Park Soon-Ki, Kang Min-Ju, Ko Kyung-Phil, Chi Sung-Gil
Department of Life Sciences, Korea University, Seoul, Korea.
Cancer Res Treat. 2025 Apr 18. doi: 10.4143/crt.2025.135.
Ras association domain family 4 (RASSF4) is a putative tumor suppressor that is frequently inactivated in multiple human cancers. However, its candidacy as a suppressor in gastric tumorigenesis remains undefined. To understand the role for RASSF4 in gastric tumorigenesis, we investigated its expression status in cancer cell lines and tissues and regulatory role in tumor growth.
RASSF4 expression was analyzed in 13 cancer cell lines and 20 carcinoma tissues using PCR and immunoblot assays. RASSF4 effect on cell proliferation and apoptosis was examined by flow cytometry, colony formation, and [3H]thymidine incorporation assays and its regulation of p53 was determined using cycloheximide chase, promoter reporter, and immunoprecipitation assays. Mouse xenograft assay was performed to verify RASSF4 effect on tumor growth and therapeutic response.
RASSF4 expression is epigenetically inactivated in 8 of 13 (61.5%) cancer cell lines and 15 of 20 (75%) primary carcinomas. RASSF4 suppresses cell proliferation by inducing a G2/M cell-cycle arrest and enhances apoptotic response to therapeutic drugs. RASSF4 is induced in response to genotoxic agents to facilitate stress-induced apoptosis in a highly p53-dependent fashion. Mechanistically, RASSF4 stabilizes p53 through Chk2 activation and its apoptotic function is profoundly impaired by depletion of either p53 or Chk2. RASSF4 attenuates xenograft tumor growth and enhances tumor response to 5-FU. Clinically, RASSF4 expression correlates strongly with the overall survival of gastric cancer patients.
RASSF4 suppresses gastric tumor growth through the activation of the Chk2-p53 axis, illuminating the mechanistic consequence of its inactivation in gastric tumorigenesis.
Ras 关联结构域家族 4（RASSF4）是一种假定的肿瘤抑制因子，在多种人类癌症中经常失活。然而，其作为胃癌发生抑制因子的候选地位仍不明确。为了解 RASSF4 在胃癌发生中的作用，我们研究了其在癌细胞系和组织中的表达状态以及对肿瘤生长的调节作用。
使用 PCR 和免疫印迹分析检测 13 种癌细胞系和 20 例癌组织中的 RASSF4 表达。通过流式细胞术、集落形成和[3H]胸苷掺入试验检测 RASSF4 对细胞增殖和凋亡的影响，并使用环己酰亚胺追踪、启动子报告基因和免疫沉淀试验确定其对 p53 的调节作用。进行小鼠异种移植试验以验证 RASSF4 对肿瘤生长和治疗反应的影响。
RASSF4 表达在 13 种（61.5%）癌细胞系中的 8 种以及 20 例原发性癌中的 15 例（75%）中发生表观遗传失活。RASSF4 通过诱导 G2/M 期细胞周期阻滞抑制细胞增殖，并增强对治疗药物的凋亡反应。RASSF4 在基因毒性剂作用下被诱导，以高度依赖 p53 的方式促进应激诱导的凋亡。机制上，RASSF4 通过激活 Chk2 稳定 p53，其凋亡功能在 p53 或 Chk2 缺失时受到严重损害。RASSF4 减弱异种移植肿瘤的生长并增强肿瘤对 5-氟尿嘧啶的反应。临床上，RASSF4 表达与胃癌患者的总生存期密切相关。
RASSF4 通过激活 Chk2-p53 轴抑制胃癌生长，阐明了其在胃癌发生中失活的机制后果。
