BRAF抑制剂诱导BRAF突变型结直肠癌细胞休眠介导复发
BRAF inhibitors-induced dormancy mediates relapse in BRAF-mutated colorectal cancer cells
摘要
目的：探究BRAF抑制剂维莫非尼是否通过诱导BRAF突变型结直肠癌细胞休眠，进而介导肿瘤复发。方法：采用MTT法检测维莫非尼作用后细胞存活情况；Ki67免疫荧光染色评估细胞增殖；WB与qPCR实验检测休眠标志物p27的蛋白及mRNA表达水平；MTT及流式细胞术实验分析维莫非尼处理后残留肿瘤细胞对化疗药的敏感性；皮下荷瘤小鼠模型评估维莫非尼在体内诱导肿瘤细胞休眠及停药后复发的效应。结果：维莫非尼处理后，MTT、免疫荧光、WB及qPCR实验数据一致表明BRAF突变型结直肠癌细胞存活但增殖受抑，Ki67阳性率显著降低，p27蛋白与mRNA水平均上调，呈现典型休眠表型。MTT和细胞凋亡实验证实残留肿瘤细胞对化疗药敏感性下降。体内动物实验提示维莫非尼可通过诱导肿瘤细胞休眠介导复发。结论：维莫非尼可诱导BRAF突变型结直肠癌细胞进入以增殖受抑和p27上调为特征的休眠状态，并由此导致化疗敏感性下降及停药后肿瘤复发。
Abstract
Objective: To investigate whether the BRAF inhibitor vemurafenib mediates tumor relapse by inducing dormancy in BRAF-mutant colorectal cancer cells. Methods: Cell viability was assessed byMTT assay following vemurafenib treatment. Proliferation was evaluated by Ki67 immunofluorescence staining. The protein and mRNA expression levels of the dormancy marker p27 were determined by Western blot and qPCR, respectively. Chemosensitivity of residual tumor cells following vemurafenib treatment was analyzed by MTT assay and flow cytometry. A subcutaneous xenograft mouse model was employed to evaluate the induction of tumor cell dormancy by vemurafenib in vivo and tumor recurrence after drug withdrawal. Results: Following vemurafenib treatment, data from MTT assay, immunofluorescence staining, Western blot, and qPCR consistently demonstrated that BRAF-mutant colorectal cancer cells remained viable but exhibited suppressed proliferation, with a significantly reduced Ki67 positivity rate and upregulation of both p27 protein and mRNA levels, indicating a typical dormant phenotype. MTT and apoptosis assays further confirmed that the residual tumor cells displayed decreased chemosensitivity. In vivo animal experiments suggested that vemurafenib may mediate tumor recurrence through the induction of tumor cell dormancy. Conclusion: Vemurafenib induces a dormant state in BRAF-mutant colorectal cancer cells characterized by suppressed proliferation and upregulation of p27, thereby leading to reduced chemosensitivity and tumor recurrence following drug withdrawal.关键词
肿瘤药理学/BRAF抑制剂/休眠/结直肠癌Key words
Cancer pharmacology/BRAF inhibitor/dormancy/colorectal cancer引用本文复制引用
潘雨萱,张熠.BRAF抑制剂诱导BRAF突变型结直肠癌细胞休眠介导复发[EB/OL].(2026-07-21)[2026-07-23].http://www.paper.edu.cn/releasepaper/content/202607-23.学科分类
肿瘤学
