IL-35在低氧下通过调节细胞自噬对乳腺癌进展的影响及其机制研究

IL-35, as a novel immunosuppressive cytokine, plays an important role in the process of tumorigenesis and development. Our previous study showed that breast cancer cell could express IL-35 and its receptor, and the expression of IL-35 receptor was significantly increased under hypoxia. Exogeneous IL-35 could up-regulate the autophagy level and decrease phosphated mTOR in breast cancer cells. As a typical solid tumor, breast cancer has a wide range of hypoxia regions in the microenvironment, and autophagy remarkably improve their tolerance to hypoxic. However，it is not clear whether IL-35 was involved in the progression of breast cancer through autophagy？Via which signaling pathway? Based on the above results, we will comprehensively analyze the relationship between the expression of IL-35 and the Hif-1α、LC3B in breast cancer, adjacent normal tissue, immunocytes in tumor microenvironment, and fully explore the related molecular mechanism of IL-35 in the growth, invasion and metastasis of breast cancer under hypoxia via various molecular techniques and animal experiments. This study will not only further improve and accumulate the knowledge of IL-35, but also provide a new biological target for prevention and therapy of breast cancer.

IL-35作为新型免疫抑制性细胞因子，在肿瘤发生发展过程中发挥着重要作用。我们前期研究发现，人乳腺肿瘤细胞可表达IL-35及其受体，且在低氧下IL-35受体表达明显升高，同时IL-35可促进乳腺肿瘤细胞自噬和减弱mTOR磷酸化。乳腺癌作为一种典型的实体性肿瘤，微环境中存在广泛的低氧区，而细胞的自噬现象显著提高了其对低氧的耐受能力。IL-35是否通过上调细胞自噬促进乳腺肿瘤的进展？是通过何种信号通路？尚不清楚。本研究拟在前期结果的基础上，从IL-35在各种亚型乳腺癌、癌旁组织及肿瘤微环境免疫细胞中的表达与肿瘤组织中Hif-1α、LC3B的表达相关性入手，利用多种分子生物学技术和动物实验对其作用机制进行深入剖析，探讨IL-35在低氧下通过诱导乳腺癌细胞自噬参与乳腺癌生长、侵袭及转移的分子机制。本研究不仅是对IL-35功能研究的进一步完善和积累，也为乳腺癌的预防和治疗提供新的思路和靶点。

IL-35作为免疫抑制性细胞因子，不仅表达于免疫细胞，同时在肿瘤组织中也呈现高表达状态，其在乳腺癌中发挥的促癌机制尚不明确。本课题首先通过免疫组化、免疫荧光技术证实了IL-35可组成性、高水平表达于乳腺癌组织和细胞中，通过组织连续切片发现IL-35与HIF1A、LC3B存在显著相关性。其次通过各种体外生物学实验揭示了IL-35在低氧下可通过诱导乳腺肿瘤细胞自噬促进肿瘤的增殖、侵袭、迁移，抑制凋亡等恶性生物学行为，分子生物学技术进一步验证mTOR/AKT/PI3K是其重要的信号传导通路。最后通过体内动物实验发现，阻断IL-35的表达可明显抑制肿瘤的生长。本研究首次报道了这种IL-35促进实性乳腺肿瘤恶性演进的新机制，并为乳腺肿瘤的辅助治疗提供了全新的治疗靶点。