title: VEGF-C mediates RhoGDI2-induced gastric cancer cell metastasis and cisplatin resistance.
abstract: Rho GDP dissociation inhibitor 2 (RhoGDI2) expression is correlated with tumor growth, metastasis and chemoresistance in gastric cancer. However, the mechanisms by which RhoGDI2 promotes tumor cell survival and metastasis remain unclear. In this study, we clearly demonstrate that RhoGDI2 upregulates VEGF-C expression and RhoGDI2 expression is positively correlated with VEGF-C expression in human gastric tumor tissues as well as parental gastric cancer cell lines. VEGF-C depletion suppressed RhoGDI2-induced gastric cancer metastasis and sensitized RhoGDI2-overexpressing cells to cisplatin-induced apoptosis in vitro and in vivo. Secreted VEGF-C enhanced gastric cancer cell invasion and conferred cisplatin resistance to RhoGDI2-overexpressing cells. We also show that RhoGDI2 positively regulates Rac1 activity in gastric cancer cells. Inhibition of Rac1 expression suppressed RhoGDI2-induced VEGF-C expression, and this inhibition was associated with decreased invasiveness and increased sensitivity to cisplatin in RhoGDI2-overexpressing cells. Our results indicate that RhoGDI2 might be a potential therapeutic target for simultaneously reducing metastasis risk and enhancing chemotherapy efficacy in gastric cancer.
authors.forename: Hee Jun
authors.initials: HJ
authors.lastname: Cho
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Kim
authors.forename: Sun-Mi
authors.initials: SM
authors.lastname: Park
authors.forename: Kyoung Eun
authors.initials: KE
authors.lastname: Baek
authors.forename: In-Koo
authors.initials: IK
authors.lastname: Nam
authors.forename: Seung-Ho
authors.initials: SH
authors.lastname: Park
authors.forename: Ki-Jun
authors.initials: KJ
authors.lastname: Ryu
authors.forename: Jungil
authors.initials: J
authors.lastname: Choi
authors.forename: Jinhyun
authors.initials: J
authors.lastname: Ryu
authors.forename: Soon-Chan
authors.initials: SC
authors.lastname: Hong
authors.forename: Sang-Ho
authors.initials: SH
authors.lastname: Jeong
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Lee
authors.forename: Gyung-Hyuck
authors.initials: GH
authors.lastname: Ko
authors.forename: Jae
authors.initials: J
authors.lastname: Kim
authors.forename: Chang
authors.initials: C
authors.lastname: Won Lee
authors.forename: Sang
authors.initials: S
authors.lastname: Soo Kang
authors.forename: Jiyun
authors.initials: J
authors.lastname: Yoo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D062949:rho Guanine Nucleotide Dissociation Inhibitor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C569658:ARHGDIB protein, human; D000970:Antineoplastic Agents; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C467486:VEGFC protein, human; D042582:Vascular Endothelial Growth Factor C; D062949:rho Guanine Nucleotide Dissociation Inhibitor beta; D002945:Cisplatin
keywords: RhoGDI2; VEGF-C; chemoresistance; gastric cancer; metastasis