Coupling of LETM1 up-regulation with oxidative phosphorylation and platelet-derived growth factor receptor signaling via YAP1 transactivation
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Jandee Lee1, Woo Kyung Lee2, Mi-Youn Seol1, Seul Gi Lee1, Daham Kim2, Hyunji Kim1, Jongsun Park3, Sang Geun Jung4, Woong Youn Chung1, Eun Jig Lee2, Young Suk Jo2
1Department of Surgery, Open NBI Convergence Technology Research Laboratory, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
2Department of Internal Medicine, Open NBI Convergence Technology Research Laboratory, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
3Department of Pharmacology, Metabolic Diseases and Cell Signaling Laboratory, Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon, Korea
4Department of Gynecological Oncology, Bundang CHA Medical Center, CHA University, Gyeonggi-do, Korea
Young Suk Jo, email: [email protected]
Keywords: LETM1, metabolism, prognosis, electron transport chain, cell proliferation
Received: December 16, 2015 Accepted: August 13, 2016 Published: August 20, 2016
Persistent cellular proliferation and metabolic reprogramming are essential processes in carcinogenesis. Here, we performed Gene Set Enrichment Analysis (GSEA) and found that that LETM1, a mitochondrial calcium transporter, is associated with cellular growth signals such as platelet-derived growth factor (PDGF) receptor signaling and insulin signaling pathways. These results were then verified by qRT-PCR and immnunoblotting. Mechanistically, up-regulation of LETM1 induced YAP1 nuclear accumulation, increasing the expression of PDGFB, PDGFRB and THBS4. Consistent with this, LETM1 silencing caused loss of YAP1 nuclear signal, decreasing the expression of PDGFB, PDGFRB and THBS4. Immunohistochemical staining consistently indicated a positive association between LETM1 up-regulation, YAP1 nuclear localization and high PDGFB expression. In clinical data analysis, LETM1 up-regulation in thyroid cancer was found to be related to aggressive tumor features such as lymphovascular invasion (LVI, P < 0.001) and lymph node metastasis (LNM, P = 0.011). Multivariate analysis demonstrated that LETM1 up-regulation increases the risk of LVI and LNM (OR = 3.455, 95% CI = 1.537–7.766 and OR = 3.043, 95% CI = 1.282–7.225, respectively). Collectively, these data suggest that up-regulation of LETM1 induces sustained activation of proliferative signaling pathways, such as PDGF signal pathway by AKT induced YAP1 transactivation, resulting in aggressive thyroid cancer phenotypes.
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