Tetraspanin TM4SF5 mediates loss of contact inhibition through epithelial-mesenchymal transition in human hepatocarcinoma.
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.
Lee
Sin-Ae
SA
Cancer Research Institute, College of Medicine, Seoul National University, Jongno-gu, Seoul, Republic of Korea.
Lee
Sung-Yul
SY
Cho
Ik-Hyun
IH
Oh
Min-A
MA
Kang
Eun-Sil
ES
Kim
Yong-Bae
YB
Seo
Woo Duck
WD
Choi
Suyong
S
Nam
Ju-Ock
JO
Tamamori-Adachi
Mimi
M
Kitajima
Shigetaka
S
Ye
Sang-Kyu
SK
Kim
Semi
S
Hwang
Yoon-Jin
YJ
Kim
In-San
IS
Park
Ki Hun
KH
Lee
Jung Weon
JW
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002450:Cell Communication; D002460:Cell Line; D003260:Contact Inhibition; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology*; D005786:Gene Expression Regulation; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D009368:Neoplasm Transplantation; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D008565:Membrane Proteins; C111029:TM4SF5 protein, human; C570858:TM4SF5 protein, mouse; D050760:Cyclin-Dependent Kinase Inhibitor p27; D020742:rhoA GTP-Binding Protein