Department of Gastrointestinal Cancer Translational Research Laboratory, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Beijing Institute For Cancer Research, Fu-Cheng Road, Beijing, China.
Department of Oncology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, China.
Int J Biol Sci. 2021 Jul 5;17(11):2841-2852. doi: 10.7150/ijbs.57826. eCollection 2021.
Abnormal expression of CXC motif chemokine ligand 16 (CXCL16) has been demonstrated to be associated with tumor progression and metastasis, served as a prognostic factor in many cancers, with higher relative expression behaving as a marker of tumor progression. However, its role and mechanisms underlying progression and metastasis of gastric cancer (GC) are yet to be elucidated. In our investigation, public datasets and human GC tissue samples were used to determine the CXCL16 expression levels. Our results revealed that CXCL16 was upregulated in GC. The high expression CXCL16 in GC was significantly associated with histologic poor differentiation and pTNM staging. And high CXCL16 was positively correlated with the poor survival of GC patients. Gain-and loss-of-function experiments were employed to investigate the biological role of CXCL16 in proliferation and migration both and . Mechanically, Gene set enrichment analysis (GSEA) revealed that the epithelial‑mesenchymal transition (EMT), Akt and MAPK signal pathway related genes were significantly enriched in the high CXCL16 group, which was confirmed by western blot. Moreover, overexpression CXCL16 promoted the disintegrin and metalloproteases (ADAM10) and the CXC motif chemokine receptor 6 (CXCR6) expression, which mediated the CXCL16/CXCR6 positive feedback loop in GC, with activating Akt and MAPK signaling pathways. Knocking down ADAM10 would interrupted the CXCL16/CXCR6 axis in the carcinogenesis and progression of GC. In conclusion, our findings offered insights into that CXCL16 promoted GC tumorigenesis by enhancing ADAM10-dependent CXCL16/CXCR6 axis activation.
CXC 基序趋化因子配体 16（CXCL16）的异常表达已被证明与肿瘤的进展和转移有关，在许多癌症中作为预后因素，相对较高的表达水平作为肿瘤进展的标志物。然而，其在胃癌（GC）进展和转移中的作用和机制尚待阐明。在我们的研究中，使用公共数据集和人 GC 组织样本来确定 CXCL16 的表达水平。我们的结果表明，CXCL16 在 GC 中上调。GC 中高表达的 CXCL16 与组织学低分化和 pTNM 分期显著相关。并且高 CXCL16 与 GC 患者的不良生存显著相关。通过获得和缺失功能实验研究了 CXCL16 在增殖和迁移中的生物学作用。机制上，基因集富集分析（GSEA）显示，上皮-间充质转化（EMT）、Akt 和 MAPK 信号通路相关基因在高 CXCL16 组中显著富集，Western blot 进一步证实了这一点。此外，过表达 CXCL16 促进了解整合素和金属蛋白酶（ADAM10）和 CXC 基序趋化因子受体 6（CXCR6）的表达，从而介导了 GC 中的 CXCL16/CXCR6 正反馈环，激活了 Akt 和 MAPK 信号通路。敲低 ADAM10 会中断 GC 发生和进展过程中 CXCL16/CXCR6 轴。总之，我们的研究结果表明，CXCL16 通过增强 ADAM10 依赖性 CXCL16/CXCR6 轴的激活促进了 GC 肿瘤的发生。
