TACC3通过c-Myc/miRNA-129-5p通路、诱导食管鳞状细胞癌干性抵抗化疗的分子作用与机制研究

Esophageal squamous cell carcinoma (ESCC) is the most common cancer in our country, with chemotherapy resistance and poor prognosis. It is crucial to predict and rectify the chemotherapy resistance for improving patients’ survival. Using RNA sequencing technology, our previous study showed that transforming acidic coiled-coil proteins 3 (TACC3) is associated with chemo-resistance of ESCC patients. Our further preliminary results indicated TACC3 could regulate esophageal squamous cell carcinoma stemness and chemo-resistance through the c-Myc/miRNA-129-5p signaling pathway. To prove this hypothesis, we will investigate the biological function of TACC3 in regulating cancer stemness and chemo-resistance of ESCC in vivo and in vitro experiments. In addition, we will explore the molecular mechanism of TACC3 in regulating cancer stemness and chemo-resistance through the c-Myc/miRNA-129-5p signaling pathway and its downstream targets in ESCC. Furthermore, using the clinicopathological data and tissues of ESCC patients, we plan to demonstrate the clinical significance of TACC3 and its downstream targets' expression in predicting the chemotherapy sensitivity of ESCC. Our study contributes to understand the role and molecular mechanism of TACC3 in chemo-resistance of ESCC, which will provide new insights for predicting and improving chemo-resistance, guiding the patient-tailored treatment.

食管鳞状细胞癌（ESCC）高发于我国，其化疗敏感性差、严重威胁人民健康。因此，预测和改善ESCC化疗抵抗是提高疗效的关键。我们前期通过高通量RNA测序技术发现：酸性卷曲转化相关蛋白3（TACC3）与ESCC化疗抵抗密切相关；进一步的预实验结果提示：TACC3可通过c-Myc/miRNA-129-5p信号通路诱导ESCC干性、导致化疗抵抗。为验证这一假说，本项目承前启后、拟通过一系列体内外实验，进一步明确TACC3诱导ESCC干性导致化疗抵抗的分子作用；解析TACC3通过c-Myc/miRNA-129-5p信号通路诱导ESCC干性导致化疗抵抗的确切分子机制、并发掘该通路下游的重要靶基因；最后结合临床病例、检测并分析TACC3及其下游关键靶基因异常对评估ESCC化疗敏感性的肿瘤学意义。项目完成将对阐明ESCC化疗抵抗的分子机理、确证预测肿瘤化疗敏感性的分子诊疗靶标、具有重要科学意义和临床价值。

食管癌是全球发病率和死亡率前十的恶性肿瘤之一，严重威胁人类健康。中国人食管癌的病理类型有别于欧美国家人群、主要是鳞状细胞癌（Esophageal squamous cell carcinoma，ESCC），占国人全部食管癌病例的 90%以上。临床上，多数的 ESCC 病人在初次确诊时已经是肿瘤中晚期；除了极早期 ESCC 病人，大多数患者在综合治疗中均需接受相应的化学治疗[2]。近十年来，尽管ESCC 诊疗技术的不断提高，但 ESCC 病人在治疗后的复发和转移率一直居高不下，其五年生存率低于 25%、治疗效果不尽如人意。究其原因，ESCC 患者对于辅助性治疗特别是化疗的敏感性很差。而对于临床上化疗无反应或化疗抵抗的局部晚期 ESCC 患者，化疗不仅产生强烈的药物毒副作用，而且还可导致患者病程进展、甚至失去手术机会[3]。因此，深入研究并揭示 ESCC 化疗抵抗的分子机制及其相关的诊疗靶点，对评估和改善 ESCC 患者化疗效果、减少复发转移、提高患者的生存时间与质量均具有十分重要的科学意义和临床应用价值。本研究采用了 RNA 测序技术，分析食管鳞癌患者对新辅助化疗敏感组和抵抗组之间的差异表达基因，最终发现：TACC3 基因高表达与 ESCC 的化疗抵抗密切相关、并可能担当十分重要的作用。