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Tetraspanin TM4SF5 mediates loss of contact inhibition through epithelial-mesenchymal transition in human hepatocarcinoma
Sin-Ae Lee, … , Ki Hun Park, Jung Weon Lee
Sin-Ae Lee, … , Ki Hun Park, Jung Weon Lee
Published March 20, 2008
Citation Information: J Clin Invest. 2008;118(4):1354-1366. https://doi.org/10.1172/JCI33768.
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Research Article Article has an altmetric score of 11

Tetraspanin TM4SF5 mediates loss of contact inhibition through epithelial-mesenchymal transition in human hepatocarcinoma

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Abstract

The growth of normal cells is arrested when they come in contact with each other, a process known as contact inhibition. Contact inhibition is lost during tumorigenesis, resulting in uncontrolled cell growth. Here, we investigated the role of the tetraspanin transmembrane 4 superfamily member 5 (TM4SF5) in contact inhibition and tumorigenesis. We found that TM4SF5 was overexpressed in human hepatocarcinoma tissue. TM4SF5 expression in clinical samples and in human hepatocellular carcinoma cell lines correlated with enhanced p27Kip1 expression and cytosolic stabilization as well as morphological elongation mediated by RhoA inactivation. These TM4SF5-mediated effects resulted in epithelial-mesenchymal transition (EMT) via loss of E-cadherin expression. The consequence of this was aberrant cell growth, as assessed by S-phase transition in confluent conditions, anchorage-independent growth, and tumor formation in nude mice. The TM4SF5-mediated effects were abolished by suppressing the expression of either TM4SF5 or cytosolic p27Kip1, as well as by reconstituting the expression of E-cadherin. Our observations have revealed a role for TM4SF5 in causing uncontrolled growth of human hepatocarcinoma cells through EMT.

Authors

Sin-Ae Lee, Sung-Yul Lee, Ik-Hyun Cho, Min-A Oh, Eun-Sil Kang, Yong-Bae Kim, Woo Duck Seo, Suyong Choi, Ju-Ock Nam, Mimi Tamamori-Adachi, Shigetaka Kitajima, Sang-Kyu Ye, Semi Kim, Yoon-Jin Hwang, In-San Kim, Ki Hun Park, Jung Weon Lee

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Figure 3

TM4SF5 enhanced cytosolic p27Kip1 stabilization.

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TM4SF5 enhanced cytosolic p27Kip1 stabilization.
               
(A) Rep...
(A) Representative normal and tumor tissues for immunohistochemistry for p27Kip1. Original magnification, ×400. SNU449Cp and SNU449Tp were double-stained with DAPI and either anti-p27Kip1 (B) or anti-hKIS (D). (C) Lysates prepared as in Figure 1B were immunoblotted. (E) RT-PCR for p27Kip1 or GAPDH by using total RNA prepared from actinomycin D–treated cells (Act D, 10 μg/ml; upper panel) or immunoblots for p27Kip1 or α-tubulin using lysates from cycloheximide treated cells (CHX, 10 mM; middle panel) were performed. Lower panels: Band intensities were measured, normalized to control band intensities, and plotted. Scale bars: 20 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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