Abstract:Objective: To investigate the effect of gender on endoplasmic reticulumstress(ERstress) and apoptosis signals in patients with hepatocellular carcinoma. Methods: Clinical data was collected and retrospectively analyzed from 80 routine hepatocellular carcinoma(HCC) patients, including 40 male and 40 female. Normal liver parenchymal tissues were obtained as controls from 10 Chinese patients with hemangioma.The clinical typing of tumors was determined according to the TNM classification system. The histological grade of tumor differentiation was evaluated by the Edmondson grading system and liver function was assessed by ChildPugh score system. Characteristics of ERstress and apoptosis signal in patients and controls were analyzed by Western blotting. Results: The levels of ERstress signal factors including glucose regulated protein 78(GRP78),GRP94,spliced X boxbinding protein 1(sXBP1), activating transcription factor 6(ATF6),inositol requiring enzyme 1(IRE1α),C/EBP homologous protein(CHOP) were elevated significantly compared with control(P<0.05). Meanwhile, the level of Caspase3 was increased in HCC patients.The clinic features,such as stage, HBV infection, liver cirrhosis and Child grade had on obvious effect on ERstress signal.Only had age affected on GRP78 levels rather than other ERstress signal factors. Interestingly,the levels of sXBP1, ATF6, CHOP and Caspase3 elevated significantly, while GRP78 level reduced in male patients compared with those of the female(P<0.05). ATF6 was also reduced significantly in poorlydifferentiated patients(P<0.05).Further studies indicated that differentiation had no effect on ERstress and apoptosis signals. Conclusion: ERstress and apoptosis signals were induced and GRP78 level was increased in male HCC patients. These results provided a preliminary data for personalized therapy based on gender.
[1]Duffy AG,Greten TF.Liver cancer: Regorafenib as secondline therapy in hepatocellular carcinoma\[J\].Nat Rev Gastroenterol Hepatol,2017,14(3):141-142.[2]Li CL,Yeh KH,Liu WH, et al.Elevated p53 promotes the processing of miR18a to decrease estrogen receptoralpha in female hepatocellular carcinoma\[J\].Int J Cancer,2015, 136(4):761-770.[3]Li T,Qin LX,Gong X,et al.Clinical characteristics, outcome, and risk factors for early and late intrahepatic recurrence of female patients after curative resection of hepatocellular carcinoma\[J\].Surgery,2014,156(3):651-660.[4]Zou X, Qu Z,Fang Y,et al. Endoplasmic reticulum stress mediates sulforaphaneinduced apoptosis of HepG2 human hepatocellular carcinoma cells\[J\].Mol Med Rep,2017,15(1): 331-338.[5]Zhong J,Xiu P,Dong X,et al.Meloxicam combined with sorafenib synergistically inhibits tumor growth of human hepatocellular carcinoma cells via ER stressrelated apoptosis\[J\]. Oncol Rep,2015,34(4):2142-2150.[6]Yang N,Fu Y,Zhang H,et al.LincRNAp21 activates endoplasmic reticulum stress and inhibits hepatocellular carcinoma\[J\].Oncotarget,2015,6(29):28151-28163.[7]Han H,Hu J,Lau MY,et al.Altered methylation and expression of ERassociated degradation factors in longterm alcohol and constitutive ER stressinduced murine hepatic tumors\[J\]. Front Genet,2013,4:224.[8]Wang Q,Yu T,Yuan Y,et al.Sorafenib reduces hepatic infiltrated regulatory T cells in hepatocellular carcinoma patients by suppressing TGFβ signal\[J\].J Surg Oncol, 2013,107(4):422-427.[9]Kao E, Shinohara M,Feng M,et al.Human immunodeficiency virus protease inhibitors modulate Ca2+ homeostasis and potentiate alcoholic stress and injury in mice and primary mouse and human hepatocytes\[J\].Hepatology,2012,56(2):594-604.[10]Gao J,Jiang Z,Wang S,et al. Endoplasmic reticulum stress of Kupffer cells involved in the conversion of natural regulatory T cells to Th17 cells in liver ischemiareperfusion injury\[J\].J Gastroenterol Hepatol,2016,31(4):883-889.[11]Yang Y,Wang G,He J,et al.Gender differences in colorectal cancer survival: A metaanalysis\[J\].Int J Cancer,2017.doi:10.1002/ijc.30827.\[Epub ahead of print\][12]Isla D,Majem M,Vinolas N,et al.A consensus statement on the gender perspective in lung cancer\[J\].Clin Transl Oncol,2017,19(5):527-535.[13]Lucca I,Klatte T,Fajkovic H,et al.Gender differences in incidence and outcomes of urothelial and kidney cancer\[J\].Nat Rev Urol,2015,12(10):585-592.[14]Jung EM, An BS, Choi KC,et al.Apoptosis and endoplasmic reticulum stressrelated genes were regulated by estrogen and progesterone in the uteri of calbindinD(9k) and D(28k) knockout mice\[J\].J Cell Biochem,2012,113(1):194-203.[15]Shuda M, Kondoh N, Imazeki N,et al.Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: a possible involvement of the ER stress pathway in hepatocarcinogenesis\[J\].J Hepatol,2003,38(5):605-614.