Foxm1在喉癌生长转移中的作用及机制研究

Laryngeal cancer is a common head and neck cancer, survival rate for advanced laryngeal cancer, and to surgical excision of the treatment led to postoperative voice dysfunction, serious impact on patient quality of life and survival. Search for new treatments become the key point to solve this problem. Oncogene Foxm1 may become a new target for cancer therapy received extensive attention. In our previous experiment, we found that Foxm1 has a close relationship with laryngeal cancer in degree of differentiation, T stage, lymph node metastasis, clinical stage;the capability of Hep-2 cell proliferation, invasion, metastasis reduced significantly after specific inhibition of FoxM1 treated. But Foxm1 the development of laryngeal cancer and the specific role of specific molecular mechanism is unclear, and thus whether Foxm1 become the treatment of laryngeal new target for molecular targeted therapy can be further verified. This application will be for the Foxm1 gene, RNA interference by building low-Foxm1 expression vector, from the molecular, cellular, multi-level study of Foxm1 in vivo cell proliferation of laryngeal carcinoma, invasion and metastasis such as the role of the ability to clarify Foxm1 promote the development of laryngeal carcinoma metastasis molecular mechanism with a view to the clinical treatment of laryngeal cancer provide new therapeutic targets.

喉癌是我国常见头颈部恶性肿瘤，因晚期喉癌生存率低，并且以手术切除为主的治疗方式导致患者术后发声功能障碍，严重影响患者生命及术后生存质量。寻找新的治疗方法成为解决这一问题的关键点。癌基因Foxm1因其广泛高表达于多种肿瘤并且有特异性抑制剂，可能成为肿瘤治疗新靶点。本课题小组在前期实验中初步证实Foxm1与喉癌的分化程度、T分期、淋巴结转移、临床分期等有着密切关系；特异性抑制FoxM1后，喉癌Hep-2细胞的增殖、侵袭、转移能力明显降低。但Foxm1对喉癌的发生发展的具体作用以及具体分子机理还不清楚，因而Foxm1是否可成为喉癌治疗的分子靶向治疗新靶点也有待进一步验证。本项目构建Foxm1的RNA干扰高表达及低表达的质粒，从分子、细胞、体内多层次探讨Foxm1对喉癌细胞增殖、侵袭、转移等能力的作用，阐明Foxm1促进喉癌发生发展转移的分子机理，以期为喉癌的临床治疗提供新的治疗靶点。

喉癌是我国常见头颈部恶性肿瘤，而晚期喉癌患者生存率较低，故需探讨针对晚期喉癌治疗的新策略。癌基因FoxM1因其广泛高表达于多种肿瘤，可能成为肿瘤治疗新靶点。本课题研究FoxM1在喉癌生长和转移的作用及分子机制。首先通过体外实验探讨抑制剂硫链丝菌肽下调FoxM1对喉癌细胞增殖、凋亡、侵袭、转移中的影响及分子机制。然后建立裸鼠喉癌模型，通过体内实验探讨抑制剂或shRNA下调FoxM1对喉癌细胞在裸鼠体内增殖、凋亡的影响及分子机制。结果发现，下调FoxM1表达可抑制喉癌Hep-2细胞体外增殖能力，其机制通过下调cyclinD1 和 cyclinE1的表达，将细胞周期阻滞于S期。而下调FoxM1表达通过调控线粒体-caspase通路、Fas信号通路、IAP蛋白家族，最终促进喉癌Hep-2细胞凋亡。下调FoxM1表达抑制了Hep-2侵袭和转移能力，其机制可能通过下调侵袭、转移因子MMP-2和MMP-9的表达。下调FoxM1抑制了Hep-2细胞体外克隆形成能力，以及抑制了喉癌细胞在裸鼠体内增殖和促进其凋亡。此外，我们增加了下调FoxM1对鼻咽癌细胞增殖、凋亡、侵袭、转移的影响及分子机制的研究。结果同样发现下调FoxM1可抑制鼻咽癌细胞增殖，促进其凋亡，抑制其侵袭转移。总之，本研究为FoxM1在喉癌发生、发展中的作用及分子机制研究提供了新的实验数据，可能对喉癌的靶向干预治疗提供新的策略。基于本项研究结果，截止目前已发表SCI论文3篇。本项研究执行期间，已培养2名博士研究生和4名硕士研究生。