Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, 2-2 Yamadaoka, Suita, Japan
Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, 2-2 Yamadaoka, Suita, Japan
Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, 2-2 Yamadaoka, Suita, Japan; Laboratory of Experimental Immunology, WPI Frontier Immunology Research Center, Osaka University, Suita, Japan
Kensaku Shojima
Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan; Gene Expression Laboratory (GEL-B), Salk Institute for Biological Studies, San Diego, United States
Toshiyuki Akama
Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan
Hidetoshi Eguchi
Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, 2-2 Yamadaoka, Suita, Japan
Pancreatic cancer has a high mortality rate due to metastasis. Whereas KRAS is mutated in most pancreatic cancer patients, controlling KRAS or its downstream effectors has not been succeeded clinically. ARL4C is a small G protein whose expression is induced by the Wnt and EGF–RAS pathways. In the present study, we found that ARL4C is frequently overexpressed in pancreatic cancer patients and showed that its localization to invasive pseudopods is required for cancer cell invasion. IQGAP1 was identified as a novel interacting protein for ARL4C. ARL4C recruited IQGAP1 and its downstream effector, MMP14, to invasive pseudopods. Specific localization of ARL4C, IQGAP1, and MMP14 was the active site of invasion, which induced degradation of the extracellular matrix. Moreover, subcutaneously injected antisense oligonucleotide against ARL4C into tumor-bearing mice suppressed metastasis of pancreatic cancer. These results suggest that ARL4C–IQGAP1–MMP14 signaling is activated at invasive pseudopods of pancreatic cancer cells.
