PTPN13在肺鳞状细胞癌侵袭转移中的作用机理研究

Lung cancer is one of the most common malignant diseases and its mortality is very high. Now it has seriously harm people’s health. The most common histopathologic type of lung cancer is squamous cell carcinoma, which is not sensitive to treat with chemoradiation therapy. Once the cancer developed clinical metastasis, the curative effect of therapy is often very bad. Thus, it is very important to develop a new strategy for early prophylaxis, early diagnosis, prognosis warning, and personalized therapy..In this study, lung squamous cell carcinoma tissues were dissected via laser capture microdissection technology firstly. SNP 6.0 gene chip was then applied analyses the genome wide molecular genetics information in 10 cases of lung squamous cell carcinoma and some chromosome segments related to invasion and metastasis were studied initiatorily. The results showed that high frequent LOH was observed on chromosome 4q in cases with lymph nodes metastasis, especially on 4q18-32.Moreover,in next verification work with gene chip, we found the LOH frequencies of PTPN13 gene is very high(48.6%). .PTPN13 is a newly discovered tumor suppressor gene, which was located in 4q21.3. We previously found that PTPN13 was negatively associated with the invasion and metastasis of lung squamous cell carcinoma. The positive expression rate of PTPN13 in lung squamous cell carcinoma was associated with clinical stages, metastasis and pathological grade. Then we found the expression of PTPN13 was negatively associated with the expression of p-FAK through Immunohistochemisty and Western blot. We speculated that PTPN13 gene may be a tumor suppressor gene related with the invasion and metastasis of lung squamous cell carcinoma and FAK phosphorylation may play a important role in the function of PTPN13 in the carcinogenesis of lung squamous cell. .On the basis of those findings, we firstly plan to verify the association between the PTPN13 and FAK and their relationship with clinical stages, metastasis and pathological grade, etc by increasing samples. Secondly, in vitro, interfering or over expressing PTPN13 gene in human non small cell lung cancer cell lines and analysising the change of invasive ability, adherence ability , migration ability though a series of tests, for example the erasion trace test, transwell test. Thirdly, verifying whether FAK is an important factor in the mechanisms of PTPN13 and studying the signaling pathway though which PTPN13 can regulate FAK. Finally, elucidating the mechanism of PTPN13 and providing a novel therapy targeted gene for the treatment of lung squamous cell carcinoma.

随着我国空气质量的恶化，肺癌发病率增高明显，侵袭转移是导致肺癌预后差、死亡率高的主要因素。PTPN13是近年来发现和肿瘤侵袭转移相关的抑癌基因。我们前期基于显微切割和芯片技术证实PTPN13在转移的肺鳞癌患者中存在高频杂合性缺失（LOH）。进一步检测发现PTPN13在肺鳞癌表达下降并与磷酸化FAK的表达负相关。本项目在前期研究基础上，拟通过大样本检测证实PTPN13与磷酸化FAK的关系，并分析其与肺鳞癌分期、分级、转移和预后的关系。进而对PTPN13进行干预，通过一系列迁移、侵袭相关实验分析其与侵袭、转移的关系，最后证实FAK是PTPN13发挥其抑制肿瘤侵袭转移作用的一个重要分子，并对PTPN13如何调控FAK的通路进行研究。最终阐明PTPN13基因抑制肺鳞癌侵袭转移的机制，为肺鳞癌的靶向治疗提供新的实验依据。