Gastrin stimulates pancreatic cancer cell directional migration by activating the Gα12/13-RhoA-ROCK signaling pathway.
Gastrin stimulates pancreatic cancer cell directional migration by activating the Gα12/13-RhoA-ROCK signaling pathway.
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胃泌素通过激活 G α 12/13-RhoA-ROCK 信号通路刺激胰腺癌细胞定向迁移
DOI：
10.1038/s12276-018-0081-6
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发表时间：
2018-05-01
影响因子：
12.8
通讯作者：
Yu H
中科院分区：
文献类型：
--
作者：
Mu G;Ding Q;Li H;Zhang L;Zhang L;He K;Wu L;Deng Y;Yang D;Wu L;Xu M;Zhou J;Yu H
胃泌素促进胰腺癌细胞转移的机制尚不清楚。极化癌细胞向细胞外基质的定向过程是侵袭和远处转移所必需的，但胃泌素是否能诱导这一过程及其潜在的机制仍有待阐明。在这项研究中，我们发现胃泌素诱导Paxlin酪氨酸31/118的磷酸化和RhoA的激活，并促进PANC-1癌细胞的转移。Gα12和Gα13的缺失抑制了Paxlin的磷酸化和Gtp-RhoA的下游激活，阻止了局部粘连的形成和聚集，促进了胃泌素诱导的肌动蛋白细丝的极化。对RhoA和ROCK的抑制也显示出相同的结果。选择性抑制CCKBR-Gα12/13-RhoA-ROCK信号通路阻断了高尔基体在迁移癌细胞前沿的重新定位。YM022和Y-27632对胃泌素诱导的胰腺癌原位肝转移有明显的抑制作用。总之，我们证明胃泌素通过CCKBR-Gα12/13-RhoA-ROCK信号通路激活帕西林，从而促进胰腺癌细胞高尔基体重定向和定向极化。在胰腺癌患者体内发现的一种荷尔蒙水平较高，通过协调细胞迁移帮助疾病传播。胰腺癌是最致命的癌症之一，侵袭性很强，有可能转移。武汉大学人民医院的余洪刚和中国的科学家们已经证明，胰腺癌患者体内表达水平较高的激素胃泌素有助于协调细胞的定向迁移，确保疾病的有效传播。胃泌素通过特定的信号通路激活两个关键分子，确保高尔基体的正确方向，高尔基体是一个负责包装蛋白质进行运输的细胞器。这反过来又激活了癌细胞的定向迁移。这些结果解释了为什么胃泌素在癌症患者的肿瘤和血液中过度表达，并可能为未来的治疗提供参考。
The mechanism by which gastrin promotes pancreatic cancer cell metastasis is unclear. The process of directing polarized cancer cells toward the extracellular matrix is principally required for invasion and distant metastasis; however, whether gastrin can induce this process and its underlying mechanism remain to be elucidated. In this study, we found that gastrin-induced phosphorylation of paxillin at tyrosine 31/118 and RhoA activation as well as promoted the metastasis of PANC-1 cancer cells. Depletion of Gα12 and Gα13 inhibited the phosphorylation of paxillin and downstream activation of GTP-RhoA, blocked the formation and aggregation of focal adhesions and facilitated polarization of actin filaments induced by gastrin. Suppression of RhoA and ROCK also exhibited identical results. Selective inhibition of the CCKBR–Gα12/13–RhoA–ROCK signaling pathway blocked the reoriented localization of the Golgi apparatus at the leading edge of migrated cancer cells. YM022 and Y-27632 significantly suppressed hepatic metastasis of orthotic pancreatic tumors induced by gastrin in vivo. Collectively, we demonstrate that gastrin promotes Golgi reorientation and directional polarization of pancreatic cancer cells by activation of paxillin via the CCKBR–Gα12/13–RhoA–ROCK signal pathway. A hormone found in high levels in pancreatic cancer sufferers helps the disease spread by co-ordinating cellular migration. Pancreatic cancer is one of the most deadly forms of cancer, being highly aggressive and likely to metastasize. Honggang Yu at Renmin Hospital of Wuhan University and scientists across China have demonstrated that gastrin, a hormone expressed at higher levels in patients with pancreatic cancer, helps to co-ordinate directional cell migration and ensure the disease spreads effectively. By activating two key molecules via a specific signalling pathway, gastrin ensures the correct orientation of the Golgi apparatus, a cellular organelle tasked with packaging proteins for transportation. This in turn activates directional migration of the cancer cells. The results explain why gastrin is over-expressed in both tumors and blood in cancer patients, and may inform future therapies.
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影响因子：
8.8
作者：
Li C;Wei Z;Fan Y;Huang W;Su Y;Li H;Dong Z;Fukuda M;Khater M;Wu G
通讯作者：
Wu G
影响因子：
28.5
作者：
López-Colomé AM;Lee-Rivera I;Benavides-Hidalgo R;López E
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López E
影响因子：
3.7
作者：
Deakin NO;Ballestrem C;Turner CE
通讯作者：
Turner CE
影响因子：
8
作者：
Cayrol, C.;Clerc, P.;Seva, C.
通讯作者：
Seva, C.
影响因子：
3.7
作者：
Juneja J;Cushman I;Casey PJ
通讯作者：
Casey PJ