title: Critical role of aquaporin 3 on growth of human esophageal and oral squamous cell carcinoma.
abstract: Aquaporins (AQP) play important roles in water and glycerol transport. We examined whether AQP3 is expressed in primary squamous cell carcinoma (SCC) such as esophageal and oral cancer and lymph node metastasis, and whether AQP3 is a potential target for tumor therapy. A high level expression of AQP3 was observed in tumor areas of human primary SCC such as esophageal and lingual cancers, and lymph node metastasis, but was not observed in normal areas. Treatment with pan-AQP inhibitor caused apoptotic cell death on the SCC cell lines in a concentration-dependent manner. Small interfering RNA (siRNA) specific for AQP3 also inhibited cell adhesion and growth of SCC, but not those of adenocarcinoma cell lines and fibroblasts. Expression of integrin α5 and β1, counter adhesion molecules for fibronectin, was inhibited by treatment with AQP3-siRNA. The phosphorylation of focal adhesion kinase (FAK) was decreased by treatment with AQP3-siRNA, which then caused decreases in phosphorylation of Erk and MAPK. These results indicate that the decreases in integrins and the inhibition of cell adhesion might cause inhibition of the FAK signaling pathways. Combination of AQP3-siRNA with cisplatin, a major anti-cancer drug, strongly inhibited the growth of SCC. Cell death caused by the inhibition of AQP3 was a result of direct interference with cell adhesion involving intracellular FAK-MAPK signaling pathways. These results imply a potentially important and novel role for the inhibition of AQP3 function via the use of specific siRNA in the treatment of SCC.
authors.affiliation: Department of Pharmacology, Graduate School of Dentistry, Osaka University, Osaka, Japan.
authors.forename: Morio
authors.initials: M
authors.lastname: Kusayama
authors.forename: Koichiro
authors.initials: K
authors.lastname: Wada
authors.forename: Masahide
authors.initials: M
authors.lastname: Nagata
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Ishimoto
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Takahashi
authors.forename: Masato
authors.initials: M
authors.lastname: Yoneda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakajima
authors.forename: Masaya
authors.initials: M
authors.lastname: Okura
authors.forename: Mikihiko
authors.initials: M
authors.lastname: Kogo
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kamisaki
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D051400:Aquaporin 3 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D039081:Integrin alpha5beta1 / Q000037:antagonists & inhibitors; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D014062:Tongue Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D039081:Integrin alpha5beta1; D034741:RNA, Small Interfering; D051400:Aquaporin 3; D051416:Focal Adhesion Protein-Tyrosine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D002945:Cisplatin