Wang Yiqiao, Huang Shihao, Cai Yangbai, Wang Taicheng, Zhao Hongyan, Lin Xianke, Wang Xueguo, Li Peng
Department of Hepatobiliary and Pancreatic Surgery, Yueqing City People's Hospital, No. 338 Qingyuan Road, Chengnan Street, Yueqing City 325699, Zhejiang Province, China.
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Hainan Medical University, No. 48 Baishuitang Road, Haikou City 570100, Hainan Province, China.
Biochim Biophys Acta Mol Basis Dis. 2025 Mar;1871(3):167696. doi: 10.1016/j.bbadis.2025.167696. Epub 2025 Jan 28.
Programmed cell death protein 5 (PDCD5) is involved in apoptosis and is regarded as a tumor suppressor in various tumors. However, its role and underlying molecular mechanisms in hepatocellular carcinoma (HCC) remain unclear.
PDCD5-overexpressing cell and xenograft tumor models were developed. Cell Counting Kit-8, 5-Ethynyl-2'-deoxyuridine, wound healing, Transwell, flow cytometry, immunohistochemistry, and hematoxylin-eosin staining were employed to explore the effects of PDCD5 on HCC cell behaviors and tumor growth. The enzyme-linked immunosorbent assay and western blot were used to detect pyroptosis-related marker levels. The molecular mechanisms underlying PDCD5's role in HCC were investigated through transcriptome sequencing and coimmunoprecipitation. SRI-011381, a TGF-β signaling activator, was applied to evaluate the impact of PDCD5 in modulating the TGF-β/Smad2/3/Snail pathway.
PDCD5 expression was reduced in HCC cells. Overexpression of PDCD5 inhibited HCC cell proliferation, migration, invasion, and xenograft tumor growth. Additionally, PDCD5 overexpression promoted apoptosis and pyroptosis, with corresponding increases in inflammatory factors and Caspase-1, GSDMD, and NLRP3 protein levels. Mechanistically, PDCD5 bound to receptor-regulated Smads (Smad2/3), inhibiting the TGF-β pathway. Treatment with the TGF-β pathway activator SRI-011381 significantly counteracted the inhibitory effects of PDCD5 overexpression on HCC progression.
Our findings suggest that PDCD5 impedes the progression of HCC by promoting pyroptosis via regulation of TGF-β/Smad2/3/Snail pathway, which could be a possible therapeutic target for HCC.
程序性细胞死亡蛋白5（PDCD5）参与细胞凋亡，在多种肿瘤中被视为肿瘤抑制因子。然而，其在肝细胞癌（HCC）中的作用及潜在分子机制仍不清楚。
构建了PDCD5过表达细胞和异种移植瘤模型。采用细胞计数试剂盒-8、5-乙炔基-2'-脱氧尿苷、伤口愈合实验、Transwell实验、流式细胞术、免疫组织化学和苏木精-伊红染色来探究PDCD5对肝癌细胞行为和肿瘤生长的影响。采用酶联免疫吸附测定和蛋白质印迹法检测焦亡相关标志物水平。通过转录组测序和免疫共沉淀研究PDCD5在肝癌中作用的分子机制。应用TGF-β信号激活剂SRI-011381来评估PDCD5在调节TGF-β/Smad2/3/Snail通路中的作用。
肝癌细胞中PDCD5表达降低。PDCD5过表达抑制肝癌细胞增殖、迁移、侵袭及异种移植瘤生长。此外，PDCD5过表达促进细胞凋亡和焦亡，炎症因子以及Caspase-1、GSDMD和NLRP3蛋白水平相应升高。机制上，PDCD5与受体调节型Smads（Smad2/3）结合，抑制TGF-β通路。用TGF-β通路激活剂SRI-011381处理可显著抵消PDCD5过表达对肝癌进展的抑制作用。
我们的研究结果表明，PDCD5通过调节TGF-β/Smad2/3/Snail通路促进焦亡，从而阻碍肝癌进展，这可能是肝癌的一个潜在治疗靶点。
