KSR1 is coordinately regulated with notch signaling and oxidative phosphorylation in thyroid cancer

Jandee Lee, Mi Youn Seol, Seonhyang Jeong, Hyeongju Kwon, Cho Rok Lee, Cheol Ryong Ku, Sang Wook Kang, Jong Ju Jeong, Dong Yeob Shin, Kee Hyun Nam, Eunjig Lee, Woong Youn Chung, Young Suk Jo

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Kinase suppressor of RAS1 (KSR1) is a scaffold protein implicated in RAS-mediated RAF activation. However, the molecular function of KSR in papillary thyroid cancer (PTC) is unknown. Thus, this study aimed to characterize the role of KSR1 in patients with PTC. qRT-PCR and immunohistochemistry (IHC) revealed inter-tumor heterogeneities in the expression of KSR1 in PTC tissues. Interestingly, BRAFV600E-positive PTC showed higher KSR1 mRNA expression than BRAFV600E-negative PTC (P<0.001). Gene Set Enrichment Analysis (GSEA) using public repositories showed that high KSR1 expression coordinately upregulated Notch signaling (nominal P=0.019, false discovery rate (FDR) q-value=0.165); this finding was supported by GeneNetwork analysis, indicating that KSR1 expression is positively correlated with NOTCH1 expression (p=0.677, P=6.15×10 -9 ). siRNA against KSR1 (siKSR1) significantly decreased ERK phosphorylation induced by BRAFV600E, resulting in reduced expression of NOTCH1 and HES1, targets of Notch signaling. GSEA revealed that high KSR1 expression was also associated with downregulation of genes related to oxidative phosphorylation (OxPhos). Consistent with this, electron microscopy showed that PTCs with high KSR1 expression exhibited structural defects of the mitochondrial cristae. Furthermore, siKSR1-transfected BCPAP and 8505C cells generated fewer colonies in colony-forming assays. In addition, GSEA showed that high expression of KSR2 and connector enhancer of KSR1 (CNKSR1) also coordinately upregulated Notch signaling (KSR2: nominal P=0.0097, FDR q-value=0.154 and CNKSR1: nominal P<0.0001, FDR q-value=0.00554), and high CNKSR2 was associated with downregulation of the OxPhos gene set (nominal P<0.0001, FDR q-value <0.0001). In conclusion, KSR1 is coordinately regulated with Notch signaling and OxPhos in PTC, because its scaffold function might be required to sustain the proliferative signaling and metabolic remodeling associated with this type of cancer.

Original languageEnglish
Pages (from-to)115-124
Number of pages10
JournalJournal of molecular endocrinology
Volume54
Issue number2
DOIs
Publication statusPublished - 2015 Jan 21

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Oxidative Phosphorylation
Thyroid Neoplasms
Phosphotransferases
Genes
Small Interfering RNA
Down-Regulation
Factor IX
Papillary Thyroid cancer
Neoplasms
Electron Microscopy
Immunohistochemistry
Phosphorylation
Polymerase Chain Reaction
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Endocrinology

