The Growth Promoting Effect of LETM1 Coupled with Oxidative Phosphorylation in Human Anaplastic Thyroid Cancers
Seulgi Lee1, Woo Kyung Lee2, Hyunji Kim1,Seonhyang Jeong2, Sang Geun Jung3, Jandee Lee1, and Young Suk Jo2 1Department of Surgery and 2Internal Medicine, Open NBI Convergence Technology Research Laboratory, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, 03722, Seoul, South Korea; 3Department of Gynecological Oncology, Bundang CHA Medical Center, CHA University, 13496, Gyeonggi-do, South Korea Corresponding author: Jandee Lee, MD, PhD; Jandee@yuhs.ac Or Young Suk Jo, MD, PhD; JOYS@yuhs.ac
Background: Energy metabolism integrated with mitochondrial oxidative phosphorylation (OxPhos) is related to aggressive phenotypical changes and drug resistance in certain types of cancers. Objectives: The aim of this study was to characterize metabolic phenotypes of human anaplastic thyroid cancers and to investigate the potential role of LETM1, a mitochondrial calcium transporter, in tumorigenesis of thyroid cancers. Methods: Gene set enrichment analysis (GSEA) followed by RT-qPCR was conducted using public repository data and our own tissue samples. Using anaplastic thyroid cancer cell lines, western blotting, BN-PAGE and cell proliferation assays were conducted to investigate the effects of LETM1 on OxPhos expression and cell survival. Results: GSEA clearly presented that the expression of LETM1 is strongly associated with PDGF receptor signaling and insulin signaling pathways. Immunohistochemical (IHC) staining also indicated a positive association of LETM1 upregulation with high PDGFB expression. Consistent with our previous report, high LETM1 expression was related to aggressive tumor behaviors in clinical data statistical analysis. In cell based assays, LETM1 transfection increased S473 phosphorylation of Akt and nuclear localization of YAP1, promoting cell proliferation. Conclusion: LETM1 up-regulation appears to play a pivotal role in mitochondrial metabolism and tumor behavior in aggressive thyroid cancers such as poorly differentiated and anaplastic thyroid cancers.