title: Arl4c expression in colorectal and lung cancers promotes tumorigenesis and may represent a novel therapeutic target.
abstract: We recently demonstrated that expression of ADP-ribosylation factor (ARF)-like 4c (Arl4c) induced by a combination of Wnt/β-catenin and epidermal growth factor/Ras signaling in normal epithelial cells grown in three-dimensional culture promotes cellular migration and proliferation, resulting in formation of tube-like structures, suggesting the involvement of Arl4c in epithelial morphogenesis. It is conceivable that there could be a common mechanism between epithelial morphogenesis and carcinogenesis. Therefore the current study was conducted to investigate whether Arl4c might be involved in tumorigenesis. Immunohistochemical analyses of tissue specimens obtained from colorectal and lung cancer patients revealed that Arl4c was not observed in non-tumor regions but was strongly expressed at high frequencies in tumor lesions. Inhibition of Wnt/β-catenin or Ras/mitogen-activated protein kinase signaling reduced Arl4c mRNA levels in HCT116 colorectal cancer cells and A549 lung cancer cells. Knockdown of Arl4c inhibited Rac activity and also prevented nuclear localization of yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) in these cancer cells. Arl4c-depleted cancer cells consistently showed decreased migration, invasion and proliferation capabilities both in vitro and in vivo. Furthermore, direct injection of Arl4c small interfering RNA (siRNA) into HCT116 cell-derived tumors (in vivo treatment with siRNA) inhibited tumor growth in immunodeficient mice. These results suggest that Arl4c is involved in tumorigenesis and might represent a novel therapeutic target for suppressing proliferation and invasion of colorectal and lung cancer cells.
authors.affiliation: Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan.|Interdisciplinary Program for Biomedical Sciences (IPBS), Institute for Academic Initiatives, Osaka University, Suita, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Fujii
authors.affiliation: Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: Department of Pathology, Graduate School of Medicine, Osaka University, Suita, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Nojima
authors.affiliation: Department of Pathology, Graduate School of Medicine, Osaka University, Suita, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Morii
authors.affiliation: Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kikuchi
mesh_terms: D020727:ADP-Ribosylation Factors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D034741:RNA, Small Interfering; D020727:ADP-Ribosylation Factors; C541133:ARL4C protein, human