한빛사논문
- 조회742
충남대학교병원
Byong-Sop Song1, Ji Sun Moon2, Jingwen Tian2,3, Ho Yeop Lee2,3, Byeong Chang Sim2,3, Seok-Hwan Kim4, Seul Gi Kang3, Jung Tae Kim3, Ha Thi Nga2,3, Rui Benfeitas5, Yeongmin Kim6, Sanghee Park7, Robert R. Wolfe8, Hyuk Soo Eun9, Minho Shong9, Sunjae Lee10, Il-Young Kim6,7 and Hyon-Seung Yi1,2,3,9
1Department of Core Laboratory of Translational Research, Biomedical Convergence Research Center, Chungnam National University Hospital, Daejeon, South Korea
2Laboratory of Endocrinology and Immune System, Chungnam National University School of Medicine, Daejeon, South Korea
3Department of Medical Science, Chungnam National University School of Medicine, Daejeon, South Korea
4Department of Surgery, Chungnam National University School of Medicine, Daejeon, South Korea
5National Bioinformatics Infrastructure Sweden (NBIS), Science for Life Laboratory, Stockholm, Sweden
6Department of Health Sciences and Technology, Gachon Advanced Institute for Health Sciences & Technology (GAIHST), Incheon, South Korea
7Department of Molecular Medicine, College of Medicine, Gachon University, Incheon, South Korea
8Department of Geriatrics, the Center for Translational Research in Aging & Longevity, Donald W. Reynolds Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR, USA
9Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, South Korea
10School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, South Korea
Correspondence to Professor Hyon-Seung Yi; Dr Il-Young Kim; Dr Sunjae Lee
Abstract
Background Mitochondria are involved in cancer energy metabolism, although the mechanisms underlying the involvement of mitoribosomal dysfunction in hepatocellular carcinoma (HCC) remain poorly understood. Here, we investigated the effects of mitoribosomal impairment-mediated alterations on the immunometabolic characteristics of liver cancer.
Methods We used a mouse model of HCC, liver tissues from patients with HCC, and datasets from The Cancer Genome Atlas (TCGA) to elucidate the relationship between mitoribosomal proteins (MRPs) and HCC. In a mouse model, we selectively disrupted expression of the mitochondrial ribosomal protein CR6-interacting factor 1 (CRIF1) in hepatocytes to determine the impact of hepatocyte-specific impairment of mitoribosomal function on liver cancer progression. The metabolism and immunophenotype of liver cancer was assessed by glucose flux assays and flow cytometry, respectively.
Results Single-cell RNA-seq analysis of tumor tissue and TCGA HCC transcriptome analysis identified mitochondrial defects associated with high-MRP expression and poor survival outcomes. In the mouse model, hepatocyte-specific disruption of the mitochondrial ribosomal protein CRIF1 revealed the impact of mitoribosomal dysfunction on liver cancer progression. Crif1 deficiency promoted programmed cell death protein 1 expression by immune cells in the hepatic tumor microenvironment. A [U-13C6]-glucose tracer demonstrated enhanced glucose entry into the tricarboxylic acid cycle and lactate production in mice with mitoribosomal defects during cancer progression. Mice with hepatic mitoribosomal defects also exhibited enhanced progression of liver cancer accompanied by highly exhausted tumor-infiltrating T cells. Crif1 deficiency induced an environment unfavorable to T cells, leading to exhaustion of T cells via elevation of reactive oxygen species and lactate production.
Conclusions Hepatic mitoribosomal defects promote glucose partitioning toward glycolytic flux and lactate synthesis, leading to T cell exhaustion and cancer progression. Overall, the results suggest a distinct role for mitoribosomes in regulating the immunometabolic microenvironment during HCC progression.
논문정보
- Research article
- 2022년 05월 (BRIC 등록일 2022-05-23)
- 국내(교신)+국외 연구진
- 의약학 > 응용의학
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