Wnt5a-Ror2 signaling in mesenchymal stem cells promotes proliferation of gastric cancer cells by activating CXCL16-CXCR6 axis.
Wnt5a-Ror2 signaling in mesenchymal stem cells promotes proliferation of gastric cancer cells by activating CXCL16-CXCR6 axis.
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DOI：
10.1111/cas.12871
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发表时间：
2016-03
期刊：
影响因子：
5.7
通讯作者：
Minami Y
中科院分区：
文献类型：
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作者：
Takiguchi G;Nishita M;Kurita K;Kakeji Y;Minami Y
Wnt5a‐Ror2信号已被证明在促进各种癌细胞的细胞自主方式的侵袭性中发挥重要作用。然而，其在癌症相关的基质细胞，包括间充质干细胞（MSCs）中的功能知之甚少。因此，我们研究了骨髓来源的MSCs中Wnt5a‐Ror2信号在调节未分化胃癌细胞增殖中的作用。胃癌细胞系MKN45与MSCs共培养可直接或间接促进MKN45细胞的增殖，并在共培养前抑制MSCs中Ror2的表达，从而抑制MKN45细胞的增殖。此外，MSCs的条件培养基，用对照siRNA处理，而不是针对Ror2的siRNA，可以增强MKN45细胞的增殖。有趣的是，研究发现MSCs中CXCL16的表达被Wnt5a‐Ror2信号通路增强，重组趋化因子（C‐X‐C motif）配体（CXCL）16蛋白可以在缺乏MKN45细胞的情况下增强MKN45细胞的增殖。事实上，抑制MSCs中CXCL16的表达或添加针对CXCL16的中和抗体都不能促进MKN45细胞与MSCs直接或间接共培养的增殖。重要的是，我们发现MKN45细胞表达趋化因子（C‐X‐C motif）受体（CXCR）6，这是CXCL16的受体，并且在MKN45细胞中抑制CXCR6的表达导致其在与MSCs的直接或间接共培养中增殖增强失败。这些发现表明Wnt5a‐Ror2信号通路增强MSCs中CXCL16的表达，因此MSCs分泌CXCL16的增强可能作用于MKN45上表达的CXCR6，从而促进其增殖。
Wnt5a‐Ror2 signaling has been shown to play important roles in promoting aggressiveness of various cancer cells in a cell‐autonomous manner. However, little is known about its function in cancer‐associated stromal cells, including mesenchymal stem cells (MSCs). Thus, we examined the role of Wnt5a‐Ror2 signaling in bone marrow‐derived MSCs in regulating proliferation of undifferentiated gastric cancer cells. Coculture of a gastric cancer cell line, MKN45, with MSCs either directly or indirectly promotes proliferation of MKN45 cells, and suppressed expression of Ror2 in MSCs prior to coculture inhibits enhanced proliferation of MKN45 cells. In addition, conditioned media from MSCs, treated with control siRNA, but not siRNAs against Ror2, can enhance proliferation of MKN45 cells. Interestingly, it was found that expression of CXCL16 in MSCs is augmented by Wnt5a‐Ror2 signaling, and that recombinant chemokine (C‐X‐C motif) ligand (CXCL)16 protein can enhance proliferation of MKN45 cells in the absence of MSCs. In fact, suppressed expression of CXCL16 in MSCs or an addition of a neutralizing antibody against CXCL16 fails to promote proliferation of MKN45 cells in either direct or indirect coculture with MSCs. Importantly, we show that MKN45 cells express chemokine (C‐X‐C motif) receptor (CXCR)6, a receptor for CXCL16, and that suppressed expression of CXCR6 in MKN45 cells results in a failure of its enhanced proliferation in either direct or indirect coculture with MSCs. These findings indicate that Wnt5a‐Ror2 signaling enhances expression of CXCL16 in MSCs and, as a result, enhanced secretion of CXCL16 from MSCs might act on CXCR6 expressed on MKN45, leading to the promotion of its proliferation.