Du Chaoxiang, Hu Yunfan, Yang Xinyu, Zhang Zhe, Gu Jianmin, Zhang Tao, Wang Renfeng, Zhang Shaoyuan, Tan Lijie, Yu Guiping
Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 200032 Shanghai, China.
Department of Thoracic Surgery, Zhongshan Hospital (Xiamen), Fudan University, 361006 Xiamen, Fujian, China.
Front Biosci (Landmark Ed). 2025 Jan 22;30(1):27047. doi: 10.31083/FBL27047.
This study investigates the role of small ubiquitin-like modifier (SUMO)-specific peptidase 5 (SENP5), a key regulator of SUMOylation, in esophageal squamous cell carcinoma (ESCC), a lethal disease, and its underlying molecular mechanisms.
Differentially expressed genes between ESCC mouse oesophageal cancer tissues and normal tissues were analysed via RNA-seq; among them, SENP5 expression was upregulated, and this gene was selected for further analysis. Immunohistochemistry and western blotting were then used to validate the increased protein level of SENP5 in both mouse and human ESCC samples. The Kaplan‒Meier method and multivariate analysis were used to analyse the relationship between SENP5 expression and ESCC prognosis. Stable SENP5-knockdown (KD) cell lines and conditional knockout (cKO) mice were established to verify the biological function of SENP5. Further RNA-seq comparisons between short hairpin SENP5 (shSENP5)- and short hairpin negative control (shNC)-transfected ESCC cell lines were conducted, and the nuclear factor kappa B (NF-κB)- axis was identified through bioinformatics analysis. The correlation of SENP5 with signalling pathway components was validated via real-time quantitative PCR (qPCR), western blotting (WB), and immunoprecipitation.
Our study revealed that SENP5 was upregulated in human and mouse ESCC samples, and clinical data analysis revealed a correlation between high SENP5 expression and poor patient prognosis. SENP5 knockdown inhibited tumorigenesis and growth and suppressed the proliferation, migration, and invasion of ESCC cell lines . Our study also revealed that SENP5 knockdown enhanced the SUMO1-mediated SUMOylation of NF-kappa-B inhibitor alpha (IκBα), thereby inhibiting the activation of the NF-κB- axis, which subsequently suppresses ESCC cell energy metabolism and impedes ESCC progression.
Suppression of SENP5 slows the development of ESCC by inhibiting the NF-κB axis through SUMO1-mediated SUMOylation of IκBα. Our research suggests that SENP5 could serve as a prognostic indicator and a target for therapeutic intervention for ESCC patients.
本研究调查小泛素样修饰物（SUMO）特异性肽酶5（SENP5）这一SUMO化关键调节因子在致死性疾病食管鳞状细胞癌（ESCC）中的作用及其潜在分子机制。
通过RNA测序分析ESCC小鼠食管癌组织与正常组织之间的差异表达基因；其中，SENP5表达上调，选取该基因进行进一步分析。随后采用免疫组织化学和蛋白质印迹法验证小鼠和人ESCC样本中SENP5蛋白水平升高。采用Kaplan-Meier法和多因素分析来分析SENP5表达与ESCC预后之间的关系。建立稳定的SENP5敲低（KD）细胞系和条件性敲除（cKO）小鼠以验证SENP5的生物学功能。对短发夹SENP5（shSENP5）和短发夹阴性对照（shNC）转染的ESCC细胞系进行进一步的RNA测序比较，并通过生物信息学分析确定核因子κB（NF-κB）轴。通过实时定量PCR（qPCR）、蛋白质印迹法（WB）和免疫沉淀验证SENP5与信号通路成分的相关性。
我们的研究表明，SENP5在人和小鼠ESCC样本中上调，临床数据分析显示SENP5高表达与患者预后不良相关。SENP5敲低抑制肿瘤发生和生长，并抑制ESCC细胞系的增殖、迁移和侵袭。我们的研究还表明，SENP5敲低增强了SUMO1介导的NF-κB抑制因子α（IκBα）的SUMO化，从而抑制NF-κB轴的激活，进而抑制ESCC细胞能量代谢并阻碍ESCC进展。
抑制SENP5通过SUMO1介导的IκBα SUMO化抑制NF-κB轴，减缓ESCC的发展。我们的研究表明，SENP5可作为ESCC患者的预后指标和治疗干预靶点。
