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

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 qRTPCR 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 upregulation 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.

Original languageEnglish
Pages (from-to)66728-66739
Number of pages12
JournalOncotarget
Volume7
Issue number41
DOIs
Publication statusPublished - 2016 Jan 1

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Platelet-Derived Growth Factor Receptors
Oxidative Phosphorylation
Transcriptional Activation
Proto-Oncogene Proteins c-sis
Up-Regulation
Platelet-Derived Growth Factor beta Receptor
Thyroid Neoplasms
Platelet-Derived Growth Factor
Signal Transduction
Carcinogenesis
Multivariate Analysis
Lymph Nodes
Cell Proliferation
Insulin
Staining and Labeling
Neoplasm Metastasis
Calcium
Phenotype
Growth
Genes

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Lee, Jandee ; Lee, Woo Kyung ; Seol, Mi Youn ; Lee, Seul Gi ; Kim, Daham ; Kim, Hyunji ; Park, Jongsun ; Jung, Sang Geun ; Chung, Woong Youn ; Lee, Eun Jig ; Jo, Young Suk. / Coupling of LETM1 up-regulation with oxidative phosphorylation and platelet-derived growth factor receptor signaling via YAP1 transactivation. In: Oncotarget. 2016 ; Vol. 7, No. 41. pp. 66728-66739.
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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 qRTPCR 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 upregulation 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.",
author = "Jandee Lee and Lee, {Woo Kyung} and Seol, {Mi Youn} and Lee, {Seul Gi} and Daham Kim and Hyunji Kim and Jongsun Park and Jung, {Sang Geun} and Chung, {Woong Youn} and Lee, {Eun Jig} and Jo, {Young Suk}",
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Lee, J, Lee, WK, Seol, MY, Lee, SG, Kim, D, Kim, H, Park, J, Jung, SG, Chung, WY, Lee, EJ & Jo, YS 2016, 'Coupling of LETM1 up-regulation with oxidative phosphorylation and platelet-derived growth factor receptor signaling via YAP1 transactivation', Oncotarget, vol. 7, no. 41, pp. 66728-66739. https://doi.org/10.18632/oncotarget.11456

Coupling of LETM1 up-regulation with oxidative phosphorylation and platelet-derived growth factor receptor signaling via YAP1 transactivation. / Lee, Jandee; Lee, Woo Kyung; Seol, Mi Youn; Lee, Seul Gi; Kim, Daham; Kim, Hyunji; Park, Jongsun; Jung, Sang Geun; Chung, Woong Youn; Lee, Eun Jig; Jo, Young Suk.

In: Oncotarget, Vol. 7, No. 41, 01.01.2016, p. 66728-66739.

Research output: Contribution to journalArticle

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T1 - Coupling of LETM1 up-regulation with oxidative phosphorylation and platelet-derived growth factor receptor signaling via YAP1 transactivation

AU - Lee, Jandee

AU - Lee, Woo Kyung

AU - Seol, Mi Youn

AU - Lee, Seul Gi

AU - Kim, Daham

AU - Kim, Hyunji

AU - Park, Jongsun

AU - Jung, Sang Geun

AU - Chung, Woong Youn

AU - Lee, Eun Jig

AU - Jo, Young Suk

PY - 2016/1/1

Y1 - 2016/1/1

N2 - 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 qRTPCR 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 upregulation 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.

AB - 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 qRTPCR 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 upregulation 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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