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。

长链非编码RNA在包括头颈部鳞癌在内的肿瘤中发挥多重作用。肺腺癌转移相关转录本-1（MALAT1）作为一种广泛表达的lncRNA，参与了肿瘤生物学过程的诸多方面。课题组前期工作证实MALAT1在头颈部鳞癌中异常高表达，然而其在头颈部鳞癌中的具体功能机制尚不明确。本研究在肿瘤标本组织、体外细胞实验和体内动物实验三个层面探索MALAT1在头颈部鳞癌生长侵袭中的功能和分子机制。结果显示相较于正常组织，MALAT1在146例头颈部鳞癌，尤其是组织分化差或伴淋巴结转移的头颈部鳞癌中显著高表达，并且高表达MALAT1提示患者预后不良。相反，VHL在头颈部鳞癌中低表达，与MALAT1表达呈负相关。体内外实验提示敲低MALAT1表达能显著抑制头颈部鳞癌细胞增殖、迁移和侵袭能力，逆转头颈部鳞癌细胞EMT过程。进一步研究显示MALAT1能够通过EZH2依赖的方式抑制VHL表达从而激活β-catenin、P65促进头颈部鳞癌的生长侵袭。本项目揭示了MALAT1促进头颈部鳞癌生长侵袭的作用机制，为头颈部鳞癌的临床诊断和治疗提供了潜在靶点。