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Coupling of LETM1 up-regulation with oxidative phosphorylation and platelet-derived growth factor receptor signaling via YAP1 transactivation

 Jandee Lee  ;  Woo Kyung Lee  ;  Mi-Youn Seol  ;  Seul Gi Lee  ;  Daham Kim  ;  Hyunji Kim  ;  Jongsun Park  ;  Sang Geun Jung  ;  Woong Youn Chung  ;  Eun Jig Lee  ;  Young Suk Jo 
 ONCOTARGET , Vol.7(41) : 66728-66739, 2016 
Journal Title
Issue Date
Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism* ; Adult ; Calcium-Binding Proteins/genetics ; Calcium-Binding Proteins/metabolism* ; Cell Line, Tumor ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Membrane Proteins/genetics ; Membrane Proteins/metabolism* ; Middle Aged ; Oxidative Phosphorylation* ; Phosphoproteins/genetics ; Phosphoproteins/metabolism* ; RNA Interference ; Receptor, Platelet-Derived Growth Factor beta/genetics ; Receptor, Platelet-Derived Growth Factor beta/metabolism* ; Thyroid Neoplasms/genetics ; Thyroid Neoplasms/metabolism ; Thyroid Neoplasms/pathology ; Transcriptional Activation ; Up-Regulation*
LETM1 ; cell proliferation ; electron transport chain ; metabolism ; prognosis
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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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Daham(김다함) ORCID logo https://orcid.org/0000-0003-1871-686X
Lee, Seul Gi(이슬기) ORCID logo https://orcid.org/0000-0003-3233-7823
Lee, Woo Kyung(이우경) ORCID logo https://orcid.org/0000-0002-6737-3173
Lee, Eun Jig(이은직) ORCID logo https://orcid.org/0000-0002-9876-8370
Lee, Jan Dee(이잔디) ORCID logo https://orcid.org/0000-0003-4090-0049
Chung, Woung Youn(정웅윤)
Jo, Young Suk(조영석) ORCID logo https://orcid.org/0000-0001-9926-8389
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