BCL11A在肺鳞癌中的癌基因功能研究

In recent years, more and more target therapy drugs were used successfully in clinical practice due to many driver genes including EGFR,ALK genes were validated in lung adenocarcinoma. However, the driver genes in lung squamous cell lung carcinoma(SQCC) have not been comprehensively characterized, and no molecularly targeted agents have been specifically developed for its treatment,prompting the necessity of identifying driver oncogenic events for this subset of patients. In our previous study, we found that a proto-oncogene BCL11A was deregulated in 53 non-small cell lung cancer(NSCLC) tissues compared to the paired non-cancerous lung tissue based on Affymetrix mRNA array ,aCGH(comparative genomic hybridization array) and tissue microarray. We also found BCL11A knockdown in H520 cell lines promote cell apoptosis. A recent study found BCL11A is a triple-negative breast cancer gene. We hypothesize that amplification of this gene in SQCC is likely to be of functional significance based on our previous results and breast cancer experiment, but the molecular mechanisms in detail keep unknown. In this study, we plan to validate the "driver gene" role of BCL11A in SQCC by gene transfection . We also plan to investigate the effect of BCL11A on the malignant penotype via ectopically expressed and knocked down of BCL11A. Finally, we further explore the potential targets and downstream signal pathway,These aims are to characterize the "driver gene" role of BCL11A in lung SQCC and to explore potential therapeutic target for this disease.

随着EGFR，ALK等驱动基因的证实,针对这些基因的靶向药物已经用于肺腺癌的治疗并取得较好的治疗效果。而临床上目前仍然没有针对肺鳞癌的靶向药物获批,主要是对肺鳞癌的驱动基因仍知之甚少。本课题组通过mRNA基因芯片、比较基因组杂交以及组织芯片技术从 53 对早期非小细胞肺癌(NSCLC)与 癌旁组织中筛选出一个在肺鳞癌中异常扩增活化的原癌基因BCL11A, 我们的细胞实验也提示下调BCL11A表达能诱导肺鳞癌细胞株H520凋亡。结合我们前期基础及最近乳腺癌中的研究结果，我们提出BCL11A 在肺鳞癌中的异常扩增活化可能参与肺鳞癌的发生、发展,但其具体作用机理尚不清楚。本研究拟通过基因转染等技术观察 BCL11A 的恶性转化能力及对肺鳞癌细胞恶性表型的影响,最后用基因芯片和 ChIP-seq 技术探讨 BCL11A 的调控靶点及下游信号通路，为开发肺鳞癌治疗靶点提供理论依据。

随着EGFR，ALK等驱动基因的证实,针对这些基因的靶向药物已经用于肺腺癌的治疗并取得较好的治疗效果。而临床上目前仍然没有针对肺鳞癌的靶向药物获批,主要是对肺鳞癌的驱动基因仍知之甚少。本课题组前期的研究结果表明BCL11A 在肺鳞癌中的异常扩增活化可能参与肺鳞癌的发生、发展, 但其具体作用机理尚不清楚。. 本研究拟验证BCL11A在肺鳞癌中的癌基因功能，为找到肺鳞癌靶向治疗靶点提供理论基础。但在项目实施过程中，国外其他机构已经先行证实了本项目的假设，而且部分结果相当一致，为了避免不必要的重复，我们进行了研究方向调整为肺癌脑膜转移相关研究。研究结果发现：1. 脑膜转移好发于EGFR突变的肺腺癌患者；2. EGFR-TKI能改善肺癌脑膜转移患者的预后；3.全脑放疗未能提高肺癌脑膜转移患者的生存率；4. 捕获的脑脊液沉渣细胞驱动基因与原发灶基因状态高度匹配；5. 相对于原发灶、外周血和脑脊液沉渣，脑脊液上清游离DNA是最佳的脑膜转移基因检测材料；脑脊液游离DNA能检测到独特的基因谱。6. 筛选出脑膜转移特异的脑脊液外泌体miRNAs。本研究建立了基于cell search为基础的脑脊液细胞捕获平台，绘制出EGFR突变肺腺癌脑膜转移独特的基因谱，开启了脑脊液检测的新篇章, 提高了肺癌脑膜转移的诊治水平。. 发表SCI论文3篇，一篇标注该基金资助，目前有一篇标注项目基金资助的SCI文章正在投稿之中。. 参加国内和国际会议，如CSCO、IASCL 会议、AACR、ASCO 、ESMO 年度会议等进行研究成果交流。