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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.

SUBMITTER: Choi SI

PROVIDER: S-EPMC4259440 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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TM4SF4 overexpression in radiation-resistant lung carcinoma cells activates IGF1R via elevation of IGF1.

Choi Soo-Im SI Kim Seo-Yeon SY Lee Jaeha J Cho Eun-Wie EW Kim In-Gyu IG

Oncotarget 20141001 20

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 ...[more]

PMID: 25344917

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Project description:BackgroundEpithelial ovarian cancer (EOC) is the leading cause of death from gynaecologic malignancies and has a poor prognosis due to metastasis. Drugs targeting the angiogenesis pathway significantly improve patient outcome. However, the key factors linking angiogenesis and metastasis have not been elucidated. In this study, we found Tie2 expressing monocytes (CD14+Tie2+, TEMs) as key contributors to angiogenesis and metastasis of EOC.MethodsTissue slides were evaluated by immunofluorescence for the presence of total tissue macrophages and TEMs. The correlation between microvascular density (MVD) values and the TEMs number or ratio was calculated in both ovarian cancer tissues and peritoneum. The rate of TEMs in monocytes was evaluated in the peripheral blood of female healthy donors, benign cysts patients, and EOC patients using flow cytometry. The TEMs rate in ascites from EOC patients was also evaluated by flow cytometry. The concentration of Ang2, as the ligand of Tie2, was examined by ELISA in serum samples of EOC patients, benign cysts patients, and ascites samples of EOC patients. The effects of Ang2 on the migration and the cytokine expression of TEMs were further examined. The pro- angiogenesis activity of TEMs via IGF1 was performed in both in vivo and in vitro. And the IGF1 blocking test was performed using neutralising antibody.ResultsTEMs were significantly higher in tumour foci, peripheral blood and ascites in EOC patients. The proportion of TEMs among total tissue macrophages was positively correlated with tumour MVD. In vivo animal results showed that TEMs promoted EOC angiogenesis and metastasis. Further functional and mechanisms studies revealed that concentration of angiopoietin 2 (Ang2), a ligand of Tie2, was elevated in EOC ascites which further recruit TEMs in a dose-dependent manner as a powerful chemokine to TEMs. Recruited TEMs promoted endothelial cell function through IGF1-activated downstream signalling. Blocking secreted IGF1 using inhibiting antibody reduced TEMs mediated angiogenesis and metastasis.ConclusionsTEMs significantly increased in EOC patients and were recruited to tumour loci by the increased Ang2. The increased TEMs have diagnostic value in ovarian cancer and were positively correlated with the MVD in ovarian cancer tissue. Furthermore, TEMs promote angiogenesis via IGF1 in both in vivo and in vitro experimental systems after stimulation by Ang2. Altogether, this study paves the way to develop novel therapy targets as the axis of Ang2-TEMs-IGF1 in EOC.

Dataset Information

TM4SF4 overexpression in radiation-resistant lung carcinoma cells activates IGF1R via elevation of IGF1.

Publications

TM4SF4 overexpression in radiation-resistant lung carcinoma cells activates IGF1R via elevation of IGF1.

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