Cite this

Lee, Jandee ; Seol, Mi Youn ; Jeong, Seonhyang ; Kwon, Hyeongju ; Lee, Cho Rok ; Ku, Cheol Ryong ; Kang, Sang Wook ; Jeong, Jong Ju ; Shin, Dong Yeob ; Nam, Kee Hyun ; Lee, Eunjig ; Chung, Woong Youn ; Jo, Young Suk. / KSR1 is coordinately regulated with notch signaling and oxidative phosphorylation in thyroid cancer. In: Journal of molecular endocrinology. 2015 ; Vol. 54, No. 2. pp. 115-124.
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title = "KSR1 is coordinately regulated with notch signaling and oxidative phosphorylation in thyroid cancer",
abstract = "Kinase suppressor of RAS1 (KSR1) is a scaffold protein implicated in RAS-mediated RAF activation. However, the molecular function of KSR in papillary thyroid cancer (PTC) is unknown. Thus, this study aimed to characterize the role of KSR1 in patients with PTC. qRT-PCR and immunohistochemistry (IHC) revealed inter-tumor heterogeneities in the expression of KSR1 in PTC tissues. Interestingly, BRAFV600E-positive PTC showed higher KSR1 mRNA expression than BRAFV600E-negative PTC (P<0.001). Gene Set Enrichment Analysis (GSEA) using public repositories showed that high KSR1 expression coordinately upregulated Notch signaling (nominal P=0.019, false discovery rate (FDR) q-value=0.165); this finding was supported by GeneNetwork analysis, indicating that KSR1 expression is positively correlated with NOTCH1 expression (p=0.677, P=6.15×10 -9 ). siRNA against KSR1 (siKSR1) significantly decreased ERK phosphorylation induced by BRAFV600E, resulting in reduced expression of NOTCH1 and HES1, targets of Notch signaling. GSEA revealed that high KSR1 expression was also associated with downregulation of genes related to oxidative phosphorylation (OxPhos). Consistent with this, electron microscopy showed that PTCs with high KSR1 expression exhibited structural defects of the mitochondrial cristae. Furthermore, siKSR1-transfected BCPAP and 8505C cells generated fewer colonies in colony-forming assays. In addition, GSEA showed that high expression of KSR2 and connector enhancer of KSR1 (CNKSR1) also coordinately upregulated Notch signaling (KSR2: nominal P=0.0097, FDR q-value=0.154 and CNKSR1: nominal P<0.0001, FDR q-value=0.00554), and high CNKSR2 was associated with downregulation of the OxPhos gene set (nominal P<0.0001, FDR q-value <0.0001). In conclusion, KSR1 is coordinately regulated with Notch signaling and OxPhos in PTC, because its scaffold function might be required to sustain the proliferative signaling and metabolic remodeling associated with this type of cancer.",
author = "Jandee Lee and Seol, {Mi Youn} and Seonhyang Jeong and Hyeongju Kwon and Lee, {Cho Rok} and Ku, {Cheol Ryong} and Kang, {Sang Wook} and Jeong, {Jong Ju} and Shin, {Dong Yeob} and Nam, {Kee Hyun} and Eunjig Lee and Chung, {Woong Youn} and Jo, {Young Suk}",
year = "2015",
month = "1",
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doi = "10.1530/JME-14-0270",
language = "English",
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pages = "115--124",
journal = "Journal of Molecular Endocrinology",
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Lee, J, Seol, MY, Jeong, S, Kwon, H, Lee, CR, Ku, CR, Kang, SW, Jeong, JJ, Shin, DY, Nam, KH, Lee, E, Chung, WY & Jo, YS 2015, 'KSR1 is coordinately regulated with notch signaling and oxidative phosphorylation in thyroid cancer', Journal of molecular endocrinology, vol. 54, no. 2, pp. 115-124. https://doi.org/10.1530/JME-14-0270

KSR1 is coordinately regulated with notch signaling and oxidative phosphorylation in thyroid cancer. / Lee, Jandee; Seol, Mi Youn; Jeong, Seonhyang; Kwon, Hyeongju; Lee, Cho Rok; Ku, Cheol Ryong; Kang, Sang Wook; Jeong, Jong Ju; Shin, Dong Yeob; Nam, Kee Hyun; Lee, Eunjig; Chung, Woong Youn; Jo, Young Suk.

In: Journal of molecular endocrinology, Vol. 54, No. 2, 21.01.2015, p. 115-124.

Research output: Contribution to journalArticle

TY - JOUR

T1 - KSR1 is coordinately regulated with notch signaling and oxidative phosphorylation in thyroid cancer

