angiopoietin-like protein 3 and 4 expression 4 and their serum levels in hepatocellular carcinoma[J].Cytokine,2017,96(8):75.
[32]La PL,ListìA,Caruso S,et al.Potential role of AN-GPTL4 in the cross talk between metabolism and cancer through PPAR signaling pathway[J].PPAR research,2017,2017(20):8187235.
[33]Wang YX.PPARs:diverse regulators in energy metabolism and metabolic diseases[J].Cell Res,2010,20(2):124-137.
[34]Yoon JC,Chickering TW,Rosen ED,et al.Peroxisome proliferator-activated receptorγtarget gene encoding a novel angiopoietin-related protein associated with adipose differentiation[J].Mol Cell Biol,2000,20(14):5343.
[35]Cubillosruiz JR,Bettigole SE,Glimcher LH.Tumorigenic and immunosuppressive effects of endoplasmic reticulum stress in cancer[J].Cell,2017,168(4):692-706.
[36]Wu Y,Shan B,Dai J,et al.Dual role for inositol-requiring enzyme 1αin promoting the development of hepatocellular carcinoma during diet-induced obesity[J].Hepatology,2018,68(2):533-546.
[37]Tam AB,Hoffmann A,Niwa M.ER stress activates NF-κB by integrating functions of basal IKK activity,IRE1 and PERK[J].Plos One,2012,7(10):e45078.
[38]Nakagawa H,Umemura A,Taniguchi K,et al.ERstress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development[J].Cancer Cell,2014,26(3):331-343.
[39]Yoshimoto S,Loo TM,Atarashi K,et al.Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome[J].Nature,2014,499(7456):97-101.
[40]Loo TM,Kamachi F,Watanabe Y,et al.Gut microbiota promotes obesity-associated liver cancer through PGE2-mediated suppression of antitumor immunity[J].Cancer Dis,2017,7(5):522-538.
[41]Khan S,Jamal S.A study of serological markers and lipid profile in non-alcoholic liver cirrhosis patients[J].Pak J Pharmaceutical Sci,2018,31(1):89.
[42]Liu D,Chi CW,Fu L,et al.Squalene epoxidase drives NAFLD-induced hepatocellular carcinoma and is a pharmaceutical target[J].Sci Transl Med,2018,10(437):eaap9840.
[43]Kaur P,Mittal A,Nayak SK,et al.Current strategies and drug targets in the management of type 2 diabetes mellitus[J].Curr Drug Targets,2018,19(15):1738-1766.
[44]Singh S,Singh PP,Singh AG,et al.Anti-diabetic medications and the risk of hepatocellular cancer:a systematic review and meta-analysis[J].Am J Gastroenterol,2013,108(6):881-891.
[45]Mei ZB,Zhang ZJ,Liu CY,et al.Survival benefits of metformin for colorectal cancer patients with diabetes:a systematic review and meta-analysis[J].Plos One,2014,9(3):e91818.
[46]Mitsuhashi A,Sato Y,Kiyokawa T,et al.Phase IIstudy of medroxyprogesterone acetate plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer[J].Ann Oncol Off JEuro Soc Med Oncol,2015,27(2):262.
[47]Chan K,Kuo C,Hsu J,et al.Metformin confers risk reduction for developing hepatocellular carcinoma recurrence after liver resection[J].Liver Int,2017,37(3):434.
[48]Zhang R,Yao RR,Li JH,et al.Activated hepatic stellate cells secrete periostin to induce stem cell-like phenotype of residual hepatocellular carcinoma cells after heat treatment[J].Sci Rep,2017,7(1):2164.
[49]Zhou X,Chen J,Chen L,et al.Negative regulation of Sirtuin 1 by AMP-activated protein kinase promotes metformin-induced senescence in hepatocellular carcinoma xenografts[J].Cancer Lett,2017,411:1.
[50]Obara A,Fujita Y,Abudukadier A,et al.DEPTOR-related m TOR suppression is involved in metformin's anti-cancer action in human liver cancer cells[J].Bioche Biophysical Res Commu,2015,460(4):1047-1052.
[51]Sun Y,Tao C,Huang X,et al.Metformin induces apoptosis of human hepatocellular carcinoma Hep G2cells by activating an AMPK/p53/miR-23a/FOXA1pathway[J].Onco Ther,2016,9(Issue 1):2845.
[52]Matusewicz L,Meissner J,Toporkiewicz M,et al.The effect of statins on cancer cells-review[J].Tum Biol J Int Soc Oncodevel Biol Med,2015,36(7):4889-4904.
[53]Kim G,Jang SY,Nam CM,et al.Statin use and the risk of hepatocellular carcinoma in patients at high risk:a nationwide nested case-control study[J].JHepatol,2018,68(3):476-484.
[54]Hung MS,Chen IC,Lee CP,et al.Statin improves survival in patients with EGFR-TKI lung cancer:A nationwide population-based study[J].Plos One,2017,12(2):e0171137.
[55]Van RW,Rahal OM,Woodward WA.Effect of statins on breast cancer recurrence and mortality:a review[J].Breast Cancer Targets Ther,2017,9:559.
[56]Nishio T,Taura K,Nakamura N,et al.Impact of statin use on the prognosis of patients with hepatocellular carcinoma undergoing liver resection:a subgroup analysis of patients without chronic hepatitis viral infection[J].Surgery,2017,163(2):264-269.
[57]Ridruejo E,Romero-Caími G,Obregón MJ,et al.Potential molecular targets of statins in the prevention of hepatocarcinogenesis[J].Ann Hepatol,2018,17(3):490.
[58]Ghalali A,Martinrenedo J,Hogberg J,et al.Atorvastatin decreases HBx-induced phospho-Akt in hepatocytes via P2X receptors[J].Mol Cancer Res Mcr,2017,15(6):molcanres.0373.2016.
[59]Li Y,Yu L,Na J,et al.Survival of cancer patients in northeast china:analysis of sampled cancers from population-based cancer registries[J].Cancer Res Treatment Off J Kor Cancer Assoc,2017,49(4):1106-1113.
[60]刘双勇,吴德全.肝癌术后复发转移原因及治疗现状[J].疑难病杂志,2018,17(3):100-103.
[61]Yoshida N,Takayama T,Midorikawa Y,et al.Surgical outcomes in patients with hepatocellular carcinoma associated with metabolic syndrome[J].World J Sur,2015,39(2):471-477.
[62]Gupta A,Das A,Majumder K,et al.Obesity is independently associated with increased risk of hepatocellular cancer-related mortality:A systematic review and meta-analysis[J].Am J Clin Oncol,2018,41(9):874-881.
[63]Su YW,Liu PH,Hsu CY,et al.Prognostic impact of diabetes mellitus on hepatocellular carcinoma:Special emphasis from the BCLC perspective[J].Plos One,2017,12(3):e0174333.
[64]Gao XH,Zhang SS,Chen H,et al.Systemic hepaticdamage index for predicting the prognosis of hepatocellular carcinoma after curative resection[J].Front Physiol,2017,8:480.