RhoC interacts with integrin α5β1 and enhances its trafficking in migrating pancreatic carcinoma cells.
RhoC interacts with integrin α5β1 and enhances its trafficking in migrating pancreatic carcinoma cells.
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DOI：
10.1371/journal.pone.0081575
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kocher HM
中科院分区：
文献类型：
--
作者：
Li NF;Gemenetzidis E;Marshall FJ;Davies D;Yu Y;Frese K;Froeling FE;Woolf AK;Feakins RM;Naito Y;Iacobuzio-Donahue C;Tuveson DA;Hart IR;Kocher HM
人胰导管腺癌（PDAC）的特点是早期全身播散。虽然RhoC与癌细胞迁移有关，但相关的潜在分子机制尚不清楚。RhoC参与了癌细胞迁移和侵袭的增强，其作用与RhoA不同（84%同源性），可能归因于c端结构域的发散。在这里，我们证实RhoC显著增强胰腺癌细胞的迁移和侵袭特性。此外，我们发现RhoC过表达降低癌细胞粘附，进而加速细胞体运动和局灶粘附转换，特别是在纤维连接蛋白覆盖的表面上。虽然RhoC过表达不会改变整合素的表达模式，但我们发现它增强了整合素α5β1的内化和再循环（运输），这种作用特异性地依赖于RhoC蛋白的c端（180-193个氨基酸）。我们还报道了RhoC和整合素α5β1在胰腺肿瘤细胞的核周区域内共定位，并且通过在RhoC蛋白的c端掩盖CAAX基序，我们能够在体外和体内消除这种相互作用。整合素α5β1和RhoC的共定位在3d器官型培养的侵袭癌细胞中被证实，并进一步模拟了自发人（两个不同的来源：手术患者和快速尸检程序）和转基因小鼠（LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre）胰腺癌的体内分析。在这两种情况下，整合素α5β1和RhoC的共定位与分化状态差和转移潜力相关。我们认为RhoC促进肿瘤细胞侵袭并促进随后的转移，部分是通过增强整合素α5β1的转运。因此，RhoC可以作为生物标志物和治疗靶点。
Human pancreatic ductal adenocarcinoma (PDAC) is characterized by early systemic dissemination. Although RhoC has been implicated in cancer cell migration, the relevant underlying molecular mechanisms remain unknown. RhoC has been implicated in the enhancement of cancer cell migration and invasion, with actions which are distinct from RhoA (84% homology), and are possibly attributed to the divergent C-terminus domain. Here, we confirm that RhoC significantly enhances the migratory and invasive properties of pancreatic carcinoma cells. In addition, we show that RhoC over-expression decreases cancer cell adhesion and, in turn, accelerates cellular body movement and focal adhesion turnover, especially, on fibronectin-coated surfaces. Whilst RhoC over-expression did not alter integrin expression patterns, we show that it enhanced integrin α5β1 internalization and re-cycling (trafficking), an effect that was dependent specifically on the C-terminus (180-193 amino acids) of RhoC protein. We also report that RhoC and integrin α5β1 co-localize within the peri-nuclear region of pancreatic tumor cells, and by masking the CAAX motif at the C-terminal of RhoC protein, we were able to abolish this interaction in vitro and in vivo. Co-localization of integrin α5β1 and RhoC was demonstrable in invading cancer cells in 3D-organotypic cultures, and further mimicked in vivo analyses of, spontaneous human, (two distinct sources: operated patients and rapid autopsy programme) and transgenic murine (LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre), pancreatic cancers. In both cases, co-localization of integrin α5β1 and RhoC correlated with poor differentiation status and metastatic potential. We propose that RhoC facilitates tumor cell invasion and promotes subsequent metastasis, in part, by enhancing integrin α5β1 trafficking. Thus, RhoC may serve as a biomarker and a therapeutic target.
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影响因子：
9.2
作者：
Bravo-Cordero, Jose Javier;Oser, Matthew;Chen, Xiaoming;Eddy, Robert;Hodgson, Louis;Condeelis, John
通讯作者：
Condeelis, John
影响因子：
3.6
作者：
Embuscado, EE;Laheru, D;Iacobuzio-Donahue, CA
通讯作者：
Iacobuzio-Donahue, CA
影响因子：
29.4
作者：
Froeling, Fieke E. M.;Feig, Christine;Kocher, Hemant M.
通讯作者：
Kocher, Hemant M.
影响因子：
64.8
作者：
Clark, EA;Golub, TR;Hynes, RO
通讯作者：
Hynes, RO
影响因子：
8
作者：
Arpaia, E.;Blaser, H.;Quintela-Fandino, M.;Duncan, G.;Leong, H. S.;Ablack, A.;Nambiar, S. C.;Lind, E. F.;Silvester, J.;Fleming, C. K.;Rufini, A.;Tusche, M. W.;Bruestle, A.;Ohashi, P. S.;Lewis, J. D.;Mak, T. W.
通讯作者：
Mak, T. W.