MALAT1调控VHL/β-catenin通路影响头颈部鳞状细胞癌侵袭转移的机制研究

Invasion and metastasis are the main factors of poor prognosis in head and neck squamous cell carcinoma(HNSCC). It's significant to explore the mechanism of invasion and metastasis. Preliminary work suggested that high expression of β-catenin and activation of the related pathway facilitated tumor metastasis, and β-catenin was regulated by MALAT1. Moreover, EZH2-catalytic histone, which is mediated by MALAT1, can dramatically supress expression of VHL. According to this, we proposed a hypothesis that "MALAT1 regulates HNSCC invasion and metastasis via targeting VHL/β-catenin signaling pathway." In this project, we will fist detect the charcaterictics of differential expression of MALAT1, VHL/β-catenin signaling, EZH2 and K3K27me3 in different functional states of HNSCCs with different lymph node metastasis. Then, identify the epigenetic mechanism that MALAT1 recruiting EZH2 and regulating the transcription of VHL. Thirdly, verify the ability that MALAT1 impacts HNSCC invasion and metastasis via targeting VHL/β-catenin signaling pathway in vitro and in vivo. Our results will reveal the mechanism by which MALAT1 acts in HNSCC metastasis, and optimize a MALAT1-core therapeutic strategy for HNSCC metastasis, via targeting VHL/β-catenin signaling.

头颈部鳞癌的侵袭转移是影响预后的重要因素，揭示其侵袭转移调控机制对寻找新的治疗策略具有重要意义。前期工作显示头颈部鳞癌中β-catenin高表达及相关信号通路活化是该肿瘤侵袭转移促进因素且该通路受长链非编码RNA MALAT1调控；同时，MALAT1可通过募集EZH2引发下游H3K27me3高表达而抑制VHL。据此，我们提出科学假说“ MALAT1调控VHL/β-catenin通路影响头颈部鳞癌侵袭转移”。拟研究：1)头颈部鳞癌中MALAT1、VHL/β-catenin通路、EZH2、H3K27表达与淋巴结转移及预后的关系；2）阐述MALAT1募集EZH2调控VHL的详细机制；3）体内外实验验证MALAT1调控VHL/β-catenin通路对头颈部鳞癌侵袭转移的影响。预期结果有望证实上述科学假说，获得MALAT1/VHL/β-catenin通路作为头颈部鳞癌抗转移治疗靶标的理论和实验依据。