PMID- 25608512 OWN - NLM STAT- MEDLINE DCOM- 20151222 LR - 20190221 IS - 1479-6813 (Electronic) IS - 0952-5041 (Linking) VI - 54 IP - 2 DP - 2015 Apr TI - KSR1 is coordinately regulated with Notch signaling and oxidative phosphorylation in thyroid cancer. PG - 115-24 LID - 10.1530/JME-14-0270 [doi] 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 (rho=0.677, P=6.15x10(-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. CI - (c) 2015 Society for Endocrinology. FAU - Lee, Jandee AU - Lee J AD - Departments of SurgeryInternal MedicinePathologyYonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, 120-752 Seoul, Korea. FAU - Seol, Mi-Youn AU - Seol MY AD - Departments of SurgeryInternal MedicinePathologyYonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, 120-752 Seoul, Korea. FAU - Jeong, Seonhyang AU - Jeong S AD - Departments of SurgeryInternal MedicinePathologyYonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, 120-752 Seoul, Korea. FAU - Kwon, Hyeong Ju AU - Kwon HJ AD - Departments of SurgeryInternal MedicinePathologyYonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, 120-752 Seoul, Korea. FAU - Lee, Cho Rok AU - Lee CR AD - Departments of SurgeryInternal MedicinePathologyYonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, 120-752 Seoul, Korea. FAU - Ku, Cheol Ryong AU - Ku CR AD - Departments of SurgeryInternal MedicinePathologyYonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, 120-752 Seoul, Korea. FAU - Kang, Sang-Wook AU - Kang SW AD - Departments of SurgeryInternal MedicinePathologyYonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, 120-752 Seoul, Korea. FAU - Jeong, Jong Ju AU - Jeong JJ AD - Departments of SurgeryInternal MedicinePathologyYonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, 120-752 Seoul, Korea. FAU - Shin, Dong Yeob AU - Shin DY AD - Departments of SurgeryInternal MedicinePathologyYonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, 120-752 Seoul, Korea. FAU - Nam, Kee-Hyun AU - Nam KH AD - Departments of SurgeryInternal MedicinePathologyYonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, 120-752 Seoul, Korea. FAU - Lee, Eun Jig AU - Lee EJ AD - Departments of SurgeryInternal MedicinePathologyYonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, 120-752 Seoul, Korea. FAU - Chung, Woong Youn AU - Chung WY AD - Departments of SurgeryInternal MedicinePathologyYonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, 120-752 Seoul, Korea. FAU - Jo, Young Suk AU - Jo YS AD - Departments of SurgeryInternal MedicinePathologyYonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, 120-752 Seoul, Korea joys@yuhs.ac. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150121 PL - England TA - J Mol Endocrinol JT - Journal of molecular endocrinology JID - 8902617 RN - 0 (Neoplasm Proteins) RN - 0 (RNA, Messenger) RN - 0 (RNA, Small Interfering) RN - 0 (Receptors, Notch) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.1.- (KSR-1 protein kinase) RN - EC 2.7.11.1 (BRAF protein, human) RN - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf) SB - IM MH - Carcinoma/genetics/metabolism/pathology MH - Carcinoma, Papillary MH - Cell Line, Tumor MH - Cell Proliferation MH - Computational Biology MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Mitochondria/metabolism/ultrastructure MH - Mutation/genetics MH - Neoplasm Proteins/genetics/metabolism MH - *Oxidative Phosphorylation MH - Protein Kinases/genetics/*metabolism MH - Proto-Oncogene Proteins B-raf/genetics MH - RNA, Messenger/genetics/metabolism MH - RNA, Small Interfering/metabolism MH - Receptors, Notch/*metabolism MH - *Signal Transduction MH - Thyroid Cancer, Papillary MH - Thyroid Gland/metabolism/pathology MH - Thyroid Neoplasms/genetics/*metabolism/pathology OTO - NOTNLM OT - connector enhancer of KSR (CNKSR) OT - kinase suppressor of RAS (KSR) OT - notch signaling OT - oxidative phosphorylation OT - thyroid cancer EDAT- 2015/01/23 06:00 MHDA- 2015/12/23 06:00 CRDT- 2015/01/23 06:00 PHST- 2015/01/23 06:00 [entrez] PHST- 2015/01/23 06:00 [pubmed] PHST- 2015/12/23 06:00 [medline] AID - JME-14-0270 [pii] AID - 10.1530/JME-14-0270 [doi] PST - ppublish SO - J Mol Endocrinol. 2015 Apr;54(2):115-24. doi: 10.1530/JME-14-0270. Epub 2015 Jan 21.