目的 探讨IL-17RA在人肝细胞癌（hepatocellular carcinoma，HCC）组织中表达情况及其对肝肿瘤切除患者预后的影响，并评价其对HCC细胞株生物学特性的影响。方法 收集163例HCC组织并制成组织芯片，免疫组化染色法检测肿瘤组织中IL-17RA的表达情况，Kaplan-Meier法和Cox回归模型分析患者总生存期的影响因素。采用siRNA瞬时转染高侵袭性肝癌细胞株MHCC-97H和Huh7以下调IL-17RA的表达，用划痕实验、Transwell侵袭实验检测转染前后MHCC-97H和Huh7细胞株迁移、侵袭能力，用CCK8方法检测转染前后奥沙利铂对MHCC-97H和Huh7细胞株的抑制率。结果 肿瘤直径大于10 cm （HR=1.820，P=0.028）、合并癌栓（HR=2.087，P=0.003）以及IL-17RA高表达（HR=1.579，P=0.042）是影响HCC患者术后总生存期的独立危险因素；siRNA瞬时转染下调HCC细胞株MHCC-97H和Huh7的IL-17RA表达后，肿瘤细胞的迁移、侵袭能力明显下降，奥沙利铂对肿瘤细胞的抑制率显著提高。结论 IL-17RA高表达是影响HCC患者术后生存的独立危险因素，抑制其表达可以降低HCC细胞株的迁移、侵袭能力，提高奥沙利铂对肝癌细胞株的抑制率。
Abstract
Objective To evaluate the expression of IL-17RA and its prognostic value for patients with hepatocellular carcinoma (HCC),and to certify it's impact on the biological characteristics of HCC cell lines. Methods Specimens tissue microarray of 163 HCC patients were used in this study.We examined intra-tumoral expression of IL-17RA by immunohistochemical staining.The Kaplan-Meier curve and Cox regression models were used to evaluate the prognostic value of IL-17RA expression for overall survival.The expression of IL-17RA of cell line MHCC-97H and Huh7 was down-regulated by transfected siRNA,the abilities of migration and invasive of MHCC-97H and Huh7 were analyzed by scratch assay and transwell chamber,the inhibition rates of oxaliplatin of tumor cells were analyzed by CCK8 kit. Results High expression of IL-17RA (HR=1.579,P=0.042) combined with tumor diameter more than 10 cm (HR=1.820,P=0.028) and tumor thrombus (HR=2.087,P=0.003)were independent prognostic effectors of overall survival for HCC patients underwent resection.The abilities of migration and invasive of MHCC-97H and Huh7 were decreased after down-regulated the expression of IL-17RA,and the inhibition rate of oxaliplatin on tumor cells was increased after down-regulated the expression of IL-17RA by siRNA. Conclusions High expression of IL-17RA was an independent prognostic effector of the overall survival for HCC patients underwent resection.Down-regulation of IL-17RA of cell line MHCC-97H and Huh7 could decrease its ability of migration and invasive and increase the inhibition rate of oxaliplatin on tumor cells.
关键词
肝细胞癌(HCC) /
IL-17RA /
预后
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Key words
hepatocellular carcinoma (HCC) /
IL-17RA /
prognostic effect
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中图分类号：
R735.7
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参考文献
[1] BRAY F,FERLAY J,SOERJOMATARAM I,et al.Global cancer statistics 2018:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J].CA Cancer J Clin, 2018,68(6):394-424.
[2] EL-KHOUEIRY AB,SANGRO B,YAU T,et al.Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040):an open-label,non-comparative,phase 1/2 dose escalation and expansion trial[J].Lancet,2017,389(10088):2492-2502.
[3] QIN S,BAI Y,LIM HY,et al.Randomized,multicenter,open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia[J].J Clin Oncol,2013,31(28):3501-3508.
[4] HURTADO CG,WAN F,HOUSSEAU F,et al.Roles for interleukin 17 and adaptive immunity in pathogenesis of colorectal cancer[J].Gastroenterology,2018,155(6):1706-1715.
[5] HUANG Q,DU J,FAN J,et al.The effect of proinflammatory cytokines on IL-17RA expression in NSCLC[J].Med Oncol,2014,31(9):144.
[6] ASUKAI K,KAWAMOTO K,EGUCHI H,et al.Prognostic impact of peritumoral IL-17-positive cells and IL-17 axis in patients with intrahepatic cholangiocarcinoma[J].Ann Surg Oncol,2015,22(Suppl 3):S1524-S1531.
[7] GU C,WU L,LI X.IL-17 family:cytokines,receptors and signaling[J].Cytokine,2013,64(2):477-485.
[8] FABRE J,GIUSTINIANI J,GARBAR C,et al.Targeting the tumor microenvironment:the protumor effects of IL-17 related to cancer type[J].Int J Mol Sci,2016,17(9):E1433.
[9] DE SIMONE V,FRANZE E,RONCHETTI G,et al.Th17-type cytokines,IL-6 and TNF-alpha synergistically activate STAT3 and NF-kB to promote colorectal cancer cell growth[J].Oncogene,2015,34(27):3493-3503.
[10] CHUNG AS,WU X,ZHUANG G,et al.An interleukin-17-mediated paracrine network promotes tumor resistance to anti-angiogenic therapy[J].Nat Med,2013,19(9):1114-1123.
[11] COFFELT S B,KERSTEN K,DOORNEBAL C W,et al.IL-17-producing gammadelta T cells and neutrophils conspire to promote breast cancer metastasis[J].Nature, 2015,522(7556):345-348.
[12] IWAKURA Y,ISHIGAME H,SAIJO S,et al.Functional specialization of interleukin-17 family members[J].Immunity,2011,34(2):149-162.
[13] JIANG YX,LI PA,YANG SW,et al.Increased chemokine receptor IL-17RA expression is associated with poor survival in gastric cancer patients[J].Int J Clin Exp Pathol,2015,8(6):7002-7008.
[14] COCHAUD S,GIUSTINIANI J,THOMAS C,et al.IL-17A is produced by breast cancer TILs and promotes chemoresistance and proliferation through ERK1/2[J].Sci Rep,2013,3:3456.
[15] WANG K,KIM MK,DI CARO G,et al. Interleukin-17 receptor a signaling in transformed enterocytes promotes early colorectal tumorigenesis[J].Immunity,2014,41(6):1052-1063.
[16] HE MK,ZOU RH,LI QJ,et al.Phase Ⅱ study of sorafenib combined with concurrent hepatic arterial infusion of oxaliplatin,5-fluorouracil and leucovorin for unresectable hepatocellular carcinoma with major portal vein thrombosis[J].Cardiovasc Intervent Radiol,2018,41(5):734-743.
[17] PATT YZ,MURAD W,FEKRAZAD MH,et al.INST OX-05-024:first line gemcitabine,oxaliplatin,and erlotinib for primary hepatocellular carcinoma and bile duct cancers:a multicenter phase Ⅱ trial[J].Cancer Med,2017,6(9):2042-2051.
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脚注
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基金
国家自然科学基金青年项目（81602034）
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