The Rho guanine nucleotide exchange factor ARHGEF5 promotes tumor malignancy via epithelial-mesenchymal transition.
Epithelial tumor cells often acquire malignant properties, such as invasion/metastasis and uncontrolled cell growth, by undergoing epithelial-mesenchymal transition (EMT). However, the mechanisms by which EMT contributes to malignant progression remain elusive. Here we show that the Rho guanine nucleotide exchange factor (GEF) ARHGEF5 promotes tumor malignancy in a manner dependent on EMT status. We previously identified ARHGEF5, a member of the Dbl family of GEFs, as a multifunctional mediator of Src-induced cell invasion and tumor growth. In the present study, ARHGEF5 was upregulated during tumor growth factor-β-induced EMT in human epithelial MCF10A cells, and promoted cell migration by activating the Rho-ROCK pathway. ARHGEF5 was necessary for the invasive and in vivo metastatic activity of human colorectal cancer HCT116 cells. These findings underscore the crucial role of ARHGEF5 in cell migration and invasion/metastasis. An in vivo tumorigenesis assay revealed that ARHGEF5 had the potential to promote tumor growth via the phosphatidylinositol 3-kinase (PI3K) pathway. However, ARHGEF5 was not required for tumor growth in epithelial-like human colorectal cancer HCT116 and HT29 cells, whereas the growth of mesenchymal-like SW480 and SW620 cells depended on ARHGEF5. Induction of EMT by tumor necrosis factor-α or Slug in HCT116 cells resulted in the dependence of tumor growth on ARHGEF5. In these mesenchymal-like cells, Akt was activated via ARHGEF5 and its activity was required for tumor growth. Analysis of a transcriptome data set revealed that the combination of ARHGEF5 upregulation and E-cadherin downregulation or Snail upregulation was significantly correlated with poor prognosis in patients with colorectal cancers. Taken together, our findings suggest that EMT-induced ARHGEF5 activation contributes to the progression of tumor malignancy. ARHGEF5 may serve as a potential therapeutic target in a subset of malignant tumors that have undergone EMT.
Department of Oncogene Research and Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
Y
Y
Komiya
Department of Molecular Biology, Hokkaido University Graduate School of Medicine, Hokkaido, Japan.
Y
Y
Onodera
Department of Oncogene Research and Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
M
M
Kuroiwa
Department of Oncogene Research and Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
S
S
Nomimura
Department of Oncogene Research and Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
Y
Y
Kubo
Department of Radiation Medicine, Hokkaido University Graduate School of Medicine, Hokkaido, Japan.|Global Station for Quantum Medical Science and Engineering, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Hokkaido, Japan.
J-M
JM
Nam
Department of Oncogene Research and Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
K
K
Kajiwara
Department of Oncogene Research and Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
S
S
Nada
Division of Microbiology and Oncology, Aichi Cancer Center Research Institute, Aichi, Japan.
C
C
Oneyama
Department of Molecular Biology, Hokkaido University Graduate School of Medicine, Hokkaido, Japan.
H
H
Sabe
Department of Oncogene Research and Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
M
http://orcid.org/0000-0002-0357-0127
M
Okada