Liver-specific gene PGRMC1 blocks c-Myc-induced hepatocarcinogenesis through ER stress-independent PERK activation
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...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55745-2 |
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| author | Fubo Ji Jianjuan Zhang Liping Mao Yaqi Tan Meihua Ye Xianglei He Yongzhi Zhao Jiaxin Liu Yan Zhang Nachuan Zhang Jiong Shi Jianing Yan Xiujun Cai Bin Zhao Jianping Jin Pinglong Xu Stephanie Roessler Xin Zheng Junfang Ji |
| author_facet | Fubo Ji Jianjuan Zhang Liping Mao Yaqi Tan Meihua Ye Xianglei He Yongzhi Zhao Jiaxin Liu Yan Zhang Nachuan Zhang Jiong Shi Jianing Yan Xiujun Cai Bin Zhao Jianping Jin Pinglong Xu Stephanie Roessler Xin Zheng Junfang Ji |
| author_sort | Fubo Ji |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-fd382c9a078748658650788bdb73a5a3 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-fd382c9a078748658650788bdb73a5a32025-01-05T12:37:29ZengNature PortfolioNature Communications2041-17232025-01-0116111710.1038/s41467-024-55745-2Liver-specific gene PGRMC1 blocks c-Myc-induced hepatocarcinogenesis through ER stress-independent PERK activationFubo Ji0Jianjuan Zhang1Liping Mao2Yaqi Tan3Meihua Ye4Xianglei He5Yongzhi Zhao6Jiaxin Liu7Yan Zhang8Nachuan Zhang9Jiong Shi10Jianing Yan11Xiujun Cai12Bin Zhao13Jianping Jin14Pinglong Xu15Stephanie Roessler16Xin Zheng17Junfang Ji18The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityThe MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityThe MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityThe MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityZhejiang Provincial People’s HospitalZhejiang Provincial People’s HospitalThe MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityThe MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityThe MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityThe MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityDepartment of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical SchoolDepartment of General Surgery, Sir Run Run Shaw Hospital Affiliated to School of Medicine, Zhejiang UniversityDepartment of General Surgery, Sir Run Run Shaw Hospital Affiliated to School of Medicine, Zhejiang UniversityThe MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityThe MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityThe MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityInstitute of Pathology, University Hospital HeidelbergTaoharmony Biotech L.L.C.The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityAbstract 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.https://doi.org/10.1038/s41467-024-55745-2 |
| spellingShingle | Fubo Ji Jianjuan Zhang Liping Mao Yaqi Tan Meihua Ye Xianglei He Yongzhi Zhao Jiaxin Liu Yan Zhang Nachuan Zhang Jiong Shi Jianing Yan Xiujun Cai Bin Zhao Jianping Jin Pinglong Xu Stephanie Roessler Xin Zheng Junfang Ji Liver-specific gene PGRMC1 blocks c-Myc-induced hepatocarcinogenesis through ER stress-independent PERK activation Nature Communications |
| title | Liver-specific gene PGRMC1 blocks c-Myc-induced hepatocarcinogenesis through ER stress-independent PERK activation |
| title_full | Liver-specific gene PGRMC1 blocks c-Myc-induced hepatocarcinogenesis through ER stress-independent PERK activation |
| title_fullStr | Liver-specific gene PGRMC1 blocks c-Myc-induced hepatocarcinogenesis through ER stress-independent PERK activation |
| title_full_unstemmed | Liver-specific gene PGRMC1 blocks c-Myc-induced hepatocarcinogenesis through ER stress-independent PERK activation |
| title_short | Liver-specific gene PGRMC1 blocks c-Myc-induced hepatocarcinogenesis through ER stress-independent PERK activation |
| title_sort | liver specific gene pgrmc1 blocks c myc induced hepatocarcinogenesis through er stress independent perk activation |
| url | https://doi.org/10.1038/s41467-024-55745-2 |
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