Capn4通过调节HMGB1乙酰化促进上皮性卵巢癌转移的分子机制研究

Metastasis of cancer cells is an important prognostic factor in patients with epithelial ovarian cancer (EOC). Our previous studies have provided the first demonstration that the overexpression of Capn4 is associated with the metastasis of EOC. Further studies indicated that Capn4 promoted EOC metastasis by interacting with the Wnt/β-catenin signaling pathway to up-regulate OPN expression. However, the function and the molecular mechanism of Capn4 in EOC need to be further verified. It has been reported that OPN plays an important role in the release of HMGB1 from the nucleus to the cytoplasm. The results of the previous study of our research group pointed out that OPN can promote the acetylation of HMGB1. Therefore, we hypothesize that Capn4 could promote the expression and acetylation of HMGB1 in ovarian cancer cells by up-regulating the expression of OPN. Then, the highly expression of OPN and HMGB1 may interact with their corresponding receptors to promote metastasis of EOC. So, our research will further verify the role of Capn4 in the metastasis of EOC in vivo and in vitro; elucidate the molecular mechanism by which Capn4 promote the expression of OPN; and explore the effect of OPN on the expression and acetylation of HMGB1. Finally, we will reveal a novel signaling pathway of Capn4-OPN-HMGB1 in EOC. Our results will help to clarify the role of Capn4 and its molecular mechanisms in EOC and contribute to find a new predictive marker and therapeutic target for EOC.

卵巢癌细胞的转移是患者预后不良的重要因素。本课题组前期研究首次发现Capn4高表达与上皮性卵巢癌转移相关,进一步研究指出Capn4可通过激活Wnt/β-catenin通路促进OPN表达，进而促进卵巢癌细胞的增殖及转移。但上皮性卵巢癌中Capn4的促转移作用及分子机制尚需深入探讨。文献报道OPN对HMGB1从胞核到胞浆的转移发挥重要作用，本课题组前期实验结果进一步指出OPN可促进HMGB1乙酰化，据此我们推测Capn4可通过促进OPN表达调节HMGB1乙酰化发挥促卵巢癌细胞转移的作用。为证实以上假设，本项目将进一步验证上皮性卵巢癌中Capn4的促转移作用；阐明Capn4调节OPN表达进而促进HMGB1乙酰化的分子机制，揭示上皮性卵巢癌中Capn4-OPN-HMGB1新型信号通路。此项目有利于明确Capn4基因在上皮性卵巢癌中的作用，阐明其分子机制，有助于找到卵巢癌新的治疗和预防方法。

卵巢癌细胞的转移是患者预后不良的重要因素。本课题组前期研究首次发现Capn4高表达与上皮性卵巢癌转移相关,进一步研究指出Capn4可通过激活Wnt/β-catenin通路促进OPN表达，进而促进卵巢癌细胞的增殖及转移。我们进一步的研究明确了OPN 在上皮性卵巢癌增殖、迁移及侵袭中的重要作用，发现了OPN可提高HMGB1 的乙酰化水平从而促进HMGB1 核浆转移过程，细胞浆内HMGB1表达增高进而发挥促进肿瘤细胞转移的作用。在上皮性卵巢癌内首次提出OPN 可调控HMGB1 乙酰化促进卵巢癌细胞的增殖与转移，揭示上皮性卵巢癌中Capn4-OPN-HMGB1新型信号通路。我们的研究明确了Capn4基因在上皮性卵巢癌中的作用，发现新的上皮性卵巢癌转移分子机制，为上皮性卵巢癌的诊断和靶向治疗提供理论基础。同时受本项目部分资助，我们还发现了一种可以明显抑制上皮性卵巢癌细胞迁移与侵袭的小分子化合物α-NETA，为新药开发奠定了前期基础。