FMNL1调控MTA1诱导侵袭性伪足形成促进鼻咽癌转移的作用及其机制研究

Tumor invasion and metastasis are responsible for the poor prognosis of nasopharyngeal carcinoma (NPC). The invadopodia plays an important role in tumor invasion and metastasis. FMNL1 has been reported to be associated with the invadopodia formation. However, the role and underlying mechanism of FMNL1 in NPCs have not been evaluated. Recently, we found that overexpression of FMNL1 is closely associated with the development and/or progression of nasopharyngeal carcinoma. FMNL1 might promote invadopodia formation and tumor metastasis. In this project, firstly, ectopic FMNL1 expression vector will be transfected into the NPC cells to assess the effect of FMNL1 on the invadopodia formation and metastatic behavior of NPC cells by a series of in vitro and in vivo experiments. Next, Human Tumor Metastasis RT² Profiler™ PCR Arrays will be applied to screen the downstream targets of FMNL1 in NPC cells and the results will be verified. Furthermore, FMNL1 and its downstream gene MTA1 expressions in NPC tissues will be tested by immunohistochemistry,respectively, and the association between expressions of FMNL1 and MTA1 will be assessed. Finally, the mechanism of FMNL1 regulating its critical target MTA1 will be explored through luciferase reporter gene arrays and chromatin immunoprecipitation (ChIP) assays. Hence, we aim to explore the biological function and potential mechanism of FMNL1 in NPC metastasis, which might provide new biomarkers and targets for the diagnosis and treatment of NPC.

侵袭转移是鼻咽癌患者预后差的主要因素，肿瘤细胞侵袭性伪足的形成在肿瘤转移过程中起着重要的作用。FMNL1是调控肿瘤细胞侵袭性伪足形成的重要基因，但其在鼻咽癌中的作用及其分子机制目前仍未阐明。申请人前期研究发现，FMNL1在鼻咽癌细胞及组织中表达明显升高，与鼻咽癌的侵袭转移正相关；FMNL1在鼻咽癌细胞中促进侵袭性伪足的形成。本项目拟首先探讨FMNL1对鼻咽癌侵袭性伪足形成及肿瘤转移等生物学行为的影响；通过肿瘤转移基因表达谱芯片，筛选FMNL1调控的下游靶基因MTA1，并在大病例临床组织中明确FMNL1及靶基因MTA1表达的相关性和临床肿瘤学意义；进一步通过荧光素酶报告基因实验、免疫共沉淀等实验，重点阐明FMNL1对MTA1调控的分子机制，深层次解析FMNL1靶向MTA1诱导鼻咽癌细胞侵袭性伪足形成促进肿瘤转移的分子机理。本项目将为揭示鼻咽癌转移机制提供新的科学依据。

肿瘤细胞侵袭性伪足的形成在肿瘤转移过程中起着重要的作用。FMNL1是调控肿瘤细胞侵袭性伪足形成的重要基因，但其在鼻咽癌中的作用及其分子机制目前仍未阐明。申请人研究发现，FMNL1在鼻咽癌细胞及组织中表达明显升高，与鼻咽癌的侵袭转移正相关；FMNL1在鼻咽癌细胞中促进侵袭性伪足的形成。通过肿瘤转移基因表达谱芯片，筛选FMNL1调控的下游靶基因MTA1，并通过荧光素酶报告基因实验、免疫共沉淀等实验发现，FMNL1可以将HDAC1滞留在胞浆，导致细胞核内HDAC1减少，使MTA1启动子乙酰化水平增加，导致MTA1转录水平上调。FMNL1与鼻咽癌的恶性表型相关，有可能成为判断鼻咽进展及预后的一个新的分子标志物。