title: RhoC interacts with integrin α5β1 and enhances its trafficking in migrating pancreatic carcinoma cells.
abstract: 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.
authors: Barts Cancer Institute - a CR-United Kingdom Centre of Excellence, Queen Mary University of London, Centre for Tumour Biology, London, United Kingdom.
authors: Ningfeng Fiona
authors: NF
authors: Li
authors: Emilios
authors: E
authors: Gemenetzidis
authors: Francis J
authors: FJ
authors: Marshall
authors: Derek
authors: D
authors: Davies
authors: Yongwei
authors: Y
authors: Yu
authors: Kristopher
authors: K
authors: Frese
authors: Fieke E M
authors: FE
authors: Froeling
authors: Adam K
authors: AK
authors: Woolf
authors: Roger M
authors: RM
authors: Feakins
authors: Yoshiki
authors: Y
authors: Naito
authors: Christine
authors: C
authors: Iacobuzio-Donahue
authors: David A
authors: DA
authors: Tuveson
authors: Ian R
authors: IR
authors: Hart
authors: Hemant M
authors: HM
authors: Kocher
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002454:Cell Differentiation; D002465:Cell Movement; D004789:Enzyme Activation; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000473:pathology*; D011485:Protein Binding; D021381:Protein Transport; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000075024:rhoC GTP-Binding Protein; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D039081:Integrin alpha5beta1; D019061:src-Family Kinases; C066690:RHOC protein, human; D020741:rho GTP-Binding Proteins; D000075024:rhoC GTP-Binding Protein