LncRNA MALAT1-ceRNA-miR-5195调控Sema3A 参与鼻咽癌骨转移的机制研究

Bone metastases of nasopharyngeal carcinoma lacks efficiently therapeutic strategies. Our previous study found that the high expression of Sema3A could significantly promotes bone metastasis of NPC, but the regulation mechanism of Sema3A remains unclear. Interestingly, we also found that LncRNA MALAT1 and Sema3A both could interact with miRNA-5195-3p by bioinformatics analysis. Knockdown LncRNA MALAT1 combined with miRNA-5195-3p mimic could significantly inhibit the expression of Sema3A by clinical and cell experiments. These results elucidate that LncRNA MALAT1 may promote bone metastases of nasopharyngeal carcinoma by sponging miRNA-5195-3p. Based on our preliminary findings, this project is designed to investigate: the mechanisms and functions of LncRNA MALAT1-ceRNA-miRNA-5195-3p promotes the expression of Sema3A in nasopharyngeal carcinoma cells; the clinical significances of LncRNA MALAT1-ceRNA-miRNA-5195-3p promote the expression of Sema3A to inhibit bone metastases of nasopharyngeal carcinoma. The project results will reveal a new mechanism in nasopharyngeal carcinoma with bone metastases, and provide new insights and therapeutic strategies for the treatment of nasopharyngeal carcinoma with bone.

鼻咽癌(NPC)晚期骨转移机制不明，临床疗效不佳是亟待解决的重要问题。前期证实信号素3A(Sema3A)表达增多促进NPC骨转移，但Sema3A的表达调控机制尚不明确。研究报道非编码RNA(ncRNA)与Sema3A表达密切相关。本项目生信分析发现lncRNA MALAT1和Sema3A均与miR-5195-3p存在作用位点。临床和实验发现敲低MALAT1联合miR-5195-3p模拟剂显著抑制Sema3A的表达。提示MALAT1可能作为ceRNA吸附miR-5195-3p调控Sema3A参与NPC骨转移。项目拟以细胞、动物和临床样本为模型，深入研究明确MALAT1作为ceRNA吸附miR-5195-3p调控Sema3A的分子机制和功能作用；阐明MALAT1吸附miR-5195-3p调控Sema3A参与NPC骨转移的临床意义。项目将揭示一种NPC骨转移的新机制，为骨转移治疗提供新线索。

鼻咽癌转移的机制和临床治疗是目前亟待解决的重要问题。表观遗传学在肿瘤的发生发展、转移和诊疗中发挥了重要作用，尤其是非编码RNA在转录或转录后水平调控多种肿瘤相关靶基因的表达参与肿瘤的发生发展。近年来，表观遗传学在鼻咽癌的早筛早诊、机制研究和临床治疗等方面也提供了重要的见解，本项目通过细胞和动物实验明确了LncRNA MALAT1通过miR-5195-3p调控鼻咽癌转移的分子机制和调控鼻咽癌转移的作用；通过临床样本和临床样本体外3D培养建立的鼻咽癌类器官模型明确了LncRNA MALAT1通过miR-5195-3p促进鼻咽癌转移临床意义；提供了LncRNA MALAT1作为鼻咽癌转移的治疗的新靶点提供了理论依据。此外，项目实施还发现鼻咽癌转移的重要标志物YBX3通过PI3K/AKT途径促进鼻咽癌转移的机制；以及鼻咽癌化疗抵抗的标志物XPO1新型抑制剂KPT-330通过EBNA1和LMP1抑制破坏EBV维持的分子机制。本项目在肿瘤表观遗传学和鼻咽癌转移分子机制、鼻咽癌肿瘤类器官模型和临床意义方面均取得一定成果。本项目在鼻咽癌领域解决了一些转移的机理的问题，并利用构建的类器官模型检测鼻咽癌构建的新型铂类药物的作用，对鼻咽癌临床治疗领域具有一定参考价值。