2. Academic Validation
  3. Liver-specific gene PGRMC1 blocks c-Myc-induced hepatocarcinogenesis through ER stress-independent PERK activation

Liver-specific gene PGRMC1 blocks c-Myc-induced hepatocarcinogenesis through ER stress-independent PERK activation

  • Nat Commun. 2025 Jan 2;16(1):50. doi: 10.1038/s41467-024-55745-2.
Fubo Ji # 1 2 3,  Jianjuan Zhang # 1 2 3,  Liping Mao # 1 2 3,  Yaqi Tan 1 2 3,  Meihua Ye 4,  Xianglei He 4,  Yongzhi Zhao 1 2 3,  Jiaxin Liu 1 2 3,  Yan Zhang 1 2 3,  Nachuan Zhang 1 2 3,  Jiong Shi 5,  Jianing Yan 6,  Xiujun Cai 6,  Bin Zhao 1 2 3,  Jianping Jin 1 2 3,  Pinglong Xu 1 3,  Stephanie Roessler 7,  Xin Zheng 8,  Junfang Ji 9 10 11 12
Affiliations

Affiliations

  • 1 The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
  • 2 Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang, 321000, China.
  • 3 Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
  • 4 Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, 310000, China.
  • 5 Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, 210008, China.
  • 6 Department of General Surgery, Sir Run Run Shaw Hospital Affiliated to School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China.
  • 7 Institute of Pathology, University Hospital Heidelberg, Heidelberg, 69120, Germany.
  • 8 Taoharmony Biotech L.L.C., Hangzhou, Zhejiang, 310018, China.
  • 9 The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, 310058, China. junfangji@zju.edu.cn.
  • 10 Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang, 321000, China. junfangji@zju.edu.cn.
  • 11 Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China. junfangji@zju.edu.cn.
  • 12 Department of General Surgery, Sir Run Run Shaw Hospital Affiliated to School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China. junfangji@zju.edu.cn.
  • # Contributed equally.
PMID: 39747098 DOI: 10.1038/s41467-024-55745-2
Abstract

Roles of liver-specific genes (LSGs) in tumor initiation and progression are rarely explored in hepatocellular carcinoma (HCC). Here we show that LSGs are generally downregulated in HCC tumor tissues compared to non-HCC liver tissues, and low-LSG HCCs show poor prognosis and the activated c-Myc pathway. Among the c-Myc- and patient prognosis-associated LSGs, PGRMC1 significantly blocks c-Myc-induced orthotopic HCC formation. The role of PGRMC1 depends on its localization to the endoplasmic reticulum (ER) membrane, where PGRMC1 interacts with PERK through their ER luminal domains. This interaction in turn activates PERK in an ER stress-independent manner, which phosphorylates eIF2α and consequently inhibits c-Myc protein translation. In HCC patients, PGRMC1 level is significantly reduced in tumor tissues and negatively associated with the c-Myc signature. Patients with low-PGRMC1 in their tumors have poor prognosis. Collectively, deregulated LSGs in HCC are associated with the c-Myc pathway activation and PGRMC1 blocks c-Myc-induced hepatic carcinogenesis through promoting ER stress-independent PERK activation.

Figures
Products