Reticulon 3-mediated Chk2/p53 activation suppresses hepatocellular carcinogenesis and is blocked by hepatitis B virus
Reticulon 3-mediated Chk2/p53 activation suppresses hepatocellular carcinogenesis and is blocked by hepatitis B virus
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Reticulon 3 介导的 Chk2/p53 激活抑制肝细胞癌变并被乙型肝炎病毒阻断
DOI：
10.1136/gutjnl-2020-321386
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发表时间：
2021-11-01
期刊：
影响因子：
24.5
通讯作者：
Ruan, Yuanyuan
中科院分区：
文献类型：
--
作者：
Song, Shushu;Shi, Yinghong;Ruan, Yuanyuan
目的内质网（ER）蛋白功能障碍与肝细胞癌（HCC）稳态紊乱及恶性转化密切相关。网状蛋白 (RTN) 是内质网驻留蛋白家族，对于维持内质网功能至关重要。然而，RTN 在 HCC 中的确切作用仍不清楚。该研究的目的是检查网状蛋白家族成员 RTN3 对 HCC 发展的影响并探讨其潜在机制。设计 收集临床 HCC 样本以评估 RTN3 表达与患者预后之间的关系。采用 HCC 细胞系体外检测 RTN3 对细胞增殖、凋亡和信号转导的影响。利用裸鼠模型检测RTN3在体内调节肿瘤生长的作用。结果我们发现 RTN3 在正常肝细胞中高表达，但在 HCC 中频繁下调。 RTN3 低表达以 TP53 基因突变和 HBV 感染状态依赖性方式预测 HCC 患者预后不良。 RTN3 通过激活 p53 抑制 HCC 生长并诱导细胞凋亡。机制研究表明，RTN3 通过 Chk2 促进 p53 Ser392 磷酸化，并增强随后的 p53 核定位。 RTN3 与 Chk2 相互作用，将其招募到 ER 并以 ER 钙依赖性方式促进其激活。然而，RTN3 的肿瘤抑制作用在 HBV 阳性细胞中被消除。 HBV 表面抗原与 Chk2 竞争 RTN3 结合并阻断 RTN3 介导的 Chk2/p53 激活。结论：RTN3通过激活Chk2/p53通路发挥新型HCC抑制因子的作用，为更好地了解HBV的致癌作用提供更多线索。
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.