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 in vitro and in vivo. 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.

中文翻译：

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CXCL16 通过 ADAM10 依赖性 CXCL16/CXCR6 轴促进胃癌肿瘤发生并激活 Akt 和 MAPK 信号通路

CXC基序趋化因子配体16（CXCL16）的异常表达已被证明与肿瘤进展和转移有关，是许多癌症的预后因素，较高的相对表达可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未阐明。在我们的研究中，使用公共数据集和人类 GC 组织样本来确定 CXCL16 表达水平。我们的结果显示 CXCL16 在 GC 中表达上调。GC中CXCL16的高表达与组织学低分化和pTNM分期显着相关。高CXCL16与GC患者较差的生存率呈正相关。体外和体内。机械方面，基因集富集分析（GSEA）显示，上皮间质转化（EMT）、Akt和MAPK信号通路相关基因在高CXCL16组中显着富集，这一点得到了蛋白质印迹的证实。此外，过度表达CXCL16可促进解整合素和金属蛋白酶（ADAM10）以及CXC基序趋化因子受体6（CXCR6）的表达，从而介导GC中的CXCL16/CXCR6正反馈环，并激活Akt和MAPK信号通路。敲低 ADAM10 会中断 GC 的致癌和进展中的 CXCL16/CXCR6 轴。总之，我们的研究结果揭示了 CXCL16 通过增强 ADAM10 依赖性 CXCL16/CXCR6 轴激活来促进 GC 肿瘤发生。