title: TM4SF4 overexpression in radiation-resistant lung carcinoma cells activates IGF1R via elevation of IGF1.
abstract: Transmembrane 4 L six family member 4 (TM4SF4) is a member of the tetraspanin L6 domain family. Other members of this family, TM4SF1 (also known as L6-Ag) and TM4SF5, have been shown to be upregulated in multiple tumors and involved in epithelial-to-mesenchymal transition and cell migration. However, unlike its homologs, little is known about TM4SF4. Here, we show that TM4SF4 was highly expressed in radiation-resistant lung adenocarcinoma cells, such as A549 and Calu-3 cells, and its expression activated cell growth, migration, and invasion. Overexpression of TM4SF4 in A549 cells increased the activation of PI3K, AKT, and NF-kappaB and the expression of PTEN. IGF1R was clearly activated by overexpression of TM4SF4, although EGFR was also slightly activated. TM4SF4 expression was correlated with the increased expression of IGF1, consequently resulting in IGF1R activation. Tumorigenic activity of TM4SF4 in lung adenocarcinoma cells was also demonstrated by xenograft assay; however, this activity was almost completely suppressed by treatment with anti-TM4SF4 antibody. Our results suggest that TM4SF4 overexpression in lung carcinoma cells results in resistance to radiotherapy via IGF1-induced IGF1R activation and blocking the activity of TM4SF4 using specific antibody can be a promising therapeutics against TM4SF4-overexpressing lung adenocarcinoma.
authors.affiliation: Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute (KAERI), Daedeok-daero, Yuseong-gu, Daejeon, South Korea. Department of Radiation Biotechnology and Applied Radioisotope, Korea University of Science and Technology, Daedeok-daero, Yuseong-gu, Daejeon, South Korea.
authors.forename: Soo-Im
authors.initials: SI
authors.lastname: Choi
authors.affiliation: Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute (KAERI), Daedeok-daero, Yuseong-gu, Daejeon, South Korea.
authors.forename: Seo-Yeon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute (KAERI), Daedeok-daero, Yuseong-gu, Daejeon, South Korea. Department of Radiation Biotechnology and Applied Radioisotope, Korea University of Science and Technology, Daedeok-daero, Yuseong-gu, Daejeon, South Korea.
authors.forename: Jaeha
authors.initials: J
authors.lastname: Lee
authors.affiliation: Epigenomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Gwahak-ro, Yuseong-gu, Daejeon, South Korea.
authors.forename: Eun-Wie
authors.initials: EW
authors.lastname: Cho
authors.affiliation: Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute (KAERI), Daedeok-daero, Yuseong-gu, Daejeon, South Korea. Department of Radiation Biotechnology and Applied Radioisotope, Korea University of Science and Technology, Daedeok-daero, Yuseong-gu, Daejeon, South Korea.
authors.forename: In-Gyu
authors.initials: IG
authors.lastname: Kim
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D000077192:Adenocarcinoma of Lung; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D019175:DNA Methylation; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011836:Radiation Tolerance; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000906:Antibodies; C583557:IGF1 protein, human; C000597236:IGF1R protein, human; D008562:Membrane Glycoproteins; D017451:Receptors, Somatomedin; C429031:TM4SF4 protein, human; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1