Oncotarget

Research Papers:

Novel signaling collaboration between TGF-β and adaptor protein Crk facilitates EMT in human lung cancer

Aiman Z. Elmansuri, Mishie A. Tanino, Roshan Mahabir, Lei Wang, Taichi Kimura, Hiroshi Nishihara, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Masumi Tsuda and Shinya Tanaka _

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Oncotarget. 2016; 7:27094-27107. https://doi.org/10.18632/oncotarget.8314

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Abstract

Aiman Z. Elmansuri1, Mishie A. Tanino1, Roshan Mahabir1, Lei Wang2, Taichi Kimura2, Hiroshi Nishihara2, Ichiro Kinoshita3, Hirotoshi Dosaka-Akita3, Masumi Tsuda1 and Shinya Tanaka1,2

1 Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

2 Department of Translational Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

3 Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

Correspondence to:

Shinya Tanaka, email:

Mishie A. Tanino, email:

Keywords: Crk, EMT, lung cancer, small G protein, TGF-β

Received: September 10, 2015 Accepted: March 14, 2016 Published: March 24, 2016

Abstract

The signaling adaptor protein Crk has been shown to play an important role in various human cancers. However, its regulatory machinery is not clear. Here, we demonstrated that Crk induced EMT in A549 human lung adenocarcinoma cells through differential regulation of Rac1/Snail and RhoA/Slug, leading to decreased expression of E-cadherin and increased N-cadherin, fibronectin, and MMP2 expression. Cancer cells with mesenchymal features produced TGF-β and also increased the levels of TGF-β receptor. TGF-β increased the endogenous levels of Crk and also augmented Crk-dependent expression of Snail and Slug, and conversely TGF-β receptor inhibitor suppressed the levels of Snail and Slug. Overexpression of Crk was observed at the invasive front of human lung cancer tissues and was significantly associated with poor prognosis. Thus, TGF-β and Crk collaborate to form a positive feedback loop to facilitate EMT, which may lead to the malignancy of human cancers possibly being affected by their microenvironment.


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