低氧条件下HIF-1α上调FNDC3B表达在舌鳞癌转移中的作用及机制

The primary reasons of treatment failure for the patients with tongue squamous cell carcinoma(TSCC) are metastasis and replase. Identifying the exact mechanism of metastasis is the key point of improving its prognosis. It was reported that hypoxia microenvironment played an important role during the metastasis of malignancies. We found that the expression of FNDC3B is correlated to TSCC cTNM stage and lymph node metastasis by IHC assay. Furthermore, we found that FNDC3B could promote its migratory and invasive abilities in vitro experiment. In.addition, we found that treating TSCC with CoCl2 (a hypoxia mimetic agent) upregulates the mRNA and protein expression of FNDC3B and HIF-1α. Moreover, FNDC3B could improve β-catenin expression and induce EMT(epithelial-mesenchymal transition) of TSCC. On the base of these preliminary studies, we propose that hypoxia microenvironment upregulates FNDC3B expression, and the latter improves migratory and invasive abilities of TSCC cells through inducing EMT. Then, we will explore the function and mechanism of FNDC3B on the migratory and invasive potentials of TSCC cells by knockdown or overexpression of FNDC3B in vitro. At last, the lymph node metastasis animal model using TSCC cell lines will be established, and the molecular mechanisms will be discussed. It will be very useful to treat progression and metastasis for the TSCC patients by clarifying these mechanisms.

转移及复发是舌鳞癌治疗失败的主要原因，明确其转移的机制是提高疗效和改善预后的关键。低氧微环境与肿瘤转移密切相关。前期我们通过免疫组化发现FNDC3B在舌鳞癌组织中高表达，其表达与临床分期及淋巴结转移正相关；同时体外研究证实FNDC3B可增强舌鳞癌细胞的侵袭迁移能力；进一步研究发现低氧模拟剂CoCl2以HIF-1α依赖方式诱导舌鳞癌细胞过表达FNDC3B，同时上调β-catenin表达及诱导EMT（上皮间质转化）。据此我们提出低氧条件通过HIF-1α介导舌鳞癌细胞上调FNDC3B，后者经wnt/β-catenin等通路促进其侵袭转移。本项目拟首先明确低氧条件诱导舌鳞癌细胞上调FNDC3B，沉默及过表达FNDC3B对舌鳞癌细胞侵袭迁移能力及EMT的影响和机制；进一步建立颈淋巴结转移动物模型，探讨FNDC3B作为治疗舌鳞癌转移分子靶点的可行性，该机制的阐明将为改善舌鳞癌患者的预后提供新思路。

头颈部鳞状细胞癌占头颈部恶性肿瘤的90%以上，全球每年新增约60万例，位于新增恶性肿瘤患者的第六位。临床研究表明虽然手术及放疗技术的不断提高、化疗方案的不断改进和完善，但其5年生存率一直维持在50%左右，其治疗失败的主要原因之一是淋巴结转移。研究发现口腔舌鳞癌的淋巴结转移率高达50%-60%，且与预后负相关，被认为是影响患者预后的首要因素。我们通过免疫组化发现FNDC3B在舌鳞癌组织中高表达，其表达与临床分期及颈淋巴结转移正相关，与预后负相关；同时体外实验证实FNDC3B可增强舌鳞癌细胞侵袭迁移能力；进一步研究发现低氧模拟剂CoCl2以HIF-1α依赖方式诱导舌鳞癌细胞过表达FNDC3B，同时上调β-catenin表达及诱导EMT（上皮间质转化）。我们研究发现低氧条件下经HIF-1α诱导舌鳞癌细胞过表达FNDC3B，后者经Wnt/β-catenin通路诱导 EMT促进舌鳞癌侵袭转移。同时发现由FNDC3B基因第5和6外显子形成的circFNDC3B通过调节miR-1322/MED1轴促进舌鳞癌细胞的生长。我们的研究结果提示FNDC3B可作为治疗舌鳞癌新的分子靶点，为改善舌鳞癌乃至头颈部鳞癌患者的预后提供新的思路。