CXCR4/CXCR7双通路促进胃癌转移的机制研究

CXCL12 promotes gastric cancer metastasis, and CXCR4 is its classical receptor. Recent studies demonstrated that CXCR7 was also its receptor, and was expressed by gastric cancer, but the relationship between CXCR4 and 7, and the mechanism of CXCR4/7 in gastric cancer metastasis remains unclear. Our data demonstrated that: 1. Single inhibition of CXCR4 or 7 could only partially reversed CXCL12-induced EMT and migration, while inhibition of double pathways resulted in more significant effects; 2. Inhibition of lipid raft and Cav-1 decreased the CXCL12-induced activation of c-MET; 3. CXCL12 down-regulated miR-125a-3p，while up-regulated SERPINB3, and the bioinformatic analysis predicted that SERPINB3 was the target gene of miR-125a-3p. Combined with the previous reports that c-MET or SERPINB3 promoted EMT, and RAS, one of the downstream molecules of CXCR4, increases the expression of SERPINB3, we proposed that in gastric cancer, CXCR4 and 7 cooperated, and activated classical downstream pathways, or activated c-MET through lipid raft and Cav-1,or up-regulated SERPINB3 through miR-125a-3p or RAS, finally induced EMT and promoted gastric cancer metastasis. The present study is very important for illustrating the role of CXCL12 in gastric cancer metastasis.

CXCL12促进胃癌转移， CXCR4是其经典受体。近年来研究证实CXCR7也是其受体，且被胃癌表达，但CXCR4与7的关系及在胃癌转移中的作用尚不明确。我们的数据证实：1.单纯抑制CXCR4或7仅能部分逆转CXCL12诱导的EMT及迁移，而双通路抑制效果更显著；2.抑制脂筏和Cav-1能降低CXCL12诱导的c-MET活化；3.CXCL12下调miR-125a-3p，上调SERPINB3，生物信息分析预测SERPINB3是miR-125a-3p的靶基因。结合c-MET和SERPINB3促进EMT，CXCR4下游分子RAS能上调SERPINB3的报告，我们推测在胃癌中CXCR4和7协同作用，通过经典通路，或通过脂筏/Cav-1激活c-MET，或通过miR-125a-3p/RAS上调SERPINB3，诱导EMT，促进胃癌转移。本研究对进一步阐明CXCL12在胃癌转移中的作用机制具有重要意义。

胃癌是全球第四大最常见的恶性肿瘤，也是世界肿瘤相关死亡的第二大常见原因， 其全球发病率估计约为每年100万。转移是影响胃癌患者预后的最主要原因之一。一旦发生转移，患者即失去了手术根治的机会，且传统化疗疗效有限，缺乏有效的靶向药物，导致胃癌死亡率仍然居高不下。因此，深入探讨胃癌的转移机制，对预防胃癌的复发转移及研发新的分子靶向药物具有重要意义。肿瘤微环境是肿瘤发生、生长及转移过程中所处的内环境，是影响肿瘤转移的关键因素。基质细胞衍生因子(CXCL12)是趋化因子 (CXC)家族成员，是目前在肿瘤细胞中研究最广泛最具特征的趋化因子。CXCL12促进胃癌转移，CXCR4是其经典受体。近年来研究证实CXCR7也是其受体，且被胃癌表达，但CXCR4与7的关系及在胃癌转移中的作用及机制尚不明确。我们的数据证实:1.单纯抑制CXCR4或7仅能部分逆转CXCL12诱导的EMT及迁移，而双通路抑制效果更显著，利用TCGA数据库分析发现，CXCR4/CXCR7双阳性患者预后最差；2.CXCL12通过SRC介导CXCR4与EGFR串化促进胃癌转移；3.CXCL12/CXCR4通过脂筏和Cav-1，促进c-MET活化诱导胃癌细胞EMT促进转移，CXCR4与p-c-MET双阳性的患者生存期远低于其它组患者；4.CXCL12/CXCR4通过激活NF-κB通路，上调SERPINB3蛋白促进胃癌细胞迁移及侵袭。SERPINB3及CXCR4表达阳性患者更易于淋巴结转移，预后更差。SERPINB3可以作为生物标记物对CXCR4阳性 患者进一步细化分类。CXCR7阳性患者T分期更晚，预后更差，联合CXCR7及SERPINB3可更好的判断预后。本研究对进一步阐明CXCL12-CXCR4/CXCR7在胃癌转移中的作用机制具有重要意义。