短肽MPM通过调控癌细胞及肿瘤微环境抑制肝癌进展的机制研究

肿瘤是癌细胞与肿瘤微环境共进化的结果，若能同时靶向癌细胞与肿瘤微环境，将极大提高肿瘤的治疗效果。肝癌是全球常见的恶性肿瘤；转移是导致其病死率高的重要原因。短肽是由短的开放阅读框翻译的、长度短于100个氨基酸的多肽。目前对短肽的功能及机制研究十分有限，短肽是否调控肝癌转移更是未有报道。我们前期发现一个在肝癌中下调、且能抑制肝癌细胞转移的短肽MPM；在肝原位移植瘤模型中，MPM敲除小鼠的原位肿瘤更大、肺转移更多。提示MPM可能同时调控癌细胞及肿瘤微环境，抑制肝癌进展。基于此，我们将围绕“短肽在肝癌转移中的作用及机制”这一关键问题，结合体内外模型及临床肝癌标本，探究短肽MPM对肝癌细胞转移能力的调控作用及机制；阐述MPM对肿瘤微环境的调控作用及机制；探讨MPM作为新型抗肝癌靶点的可能性。研究结果将揭示短肽MPM的新功能及肝癌转移的新机制，为发展基于短肽的新型肝癌治疗策略提供理论基础和分子靶点。

Cancer is the result of co-evolution of tumor cells and their microenvironment. Developing new anti-cancer therapy which can target these two aspects at the same time, will greatly improve the therapeutic effect. Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and metastasis is responsible for the poor survival of HCC. Micropeptides, with less than 100 amino acids in length, are encoded by the short open reading frames, and their functions and the underlying mechanism remain largely unknown. The roles of micropeptides in the metastasis of HCC are not reported yet. We have identified a micropeptide MPM that is downregulated in HCC and inhibits the metastasis of hepatoma cells. Furthermore, in mouse orthotopic xenograft model, the sizes of primary tumors and number of pulmonary metastasis nodules were bigger and higher in MPM-/- mice than that in MPM+/+ mice. It is suggested that MPM may inhibit the progression of HCC via modulating tumor cells and tumor microenvironment. Based on these preliminary studies, we will focus on the key scientific issue of "the regulatory role and mechanism of MPM in HCC metastasis" and conduct the following research in combination with cell and animal models and human clinical specimens: 1) the regulatory role and mechanism of MPM in the metastasis of hepatoma cells; 2) the regulatory role and mechanism of MPM in tumor microenvironment; 3) the possibility of MPM as a novel anti-HCC target. The results will reveal the biological function and regulation network of MPM, disclose the new mechanism of HCC development, and provide new ideas and new targets for the development of novel therapy strategies for HCC based on micropeptides.