Gamma synuclein promotes cancer metastasis through the MKK3/6-p38MAPK cascade.
Gamma synuclein promotes cancer metastasis through the MKK3/6-p38MAPK cascade.
复制标题
γ-突触核蛋白通过 MKK3/6-p38MAPK 级联促进癌症转移
DOI：
10.7150/ijbs.69155
复制
发表时间：
2022
影响因子：
9.2
通讯作者：
Jiang, Yangfu
中科院分区：
文献类型：
--
作者：
Liu, Jieya;Shao, Ting;Zhang, Jin;Liu, Qianyi;Hua, Hui;Zhang, Hongying;Wang, Jiao;Luo, Ting;Shi, Yuenian Eric;Jiang, Yangfu
γ-突触核蛋白(SNCG)是一种神经元蛋白，在各种类型的人类癌症中也异常过表达。SNCG过表达促进肿瘤的侵袭和转移。然而，SNCG表达促进肿瘤转移的机制仍不清楚。阐明SNCG促进肿瘤转移的潜在机制可能有助于发现SNCG过表达的癌症的治疗途径。在这里，我们发现SNCG促进转化生长因子-β(转化生长因子-β)诱导的p38丝裂原活化蛋白激酶(MAPK)的磷酸化。机制上，SNCG通过与MAPK激酶3/6(MKK3/6)相互作用促进p38MAPK的磷酸化，并阻止其降解。SNCG基因敲除可降低转化生长因子-β诱导的MKK3/6的磷酸化，并阻断转化生长因子-β及其靶基因Twist1诱导的基质金属蛋白酶-9的表达。此外，抑制p38MAPK可阻断SNCG促进基质金属蛋白酶-9表达和癌细胞侵袭的作用。P38MAPK和基质金属蛋白酶抑制剂均可抑制SNCG促进癌细胞侵袭的作用。最后，SNCG在肝癌细胞中的过表达促进了肺转移，这可以被p38MAPK抑制剂抑制。总之，我们的数据揭示了SNCG在促进转化生长因子-β-MKK3/6-p38MAPK信号转导中所扮演的未知角色。这项研究强调了p38MAPK在SNCG促进肿瘤转移中的关键作用，并表明p38MAPK抑制剂可能成为治疗SNCG过表达的癌症的潜在药物。
Gamma synuclein (SNCG) is a neuronal protein that is also aberrantly overexpressed in various types of human cancer. SNCG overexpression promotes cancer invasion and metastasis. However, the mechanisms that drive cancer metastasis upon SNCG expression remain elusive. Elucidation of the mechanisms underlying the promotion of cancer metastasis by SNCG may help discover therapeutic avenues for SNCG-overexpressed cancer. Here, we show that SNCG promotes transforming growth factor-β (TGF-β)-induced p38 mitogen-activated protein kinase (MAPK) phosphorylation. Mechanistically, SNCG promotes p38MAPK phosphorylation by interacting with the MAPK kinase 3/6 (MKK3/6) and prevents their degradation. SNCG knockdown leads to a decrease in TGF-β-induced phosphorylation of MKK3/6; and abrogates the induction of matrix metalloproteinase (MMP)-9 expression by TGF-β and its target gene Twist1. Furthermore, p38MAPK inhibition abrogates the promotion of MMP-9 expression and cancer cell invasion by SNCG. Both p38MAPK and MMP inhibitors can suppress the promotion of cancer cell invasion by SNCG. Finally, overexpression of SNCG in liver cancer cells promotes lung metastasis, which can be suppressed by the p38MAPK inhibitor. Together, our data uncover a previously unknown role of SNCG in promoting TGF-β-MKK3/6-p38MAPK signaling. This study highlights the critical role of p38MAPK in the promotion of cancer metastasis by SNCG, and indicates that p38MAPK inhibitor may serve as a potential therapeutic for SNCG-overexpressed cancer.
登录
查看更多内容
影响因子：
11.5
作者：
Hu, Hai;Sun, Lichao;Ran, Yuliang
通讯作者：
Ran, Yuliang
影响因子：
4.8
作者：
Engel, ME;McDonnell, MA;Moses, HL
通讯作者：
Moses, HL
DOI：
10.1152/ajprenal.00485.2006
发表时间：
2007-05-01
影响因子：
4.2
作者：
Kim, Sung Il;Kwak, Joon Hyeok;Choi, Mary E.
通讯作者：
Choi, Mary E.
影响因子：
6.4
作者：
Larsson, Per;Khaja, Azharuddin Sajid Syed;Persson, Jenny L.
通讯作者：
Persson, Jenny L.
细胞外γ-突触核蛋白通过激活β1整合素-焦点粘附激酶信号通路和增加基质金属蛋白酶-24、-2蛋白分泌来促进肿瘤细胞运动
DOI：
10.1186/s13046-018-0783-6
发表时间：
2018-06-15
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Liu C;Qu L;Zhao C;Shou C
通讯作者：
Shou C