SOX2调控EMT参与肺鳞癌顺铂耐药的机制

Although the molecular targeted therapy of lung adenocarcinoma has superior efficacy recently, but it is not an ideal treatment method for squamous cell carcinoma. Cisplatin-based chemotherapy remains the cornerstone of treatment in advanced lung squamous cell carcinoma, but the resistance to cisplatin is the main cause of treatment failure. There is no effective methods to reverse the cisplatin resistance of lung squamous carcinoma. Our previous study found that SOX2 is high expressed in lung squamous carcinoma cell line SK-MES-1 , but resistant to cisplatin, which may related to epithelial to mesenchymal transition (EMT) of lung. Clinical specimens were also found that SOX2 is high expressed in squamous cell carcinoma other than in adenocarcinoma, and high expression of SOX2 is related to the poor prognosis of patients. The current problem we encountered is that: how exactly SOX2 regulate cisplatin resistance mechanism ? The mechanism is the key to resolve the problem. Our group proposed that SOX2 gene’ regulation of EMT may be involved in cisplatin’ resistance mechanism of lung squamous carcinoma. This study will use immunohistochemistry, Western blot, PCR and RNA interference technology, combined with the tumor sphere formation and gene chip to further define SOX2’ regulation of EMT involved in cisplatin resistance of lung squamous carcinoma, then evaluated the clinical prognostic value by using clinical samples.The completion of the project will reveal cisplatin resistant mechanism of lung squamous carcinoma from a new point of view, SOX2' signal and the EMT related pathway as a new target for reversal of cisplatin resistance in lung squamous carcinoma in the future.

靶向治疗在肺腺癌取得了优越疗效，鳞癌中却不理想，含铂双药化疗仍是晚期肺鳞癌治疗的基石，但顺铂耐药是导致治疗失败的主要原因，目前尚缺乏逆转其耐药的有效方法。我们前期研究发现耐顺铂肺鳞癌细胞株SK-MES-1高表达SOX2，且与上皮间质转化（EMT）有关，临床标本中也发现鳞癌较腺癌高表达SOX2，且与患者预后相关。目前研究遇到的难题是SOX2对顺铂耐药的具体调控机制？明确其机制是解决问题的突破口。前期研究中申请者提出假说：肺鳞癌顺铂耐药可能与SOX2基因调控EMT参与顺铂耐药相关。本课题拟采用免疫组化、蛋白印迹、PCR及RNA干扰等技术，结合裸鼠成瘤、肿瘤球形成、基因芯片等实验进一步明确SOX2调控EMT调控肺鳞癌顺铂耐药的作用，并通过临床样本检测评估其临床预后价值。本项目的完成将从新的角度揭示肺鳞癌顺铂耐药调控机制，为今后以SOX信号和EMT相关通路作为逆转肺鳞癌顺铂耐药的新靶向提供依据。

顺铂耐药机制是晚期肺鳞癌化疗遇到的重大挑战之一，目前尚缺乏逆转其耐药的有效方法。肿瘤干细胞样特征与化疗耐药密切相关。我们的研究通过细胞水平实验及临床样本分析，证实干性核心转录因子SOX2作为可靠标志物通过调控上皮间质转化（EMT）参与具干细胞样特征肿瘤细胞表达E-cadherin、N-cadherin、Vimentin、c-MET，可以部分解释鳞癌患者顺铂耐药机制。本项目以SOX信号和EMT相关通路为切入点，结合既往研究显示SOX2除了直接影响肺鳞癌细胞对铂类药物的敏感性之外，还通过诱导细胞重编程的方式调控靶细胞的功能，提示我们若联合进行标志物的检测可能更好的克服化疗耐药现象。综上所述，课题组阐明了SOX2调控EMT参与肺鳞癌顺铂耐药的部分机制，从研究耐药机制出发，以进一步探索更多更有效针对肺鳞癌患者的治疗策略，最终能够克服肺鳞癌化疗耐药的临床问题。