造血细胞特异性转录因子GFI1诱导肺癌细胞失巢凋亡抵抗的功能和机制研究

Escaping from anoikis is an important molecular element during the process of malignant tumor invasion and metastasis. Our group first found that solid tumor cells might re-gain some hematopoietic restricted transcription factors to escape anoikis. Growth factor independence 1 (GFI1) is a hematopoietic specific zinc finger transcription factor that is key for the development of hematopoietic system. Our preliminary data showed that GFI1 was up regulated in small lung cancer. Overexpression of GFI1 induced anoikis resistance in the anoikis-sensitive non-small lung cancer cells. Also it can promote tumor metastasis in lung in vivo. We speculated that ectopically expressed GFI1 might epigenetically regulate the expression of chemokine receptor CXCR4, and then activate focal adhesion kinase (FAK) in lung cancer cells to induce anoikis resistance. However, little is known about the chromatin structure changes during this reprogram. Based on these findings, our proposal aims to systematically focus on GFI1 regulation and function on anoikis in human solid tumors derived from lung. We will collect human lung cancer samples of different pathology, and introduce biochemical and molecular techniques combined with 3C, ChIP, single cell RT-PCR and RNA interference approaches. The implement of this proposal will identify the new mechanism and regulation in the chemokine and chemokine receptor mediated promotion of tumor invasion and metastasis. Hopefully we may gain significant insight into the GFI1-related chromatin remodeling events and add to means of assessing the network associated with tumorigenesis and metastasis in solid tumors. Also, a better understanding of the mechanisms underlying anoikis resistance could help to prevent solid tumor progression and metastasis.

肿瘤细胞逃逸失巢凋亡是其实现侵袭转移的重要环节，我们率先发现肿瘤细胞在侵袭转移过程中可重新获得一些造血细胞特有的转录因子而逃逸失巢凋亡。GFI1是对造血系统发育关键的转录因子，我们发现GFI1在小细胞肺癌中表达上调；在对失巢凋亡敏感的非小细胞肺癌细胞中过表达GFI1，可诱导癌细胞失巢凋亡抵抗，并在体内促进肿瘤转移；机制可能与其调控趋化因子受体CXCR4的表达，促使FAK磷酸化有关。本项目拟通过收集临床不同类型肺癌样本，利用不同的裸鼠肺癌注射模型，利用免疫组化、RNA干扰、单细胞RT-PCR、3C、ChIP等多种技术系统深入细致研究：GFI1诱导肺癌细胞逃逸失巢凋亡和促进肺癌远端转移的功能和调控机制；明确趋化因子及受体在促进肿瘤转移方面的新机制和调控方式。本研究将补充小细胞肺癌异位表达血源性转录因子逃避失巢凋亡的理论，丰富对实体肿瘤转移过程中调控网络的理解，发现可用于肿瘤治疗的新的分子靶点