Abstract
The focal adhesion protein Tensin4, also known as cten (c-terminal tensin like), is structurally distinct from the three other members in the Tensin family. Its expression and potential functions in cancers including hepatocellular carcinoma (HCC) are not well understood. With immunohistochemistry, 43% (13/30) of our human HCC cases showed up-regulation of Tensin4 as compared with their corresponding non-tumorous livers. In HCC cells, treatment with epidermal growth factor (EGF) significantly induced Tensin4 transcript and protein expression, while treatment with pharmacological inhibitors against the MEK1/2 kinases abolished such induction, suggesting that Tensin4 expression was dependent on Ras/MAPK signaling. With immunofluorescence microscopy, the focal adhesion localization of Tensin4 was confirmed in HCC cells. Significantly, detailed examination using a panel of Tensin4 deletion constructs revealed that this specific focal adhesion localization required the N-terminal region together with the C-terminal SH2 domain. Up-regulation of ERK signaling by EGF in the HCC cells resulted in a change to a mesenchymal cell-like morphology through modulation of the actin cytoskeleton. Functionally, stable Tensin4 knockdown in SMMC-7721 HCC cells resulted in reduced cell proliferation and migration in vitro. Taken together, our data suggest that Tensin4 may play a pro-oncogenic role in HCC, possibly functioning as a downstream effector of Ras/MAPK signaling.
Highlights
Focal adhesions are structural links between the extracellular matrix (ECM) and actin cytoskeleton [1]
High level of Tensin4 expression was observed in LO2 and SMMC-7721 cells, while similar expression level was observed in a subset of hepatocellular carcinoma (HCC) cells (SK-Hep1, Hep3B, 97L and 97H) when compared to MIHA
We found that Tensin4 was expressed www.impactjournals.com/oncotarget in human HCC cells, though the expression level was quite variable among the different cell lines
Summary
Focal adhesions are structural links between the extracellular matrix (ECM) and actin cytoskeleton [1]. Focal adhesions are composed of diverse molecules, for instance, receptors, structural proteins, adaptors, GTPase, kinases and phosphatases. These focal adhesion proteins play critical roles in normal physiological events such as cellular adhesion, movement, cytoskeletal structure and intracellular signaling pathways. We have previously shown that focal adhesion proteins play critical roles in hepatocellular carcinoma (HCC) [7,8,9]. Understanding the molecular interactions and mechanisms of the interconnected focal adhesion proteins is of particular importance in understanding the mechanisms underlying HCC progression and development of potential effective treatment
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