AU - Lee, Jandee

AU - Seol, Mi Youn

AU - Jeong, Seonhyang

AU - Kwon, Hyeongju

AU - Lee, Cho Rok

AU - Ku, Cheol Ryong

AU - Kang, Sang Wook

AU - Jeong, Jong Ju

AU - Shin, Dong Yeob

AU - Nam, Kee Hyun

AU - Lee, Eunjig

AU - Chung, Woong Youn

AU - Jo, Young Suk

PY - 2015/1/21

Y1 - 2015/1/21

N2 - Kinase suppressor of RAS1 (KSR1) is a scaffold protein implicated in RAS-mediated RAF activation. However, the molecular function of KSR in papillary thyroid cancer (PTC) is unknown. Thus, this study aimed to characterize the role of KSR1 in patients with PTC. qRT-PCR and immunohistochemistry (IHC) revealed inter-tumor heterogeneities in the expression of KSR1 in PTC tissues. Interestingly, BRAFV600E-positive PTC showed higher KSR1 mRNA expression than BRAFV600E-negative PTC (P<0.001). Gene Set Enrichment Analysis (GSEA) using public repositories showed that high KSR1 expression coordinately upregulated Notch signaling (nominal P=0.019, false discovery rate (FDR) q-value=0.165); this finding was supported by GeneNetwork analysis, indicating that KSR1 expression is positively correlated with NOTCH1 expression (p=0.677, P=6.15×10 -9 ). siRNA against KSR1 (siKSR1) significantly decreased ERK phosphorylation induced by BRAFV600E, resulting in reduced expression of NOTCH1 and HES1, targets of Notch signaling. GSEA revealed that high KSR1 expression was also associated with downregulation of genes related to oxidative phosphorylation (OxPhos). Consistent with this, electron microscopy showed that PTCs with high KSR1 expression exhibited structural defects of the mitochondrial cristae. Furthermore, siKSR1-transfected BCPAP and 8505C cells generated fewer colonies in colony-forming assays. In addition, GSEA showed that high expression of KSR2 and connector enhancer of KSR1 (CNKSR1) also coordinately upregulated Notch signaling (KSR2: nominal P=0.0097, FDR q-value=0.154 and CNKSR1: nominal P<0.0001, FDR q-value=0.00554), and high CNKSR2 was associated with downregulation of the OxPhos gene set (nominal P<0.0001, FDR q-value <0.0001). In conclusion, KSR1 is coordinately regulated with Notch signaling and OxPhos in PTC, because its scaffold function might be required to sustain the proliferative signaling and metabolic remodeling associated with this type of cancer.

AB - Kinase suppressor of RAS1 (KSR1) is a scaffold protein implicated in RAS-mediated RAF activation. However, the molecular function of KSR in papillary thyroid cancer (PTC) is unknown. Thus, this study aimed to characterize the role of KSR1 in patients with PTC. qRT-PCR and immunohistochemistry (IHC) revealed inter-tumor heterogeneities in the expression of KSR1 in PTC tissues. Interestingly, BRAFV600E-positive PTC showed higher KSR1 mRNA expression than BRAFV600E-negative PTC (P<0.001). Gene Set Enrichment Analysis (GSEA) using public repositories showed that high KSR1 expression coordinately upregulated Notch signaling (nominal P=0.019, false discovery rate (FDR) q-value=0.165); this finding was supported by GeneNetwork analysis, indicating that KSR1 expression is positively correlated with NOTCH1 expression (p=0.677, P=6.15×10 -9 ). siRNA against KSR1 (siKSR1) significantly decreased ERK phosphorylation induced by BRAFV600E, resulting in reduced expression of NOTCH1 and HES1, targets of Notch signaling. GSEA revealed that high KSR1 expression was also associated with downregulation of genes related to oxidative phosphorylation (OxPhos). Consistent with this, electron microscopy showed that PTCs with high KSR1 expression exhibited structural defects of the mitochondrial cristae. Furthermore, siKSR1-transfected BCPAP and 8505C cells generated fewer colonies in colony-forming assays. In addition, GSEA showed that high expression of KSR2 and connector enhancer of KSR1 (CNKSR1) also coordinately upregulated Notch signaling (KSR2: nominal P=0.0097, FDR q-value=0.154 and CNKSR1: nominal P<0.0001, FDR q-value=0.00554), and high CNKSR2 was associated with downregulation of the OxPhos gene set (nominal P<0.0001, FDR q-value <0.0001). In conclusion, KSR1 is coordinately regulated with Notch signaling and OxPhos in PTC, because its scaffold function might be required to sustain the proliferative signaling and metabolic remodeling associated with this type of cancer.

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