한빛사논문
- 조회440
Cho-Rong Lee 1,15, Jungyo Suh 2,3,15, Dongjun Jang 1,4,15, Bo-Yeong Jin 1, Jaeso Cho 1, Moses Lee 1, Hyungtai Sim 1, Minyong Kang 2,5,6,7,8, Jueun Lee 9,10, Ju Hyun Park 2,3, Kyoung-Hwa Lee 2,11, Geum-Sook Hwang 9,10, Kyung Chul Moon 12, Cheryn Song 3, Ja Hyeon Ku 2, Cheol Kwak 2, Hyeon Hoe Kim 2, Sung-Yup Cho 1,4,13,14,*, Murim Choi 1,* and Chang Wook Jeong 2,*
1Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
2Department of Urology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
3Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
4Department of Biochemistry, Seoul National University College of Medicine, Seoul, Republic of Korea.
5Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
6Samsung Genome Institute, Samsung Medical Center, Seoul, Korea.
7Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea.
8Department of Digital Health, SAIHST, Sungkyunkwan University, Seoul, Korea.
9Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul, Republic of Korea.
10Department of Pharmacy, Chung-Ang University, Seoul, Republic of Korea.
11Songdo BioEngineering, Incheon Jaeneung University, Incheon, Republic of Korea.
12Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
13Medical Research Center, Genomic Medicine Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
14Cancer Research Institute, Seoul National University, Seoul, Republic of Korea.
15These authors contributed equally: Cho-Rong Lee, Jungyo Suh, Dongjun Jang.
*Corresponding authors: correspondence to Sung-Yup Cho, Murim Choi or Chang Wook Jeong
Abstract
TFE3-rearranged renal cell cancer (tRCC) is a rare form of RCC that involves chromosomal translocation of the Xp11.2 TFE3 gene. Despite its early onset and poor prognosis, the molecular mechanisms of the pathogenesis of tRCC remain elusive. This study aimed to identify novel therapeutic targets for patients with primary and recurrent tRCC. We collected 19 TFE3-positive RCC tissues that were diagnosed by immunohistochemistry and subjected them to genetic characterization to examine their genomic and transcriptomic features. Tumor-specific signatures were extracted using whole exome sequencing (WES) and RNA sequencing (RNA-seq) data, and the functional consequences were analyzed in a cell line with TFE3 translocation. Both a low burden of somatic single nucleotide variants (SNVs) and a positive correlation between the number of somatic variants and age of onset were observed. Transcriptome analysis revealed that four samples (21.1%) lacked the expected fusion event and clustered with the genomic profiles of clear cell RCC (ccRCC) tissues. The fusion event also demonstrated an enrichment of upregulated genes associated with mitochondrial respiration compared with ccRCC expression profiles. Comparison of the RNA expression profile with the TFE3 ChIP-seq pattern data indicated that PPARGC1A is a metabolic regulator of the oncogenic process. Cell proliferation was reduced when PPARGC1A and its related metabolic pathways were repressed by its inhibitor SR-18292. In conclusion, we demonstrate that PPARGC1A-mediated mitochondrial respiration can be considered a potential therapeutic target in tRCC. This study identifies an uncharacterized genetic profile of an RCC subtype with unique clinical features and provides therapeutic options specific to tRCC.
논문정보
- Research article
- 2024년 08월 (BRIC 등록일 2024-08-01)
- 국내 연구진
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