Mesenchymal stem cell-derived CXCL16 promotes progression of gastric cancer cells by STAT3-mediated expression of Ror1
Mesenchymal stem cell-derived CXCL16 promotes progression of gastric cancer cells by STAT3-mediated expression of Ror1
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DOI：
10.1111/cas.14339
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发表时间：
2020-02-25
期刊：
影响因子：
5.7
通讯作者：
Minami, Yasuhiro
中科院分区：
文献类型：
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作者：
Ikeda, Taro;Nishita, Michiru;Minami, Yasuhiro
骨髓来源的间充质干细胞或基质细胞（MSC）已被证明被募集到各种类型的肿瘤组织中，在那里它们与肿瘤细胞相互作用以促进它们的增殖、存活、侵袭和转移，这取决于肿瘤的类型。我们先前已经表明，Ror 2受体酪氨酸激酶及其配体Wnt 5a在MSC中表达，并且MSC中的Wnt 5a-Ror 2信号传导诱导CXCL 16的表达，这反过来通过CXCL 16-CXCR 6轴促进共培养的MKN 45胃癌细胞的增殖。然而，CXCL 16如何调节MKN 45细胞的增殖仍不清楚。在这里，我们表明，敲低CXCL 16在MSC的siRNA抑制不仅增殖，但也迁移共培养的MKN 45细胞。我们还发现，MSC衍生的CXCL 16或重组CXCL 16通过激活MKN 45细胞中的STAT 3上调Ror 1的表达，从而促进MKN 45细胞的体外增殖和迁移。此外，MSC与MKN 45细胞在裸鼠中的共注射以依赖于MKN 45细胞中Ror 1的表达的方式促进肿瘤形成，并且抗CXCL 16中和抗体抑制与MSC共注射的MKN 45细胞的肿瘤形成。这些结果表明，在肿瘤微环境中的MSC中通过Ror 2介导的信号传导产生的CXCL 16以旁分泌方式作用于MKN 45细胞，以激活CXCR 6-STAT 3通路，这反过来又诱导MKN 45细胞中Ror 1的表达，从而促进肿瘤进展。
Bone marrow-derived mesenchymal stem or stromal cells (MSC) have been shown to be recruited to various types of tumor tissues, where they interact with tumor cells to promote their proliferation, survival, invasion and metastasis, depending on the type of the tumor. We have previously shown that Ror2 receptor tyrosine kinase and its ligand, Wnt5a, are expressed in MSC, and Wnt5a-Ror2 signaling in MSC induces expression of CXCL16, which, in turn, promotes proliferation of co-cultured MKN45 gastric cancer cells via the CXCL16-CXCR6 axis. However, it remains unclear how CXCL16 regulates proliferation of MKN45 cells. Here, we show that knockdown of CXCL16 in MSC by siRNA suppresses not only proliferation but also migration of co-cultured MKN45 cells. We also show that MSC-derived CXCL16 or recombinant CXCL16 upregulates expression of Ror1 through activation of STAT3 in MKN45 cells, leading to promotion of proliferation and migration of MKN45 cells in vitro. Furthermore, co-injection of MSC with MKN45 cells in nude mice promoted tumor formation in a manner dependent on expression of Ror1 in MKN45 cells, and anti-CXCL16 neutralizing antibody suppressed tumor formation of MKN45 cells co-injected with MSC. These results suggest that CXCL16 produced through Ror2-mediated signaling in MSC within the tumor microenvironment acts on MKN45 cells in a paracrine manner to activate the CXCR6-STAT3 pathway, which, in turn, induces expression of Ror1 in MKN45 cells, thereby promoting tumor progression.