Key contribution of eIF4H-mediated translational control in tumor promotion
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Charlotte Vaysse1,2, Céline Philippe1,2, Yvan Martineau1,2, Cathy Quelen1,2, Corinne Hieblot1,2, Claire Renaud3, Yvan Nicaise4, Aurore Desquesnes5, Maria Pannese6, Thomas Filleron7, Ghislaine Escourrou1,4, Malcolm Lawson8, Robert C. Rintoul9, Marie Bernadette Delisle1,4, Stéphane Pyronnet1,2, Pierre Brousset1,2,10, Hervé Prats1,2, Christian Touriol1,2
1INSERM U1037, CRCT, Cancer Research Center of Toulouse, Toulouse, France
2Toulouse University, Paul Sabatier, Toulouse, France
3Department of Thoracic Surgery, Rangueil-Larrey Hospital, Toulouse, France
4Department of Pathology, CHU Rangueil, Toulouse, France
5Inserm US006 Crefre, Toulouse, France
6San Raffaele Scientific Institute, Milano, Italy
7Clinical trial office–Cellule Biostatistique Institut Universitaire du Cancer Toulouse, Toulouse, France
8Department of Respiratory Medicine, Broomfield Hospital, Chelmsford, Essex, UK
9Department of Thoracic Oncology, Papworth Hospital, Cambridge, UK
10Department of Pathology, Institut Universitaire du Cancer, Toulouse, France
Christian Touriol, e-mail: email@example.com
Keywords: lung carcinoma, chemoresistance, translation initiation factor, eIF4H, IRES, helicase
Received: May 27, 2015 Accepted: October 03, 2015 Published: October 15, 2015
Dysregulated expression of translation initiation factors has been associated with carcinogenesis, but underlying mechanisms remains to be fully understood. Here we show that eIF4H (eukaryotic translation initiation factor 4H), an activator of the RNA helicase eIF4A, is overexpressed in lung carcinomas and predictive of response to chemotherapy. In lung cancer cells, depletion of eIF4H enhances sensitization to chemotherapy, decreases cell migration and inhibits tumor growth in vivo, in association with reduced translation of mRNA encoding cell-proliferation (c-Myc, cyclin D1) angiogenic (FGF-2) and anti-apoptotic factors (CIAP-1, BCL-xL). Conversely, each isoform of eIF4H acts as an oncogene in NIH3T3 cells by stimulating transformation, invasion, tumor growth and resistance to drug-induced apoptosis together with increased translation of IRES-containing or structured 5′UTR mRNAs. These results demonstrate that eIF4H plays a crucial role in translational control and can promote cellular transformation by preferentially regulating the translation of potent growth and survival factor mRNAs, indicating that eIF4H is a promising new molecular target for cancer therapy.
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