摘要
目的:结直肠癌是我国常见且发病率逐年上升的恶性肿瘤之一。放疗是结直肠癌患者的重要治疗手段,但肿瘤的辐射抵抗是导致治疗失败及疾病复发的重要原因。本研究进一步探讨了辐射抵抗的分子机制。方法:采用生信分析筛选并研究了与结直肠癌患者无病生存率相关的基因ALDH1L2。利用过表达、敲低ALDH1L2的肠癌细胞株,通过平板克隆实验、γ-H_(2)AX蛋白量测定和彗星实验,来探究其是否与细胞的辐射敏感性相关。通过GSEA生信分析、qRT-PCR、westernblot及流式细胞学探究ALDH1L2发挥作用的可能分子机制。结果:ALDH1L2与结直肠癌患者无病生存率相关,高表达ALDH1L2提示更短的无病生存期。ALDH1L2是辐射敏感基因,其低表达可在体外加快DNA的损伤修复,促进结直肠癌细胞的辐射抵抗。ALDH1L2通过调控过氧化物酶体通路关键分子PGC1A及下游SOD2、CAT,促使胞内活性氧自由基累积导致凋亡增加,最终介导肠癌细胞的辐射敏感。结论:ALDH1L2可能通过过氧化物酶体通路来介导结直肠癌细胞的辐射敏感。
Objective:Colorectal cancer is one of the most common malignant tumors in China,and its incidence rate is increasing year by year.Radiotherapy is an important treat-ment for colorectal cancer,but the radio-resistance of tumor is an important reason resulting in treatment failure and disease recurrence.This study was carried out to study the molecular mechanism of radio-resistance in colorectal cancer.Methods:Bioinformatics analysis was used to indicate the assocication of ALDH1I2 with the disease-free survival rate of colorectal cancer patients.ALDHI L2-overexpressed or ALDHI I2 knockdown colorectal cells were used in colony formation assay,γ-H_(2)AX assay and comet assay.Gene set enrichment analysis(GSEA),qRT-PCR,westen blot and flow cytometry were used to explore possible molecular mechanisms of ALDH1I2 in mediating the radiosensitivity of colorectal cancer cells.Results:ALDH1L2 was associated with disease-free survival in pa-tients with colorectal cancer,and low expression of ALDH1I2 suggested shorter disease-free survival.Besides,ALDHII2 was a radiation-sensitive gene.Its low expression could accelerate DNA damage repair and promote radio-resistance of colorectal cancer cells in vitro.ALDH1IL2 promoted the accumulation of intracellular reactive oxygen species(ROS)by regulating the transcription and level of PGC1 A protein,the key molecule of peroxisome pathway,and its downstream mediators,SOD2 and CAT,leading to the increase of cell apoptosis,and finally mediated the radiosensitivity of colorectal cancer cells.Conclu-sion:ALDH1L2 may regulate the radiosensitivity of colorectal cancer cells through the peroxisome pathway.
作者
李双燕
翁佳雯
俞露
丁轶
Li Shuangyan;Weng Jiawen;Yu Lu;Ding Yi(Department of Radiotherapy,Nanfang Hospital,Sourthern Medical University,Guangzhou 510515,Guangdong,China;Department of Oncology,the People’s Hospital of Lincang,Lincang 677000,Yunnan,China)
出处
《肿瘤预防与治疗》
2021年第9期787-797,共11页
Journal of Cancer Control And Treatment
基金
国家自然科学基金(编号:81803063,81872470,82073342,81903125)
广东省自然科学基金(编号:2018030310297,2018A030310513)
广东省医学科学技术研究基金(编号:A2020563)
南方医科大学南方医院院长基金(编号:2020C006)。