2. Academic Validation
  3. RBM12 drives PD-L1-mediated immune evasion in hepatocellular carcinoma by increasing JAK1 mRNA translation

RBM12 drives PD-L1-mediated immune evasion in hepatocellular carcinoma by increasing JAK1 mRNA translation

  • Oncogene. 2024 Aug 26. doi: 10.1038/s41388-024-03140-y.
Hexu Han # 1,  Qian Shi # 2,  Yue Zhang # 3,  Mingdong Ding # 4,  Xianzhong He # 5,  Cuixia Liu 1,  Dakun Zhao 1,  Yifan Wang 1,  Yanping Du 1,  Yichao Zhu 6,  Yin Yuan 7,  Siliang Wang 8,  Huimin Guo 9,  Qiang Wang 10
Affiliations

Affiliations

  • 1 Department of Gastroenterology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu, 225300, China.
  • 2 Huzhou Key Laboratory of Translational Medicine, The First Affliated Hospital of Huzhou University, Huzhou, Zhejiang, 313000, China.
  • 3 Clinical Medical Laboratory Center, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, Jiangsu, 225300, China.
  • 4 Department of Infectious Diseases, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu, 225300, China.
  • 5 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Innovative Institute of Tumor Immunity and Medicine (ITIM), Anhui Provincial Innovation Institute for Pharmaceutical Basic Research, Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, Anhui, 230000, China.
  • 6 Department of Hepatobiliary Surgery, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu, 225300, China.
  • 7 Department of Hepatobiliary Surgery, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu, 225300, China. yuanyin@njmu.edu.cn.
  • 8 Department of pharmacy, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210000, China. wsl_dth@126.com.
  • 9 Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210000, China. guo_huimin@126.com.
  • 10 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Innovative Institute of Tumor Immunity and Medicine (ITIM), Anhui Provincial Innovation Institute for Pharmaceutical Basic Research, Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, Anhui, 230000, China. wangqiang@ahmu.edu.cn.
  • # Contributed equally.
PMID: 39187545 DOI: 10.1038/s41388-024-03140-y
Abstract

Immunosuppression characterizes the tumour microenvironment in HCC, and recent studies have implicated RNA-binding proteins (RBPs) in the development of HCC. Here, we conducted a screen and identified RBM12 as a key protein that increased the expression of PD-L1, thereby driving immune evasion in HCC. Furthermore, RBM12 was found to be significantly upregulated in HCC tissues and was associated with a poor prognosis for HCC patients. Through various molecular assays and high-throughput screening, we determined that RBM12 could directly bind to the JAK1 mRNA via its 4th-RRM (RNA recognition motif) domain and recruit EIF4A2 through its 2nd-RRM domain, enhancing the distribution of ribosomes on JAK1 mRNA, which promotes the translation of JAK1 and the subsequent upregulation of its expression. As a result, the activated JAK1/STAT1 pathway transcriptionally upregulates PD-L1 expression, facilitating immune evasion in HCC. In summary, our findings provide insights into the significant contribution of RBM12 to immune evasion in HCC, highlighting its potential as a therapeutic target in the future. This graphical abstract shows that elevated expression of RBM12 in HCC can augment PD-L1-mediated tumour immune evasion by increasing the efficiency of JAK1 mRNA translation.

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