慢性肝损伤诱导的细胞衰老抑制促进肝癌发生的作用和机制

Cellular senescence is an irreversible arrest of cell proliferation. It revealed that cellular senescence plays a critical suppressive role during the initiation and progression of cancer. Chronic liver injury is a complex pathologic process with progressive damage and regeneration of hepatic parenchymal cells caused by diverse damage factors, and hepatocytic senescence and its inhibition involve in hepatocarcinogenesis. In our previous work, we found that hepatocytic senescence appeared in Fah-/- mice with acute liver injury, while inhibition of hepatocytic senescence was presented in Fah-/- mice with chronic liver injury followed a significant incidence of hepatocarcinoma. Therefore we presume that inhibition of hepatocytic senescence induced by chronic liver injury in Fah-/- mice facilitated the initiation of hepatocarcinoma. Using the appraisal system of hepatocytic senescence established by our research group, in this project we will perform a comprehensive evaluation of the pathologic characters of hepatocytes undergoing chronic liver injury, and prove the determinative role of inhibition of cellular senescence induced by chronic liver injury in the hepatocarcinogenesis. Meanwhile, using Fah-/- mice with normal or deficient immunity, and the strategy of antibody neutralization, we aim to prove that the transformed senescent hepatocytes will be cleared by immune cells mediated by senescent cells secreting factor, which is the dominating mechanism inhibiting hepatocarcinogenesis. The execution of this project will provide the evidence for the implementation of regulating hepatocytic senescence and curing hepatocarcinoma by induced senescence, and provide an experiment protocol to induce hepatocytic senescence then inhibit hepatocarcinogenesis and progression.

细胞衰老是一种不可逆的细胞生长停滞状态，在肿瘤发生发展过程中起着极其重要的抑癌作用。慢性肝损伤是多种损害因素引起的进行性肝实质细胞破坏与再生的复杂病理过程，其中肝细胞的衰老与衰老抑制成为肝癌发生的重要机制问题。在前期工作中，我们发现肝损伤模型Fah-/-小鼠急性肝损伤时表现为肝细胞的衰老，而慢性肝损伤时却表现为肝细胞衰老的抑制，且肝癌发生率显著提高。我们推断慢性损伤时Fah-/-小鼠肝细胞衰老的抑制促进了肝癌的发生。利用建立的肝细胞衰老评价体系，本申请将全面评价慢性肝损伤下肝细胞的病理特征，明确慢性肝损伤诱导的肝细胞衰老抑制是肝癌发生的决定因素。应用免疫正常或缺陷Fah-/-小鼠及抗体中和策略，明确衰老细胞分泌因子诱导免疫细胞清除癌变衰老细胞，是抑制肝癌发生的主要机制。本申请的实施，将为实现肝细胞衰老可调控性和肝癌衰老诱导治疗提供理论依据，为诱导肝细胞衰老从而抑制肝癌发生发展提供实验方案。

细胞衰老是一种不可逆的细胞生长停滞状态，在肿瘤发生发展过程中起着极其重要的抑癌作用。慢性肝损伤是多种损害因素引起的进行性肝实质细胞破坏与再生的复杂病理过程，其中肝细胞的衰老与衰老抑制成为肝癌发生的重要机制问题。本项目的研究内容是全面评价慢性肝损伤下肝细胞的病理特征，明确慢性肝损伤诱导的肝细胞衰老抑制是肝癌发生的决定因素，明确衰老细胞分泌因子诱导免疫细胞清除癌变衰老细胞是抑制肝癌发生的主要机制。..通过研究开展，本项目取得如下结果：利用建立的肝细胞衰老评价体系，本项目开展了急慢性损伤下肝脏的病理变化规律和肝细胞衰老规律的研究，发现慢性肝损伤下肝细胞衰老抑制是肝癌发生的原因，转录谱分析证明不同程度的肝损伤会导致肝细胞进入衰老或者继续增殖状态。应用CDK4/6抑制剂哌泊塞克雷布可诱导慢性肝损伤下的肝细胞发生衰老，肝细胞被诱导衰老后进一步被巨噬细胞清除从而抑制了HCC的发生，表明衰老细胞分泌因子诱导免疫细胞清除癌前病变细胞是抑制肝癌发生的主要作用机制。..本基金标注的成果先后发表在Cell Death & Disease 2018a, 2018b, 2019, 2020; Frontiers in Cell and Developmental Biology 2021a, 2021b; Frontiers in Oncology 2020; Frontiers in Microbiology 2021等国际期刊。..本项目的实施，阐明了慢性肝损伤诱导的肝细胞衰老抑制是促进肝癌发生的机制，发现CDK4/6抑制剂可作为慢性肝损伤下肝细胞衰老的诱导剂从而降低肝癌的发生率，本研究为实现肝细胞衰老可调控性和肝癌衰老诱导治疗提供了理论依据，也为诱导肝细胞衰老从而抑制肝癌发生提供了实验方案。