網狀蛋白3介導的Chk2 / p53激活抑制肝細胞癌變並被乙型肝炎病

StephenW

Reticulon 3-mediated Chk2/p53 activation suppresses hepatocellular carcinogenesis and is blocked by hepatitis B virus
Shushu Song  1 , Yinghong Shi  2 , Weicheng Wu  1 , Hao Wu  1 , Lei Chang  3 , Peike Peng  1 , Lei Zhang  4 , Jia Fan  2 , Jianxin Gu  1 , Yuanyuan Ruan  5
Affiliations
Affiliations

    1
    Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
    2
    Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
    3
    State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China.
    4
    Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
    5
    Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China [email protected].

    PMID: 33303565 DOI: 10.1136/gutjnl-2020-321386

Abstract

Objective: Dysfunction of endoplasmic reticulum (ER) proteins is closely related to homeostasis disturbance and malignant transformation of hepatocellular carcinoma (HCC). Reticulons (RTN) are a family of ER-resident proteins critical for maintaining ER function. Nevertheless, the precise roles of RTN in HCC remain largely unclear. The aim of the study is to examine the effect of reticulon family member RTN3 on HCC development and explore the underlying mechanisms.

Design: Clinical HCC samples were collected to assess the relationship between RTN3 expression and patients' outcome. HCC cell lines were employed to examine the effects of RTN3 on cellular proliferation, apoptosis and signal transduction in vitro. Nude mice model was used to detect the role of RTN3 in modulating tumour growth in vivo.

Results: We found that RTN3 was highly expressed in normal hepatocytes but frequently downregulated in HCC. Low RTN3 expression predicted poor outcome in patients with HCC in TP53 gene mutation and HBV infection status-dependent manner. RTN3 restrained HCC growth and induced apoptosis by activating p53. Mechanism studies indicated that RTN3 facilitated p53 Ser392 phosphorylation via Chk2 and enhanced subsequent p53 nuclear localisation. RTN3 interacted with Chk2, recruited it to ER and promoted its activation in an ER calcium-dependent manner. Nevertheless, the tumour suppressive effects of RTN3 were abrogated in HBV-positive cells. HBV surface antigen competed with Chk2 for RTN3 binding and blocked RTN3-mediated Chk2/p53 activation.

Conclusion: The findings suggest that RTN3 functions as a novel suppressor of HCC by activating Chk2/p53 pathway and provide more clues to better understand the oncogenic effects of HBV.

Keywords: cell death; cell proliferation; hepatoma; signal transduction.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

StephenW

網狀蛋白3介導的Chk2 / p53激活抑制肝細胞癌變並被乙型肝炎病毒阻斷
宋樹書1，應紅紅2，吳維成1，浩1，雷昌3，培鵬1，張磊4，賈凡2，顧建新1，圓圓阮5
隸屬關係
隸屬關係

    1個
    復旦大學基礎醫學院生物化學與分子生物學系，上海
    2
    復旦大學附屬中山醫院肝癌研究所肝外科，上海
    3
    蛋白質組學國家重點實驗室，北京蛋白質組研究中心，國家蛋白質科學中心（北京），北京生命科學研究院，中國北京。
    4
    復旦大學附屬中山醫院普外科，上海
    5
    復旦大學基礎醫學院生物化學與分子生物學系，上海[email protected]。

    PMID：33303565 DOI：10.1136 / gutjnl-2020-321386

抽象

目的：內質網（ER）蛋白功能異常與肝細胞癌（HCC）的穩態失調和惡性轉化密切相關。網狀蛋白（RTN）是ER駐留蛋白家族，對維持ER功能至關重要。儘管如此，RTN在肝癌中的確切作用仍不清楚。該研究的目的是研究網狀家族成員RTN3對肝癌發展的影響，並探討其潛在機制。

設計：收集臨床HCC樣品以評估RTN3表達與患者預後之間的關係。 HCC細胞系用於檢查RTN3對體外細胞增殖，凋亡和信號轉導的影響。使用裸鼠模型檢測RTN3在體內調節腫瘤生長的作用。

結果：我們發現RTN3在正常肝細胞中高表達，但在HCC中經常下調。 RTN3的低表達預測TP53基因突變和HBV感染狀態依賴性的HCC患者預後不良。 RTN3通過激活p53抑制HCC生長並誘導凋亡。機制研究表明，RTN3通過Chk2促進p53 Ser392磷酸化並增強隨後的p53核定位。 RTN3與Chk2相互作用，將其招募至ER，並以ER鈣依賴性方式促進其激活。儘管如此，RTN3的腫瘤抑製作用在HBV陽性細胞中被取消。 HBV表面抗原與Chk2競爭RTN3結合併阻斷RTN3介導的Chk2 / p53激活。

結論：研究結果表明，RTN3通過激活Chk2 / p53途徑作為HCC的新型抑制物，並提供了更多線索以更好地了解HBV的致癌作用。

關鍵詞：細胞死亡；細胞增殖；肝癌信號轉導。

©作者（或其雇主）2020。不得商業重複使用。查看權限。由BMJ發布。