Chen Junjie, Chen Guoling, Fang Xinying, Sun Jie, Song Jiahui, Chen Zhiming
Clinical Medical Research Center, Affiliated Hospital of Nantong University, Nantong, China.
Department of Radiotherapy & Oncology, Affiliated Hospital of Nantong University, Nantong, China.
J Thorac Dis. 2024 Dec 31;16(12):8684-8698. doi: 10.21037/jtd-2024-2027. Epub 2024 Dec 28.
Esophageal squamous cell carcinoma (ESCC) stands as the sixth most common cause of cancer-related mortality on a global scale, with a strikingly high proportion-over half-of these fatalities occurring within China. The emergence of radiation resistance in ESCC patients significantly diminishes overall survival rates, complicating treatment regimens and reducing clinical outcomes. There is an urgent need to explore the molecular mechanisms that underpin radiation resistance in ESCC, which could lead to the identification of new therapeutic targets aimed at overcoming this resistance. This study aims to elucidate the role of myeloid cell leukemia-1 (MCL1) in ESCC and its association with radioresistance, thereby providing a novel strategy for enhancing the efficacy of radiotherapy.
We used The Cancer Genome Atlas (TCGA) database, Genotype-Tissue Expression (GTEx) project and real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) of 10 pairs of fresh endoscopic biopsy samples from patients with ESCC to analyze the messenger RNA (mRNA) expression levels of in esophageal cancer tissues as compared to normal tissues. Immunohistochemistry (IHC) staining and Western blotting were performed using an anti-MCL1 antibody to visualize protein expression. The mechanism of radioresistance of ESCC was examined by combining bioinformatics analysis, Western blotting, and clone formation and stemness sphere formation assays.
The analysis of TCGA database and the results of RT-qPCR indicated that the mRNA level of was overexpressed in esophageal cancer tissues. Subsequently, the results of IHC and Western blotting showed that the protein level of MCL1 expression in cancer tissues was significantly higher than that in adjacent normal tissues. Moreover, there was a significant upregulation of in ESCC tissues and in radioresistant tissues and cells, with its overexpression correlating with the acquisition of stemness properties in ESCC. In terms of mechanism, induced cell cycle arrest by regulating the expression of and through the signaling pathway. G0/G1 phase arrest contributed to the stem cell-like phenotype. Blocking signaling significantly improved the efficacy of radiotherapy for ESCC.
These findings indicate that is a critical cell cycle regulator that drives the stemness and radioresistance of ESCC and may thus be a potential target in a combined therapeutic strategy aimed at overcoming radioresistance.
食管鳞状细胞癌（ESCC）是全球第六大常见的癌症相关死亡原因，其中超过一半的死亡病例在中国，比例惊人。ESCC患者出现放射抗性显著降低了总生存率，使治疗方案复杂化并降低了临床疗效。迫切需要探索ESCC放射抗性的分子机制，这可能有助于确定克服这种抗性的新治疗靶点。本研究旨在阐明髓样细胞白血病-1（MCL1）在ESCC中的作用及其与放射抗性的关系，从而为提高放射治疗疗效提供新策略。
我们使用癌症基因组图谱（TCGA）数据库、基因型-组织表达（GTEx）项目以及对10对ESCC患者新鲜内镜活检样本进行实时荧光定量聚合酶链反应（RT-qPCR），以分析食管癌组织与正常组织中[具体基因名称未给出]的信使核糖核酸（mRNA）表达水平。使用抗MCL1抗体进行免疫组织化学（IHC）染色和蛋白质印迹法以观察蛋白质表达。通过结合生物信息学分析、蛋白质印迹法以及克隆形成和干性球体形成试验来研究ESCC的放射抗性机制。
TCGA数据库分析和RT-qPCR结果表明，[具体基因名称未给出]的mRNA水平在食管癌组织中过表达。随后，IHC和蛋白质印迹法结果显示，癌组织中MCL1表达的蛋白质水平显著高于相邻正常组织。此外，ESCC组织以及放射抗性组织和细胞中[具体基因名称未给出]显著上调，其过表达与ESCC中干性特性的获得相关。在机制方面，[具体基因名称未给出]通过[具体信号通路名称未给出]信号通路调节[具体基因名称未给出]和[具体基因名称未给出]的表达来诱导细胞周期停滞。G0/G1期停滞导致干细胞样表型。阻断[具体信号通路名称未给出]信号显著提高了ESCC放射治疗的疗效。
这些发现表明，[具体基因名称未给出]是驱动ESCC干性和放射抗性的关键细胞周期调节因子，因此可能是旨在克服放射抗性的联合治疗策略中的潜在靶点。
