title: Coupling of LETM1 up-regulation with oxidative phosphorylation and platelet-derived growth factor receptor signaling via YAP1 transactivation.
abstract: 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.
authors.affiliation: Department of Surgery, Open NBI Convergence Technology Research Laboratory, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jandee
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Open NBI Convergence Technology Research Laboratory, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Woo Kyung
authors.initials: WK
authors.lastname: Lee
authors.affiliation: Department of Surgery, Open NBI Convergence Technology Research Laboratory, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Mi-Youn
authors.initials: MY
authors.lastname: Seol
authors.affiliation: Department of Surgery, Open NBI Convergence Technology Research Laboratory, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Seul Gi
authors.initials: SG
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Open NBI Convergence Technology Research Laboratory, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Daham
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Surgery, Open NBI Convergence Technology Research Laboratory, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hyunji
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Metabolic Diseases and Cell Signaling Laboratory, Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon, Korea.
authors.forename: Jongsun
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Gynecological Oncology, Bundang CHA Medical Center, CHA University, Gyeonggi-do, Korea.
authors.forename: Sang Geun
authors.initials: SG
authors.lastname: Jung
authors.affiliation: Department of Surgery, Open NBI Convergence Technology Research Laboratory, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Woong Youn
authors.initials: WY
authors.lastname: Chung
authors.affiliation: Department of Internal Medicine, Open NBI Convergence Technology Research Laboratory, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Eun Jig
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Open NBI Convergence Technology Research Laboratory, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Young Suk
authors.initials: YS
authors.lastname: Jo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D010085:Oxidative Phosphorylation; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors; D015533:Transcriptional Activation; D015854:Up-Regulation; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C488528:LETM1 protein, human; D008565:Membrane Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D020797:Receptor, Platelet-Derived Growth Factor beta
keywords: LETM1; cell proliferation; electron transport chain; metabolism; prognosis