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癌症相关成纤维细胞通过激活IL-17a/JAK2/STAT3信号通路促进胃癌细胞的迁移和侵袭。

Cancer-associated fibroblasts promote the migration and invasion of gastric cancer cells via activating IL-17a/JAK2/STAT3 signaling.

作者信息

Zhang Junli, Li Sen, Zhao Yuzhou, Ma Pengfei, Cao Yanghui, Liu Chenyu, Zhang Xijie, Wang Wenpeng, Chen Li, Li Yin

机构信息

Department of General Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China.

Department of Colorectal Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.

出版信息

Ann Transl Med. 2020 Jul;8(14):877. doi: 10.21037/atm-20-4843.

Abstract

BACKGROUND

Cancer-associated fibroblasts (CAFs), as the activated stroma cells, contribute to tumor progression via the release of cytokines, growth factors, and hormones. However, neither the factors produced by CAFs nor the molecular mechanisms were illuminated very well in gastric cancer (GC).

METHODS

Immunohistochemical staining of alpha-smooth muscle actin (α-SMA) was applied to examine the number of CAFs in GC samples from 227 patients. ELISA and qRT-PCR were performed to detect the expression of interleukin 17a (IL-17a). The migration and invasion of GC cells were determined by the Transwell assay. The expressions of JAK2, STAT3, MMP-2, MMP-9, TIMP-1, and TIMP-2 were measured by western blotting. IL-17a was blocked with a polyclonal antibody, and JAK2/STAT3 signaling pathway was blocked by a specific inhibitor AG490.

RESULTS

High CAFs in GC tissues were positively correlated with advanced TNM stage and perineural invasion. Furthermore, GC patients with high CAFs in tumor tissues had an obvious worse disease-free survival (DFS) and disease-special survival (DSS). Multivariate analysis showed that high CAFs in GC tissues were an independent risk factor for DFS and DSS. CAFs expressed IL-17a significantly after GC cell co-culture. CAFs markedly enhanced the migration and invasion abilities of AGS and SGC-7901 cells. Moreover, CAFs co-culture resulted in increased levels of MMP2/9, reduced expressions of TIMP1/2, and activation of the JAK2/STAT3 signaling pathway in the GC cells. IL-17a neutralizing antibody or JAK2 inhibitor AG490 can significantly inhibit the effects of CAFs on the migration, invasion, MMP2/9, TIMP1/2, and JAK2/STAT3 pathways of GC cells.

CONCLUSIONS

CAFs correlated with unfavorable clinical features and poor prognosis of GC patients. CAFs secreted IL-17a, which promoted the migration and invasion of GC cells through activating JAK2/STAT3 signaling. These results may identify IL-17a as a promising prognostic marker and therapeutic target of GC.

摘要

背景

癌症相关成纤维细胞(CAFs)作为活化的基质细胞,通过释放细胞因子、生长因子和激素促进肿瘤进展。然而,在胃癌(GC)中,CAFs产生的因子及其分子机制尚未得到很好的阐明。

方法

应用α-平滑肌肌动蛋白(α-SMA)免疫组化染色检测227例GC患者样本中CAFs的数量。采用酶联免疫吸附测定(ELISA)和实时定量聚合酶链反应(qRT-PCR)检测白细胞介素17a(IL-17a)的表达。通过Transwell实验检测GC细胞的迁移和侵袭能力。采用蛋白质印迹法检测Janus激酶2(JAK2)、信号转导和转录激活因子3(STAT3)、基质金属蛋白酶2(MMP-2)、基质金属蛋白酶9(MMP-9)、金属蛋白酶组织抑制因子1(TIMP-1)和金属蛋白酶组织抑制因子2(TIMP-2)的表达。用多克隆抗体阻断IL-17a,用特异性抑制剂AG490阻断JAK2/STAT3信号通路。

结果

GC组织中高表达的CAFs与晚期TNM分期和神经周围浸润呈正相关。此外,肿瘤组织中CAFs高表达的GC患者无病生存期(DFS)和疾病特异性生存期(DSS)明显较差。多因素分析显示,GC组织中高表达的CAFs是DFS和DSS的独立危险因素。GC细胞共培养后,CAFs显著表达IL-17a。CAFs显著增强了AGS和SGC-7901细胞的迁移和侵袭能力。此外,CAFs共培养导致GC细胞中MMP2/9水平升高、TIMP1/2表达降低以及JAK2/STAT3信号通路激活。IL-17a中和抗体或JAK2抑制剂AG490可显著抑制CAFs对GC细胞迁移侵袭、MMP2/9、TIMP1/2及JAK2/STAT3信号通路的影响。

结论

CAFs与GC患者不良临床特征及预后不良相关。CAFs分泌IL-17a,通过激活JAK2/STAT3信号通路促进GC细胞的迁移和侵袭。这些结果可能表明IL-17a是一种有前景的GC预后标志物和治疗靶点。

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