REG-γ-NLRP1途径介导乳腺癌细胞凋亡抵抗及免疫逃逸的分子机制

Apoptotic resistance and immune escape are important biological hallmark of cancer. We previously reported that proteasome activator REG-gamma (REG-γ) over-expressed in breast cancer, which plays double roles in apoptotic resistance and immune escape through inhibiting breast cancer cells apoptosis and activity of NK. However, the mechanism remains unknown. Our previous study also showed that expression of NLRP1 was inhibited by the over-expression. As known, NLRP1 can promote apoptosis and mediate immune responses which are closely related with cancer. Therefore, we speculate that REG-γ-mediating apoptotic resistance and immune escape of cancer may depend on the inhibition of NLRP1. Based on previous findings, the current study aims to further investigate the molecular mechanism by which REG-γ inhibits the expression of NLRP1, confirm the involvement of REG-γ-NLRP1 pathway in apoptotic resistance and immune escape and clarify the underlying mechanisms. Moreover, we will try to explore the therapeutic potential of inhibition of REG-γ-NLRP1 pathway in breast cancer. The performance of current program may be helpful to understand the malignant biological characteristics of breast cancer in apoptotic resistance and immune escape, and provide new therapeutic strategies for cancer therapy.

凋亡抵抗和免疫逃逸是恶性肿瘤重要生物学特征。我们前期研究首次证实：蛋白酶体激活因子REG-γ在乳腺癌中高表达，抑制乳腺癌细胞凋亡，抑制NK细胞活性，在乳腺癌凋亡抵抗和免疫逃逸中发挥双重作用，但作用机制尚未阐明。我们前期发现乳腺癌细胞中REG-γ过表达抑制NLRP1表达，而研究已证实NLRP1在促进细胞凋亡、介导免疫方面发挥着双重作用，并与肿瘤密切相关。由此推测REG-γ可能通过抑制NLRP1介导肿瘤细胞凋亡抵抗和肿瘤细胞免疫逃逸。本项目拟在前期研究基础上，深入研究REG-γ抑制NLRP1的分子机制，阐明REG-γ-NLRP1途径调控肿瘤细胞凋亡抵抗的分子机制，证实REG-γ-NLRP1途径参与免疫逃逸并阐明其分子机制，并拟进一步探讨靶向REG-γ-NLRP1途径对乳腺癌的治疗作用。本项目的实施有助于深入理解乳腺癌细胞凋亡抵抗和免疫逃逸的分子基础，有望为乳腺癌的治疗提供新的思路和策略。

复发和转移是恶性肿瘤重要生物学特征,我们前期研究首次证实：蛋白酶体激活因子REG-γ在乳腺癌细胞高表达，抑制乳腺癌细胞凋亡，抑制NK细胞活性，在乳腺癌凋亡抵抗和免疫逃逸中发挥双重作用。我们在本项目研究过程中发现乳腺癌细胞REG-γ过表达使肿瘤细胞侵袭转移能力增强。于此同时，我们发现乳腺癌细胞上皮、间质标志呈现相应改变，即发生了上皮间质转化。另外，我们证实乳腺癌细胞过表达REG-γ可促进维持肿瘤细胞干性和肿瘤细胞免疫逃逸。本项目主要研究REG-γ与乳腺癌侵袭转移等恶性生物学行为的相互作用关系，阐明REG-γ通过促进肿瘤细胞细胞上皮间质转化，肿瘤细胞干性及改变免疫微环境等多种途径促进乳腺癌的复发转移行为，并进一步探讨靶向REG-γ对乳腺癌的治疗作用。本项目的实施有助于理解乳腺癌细胞上皮间质转化，肿瘤干细胞特性和影响免疫微环境的分子基础，有望为乳腺癌的治疗提供新的思路和策略。