IL-6调控乙酰基转移酶ARD1在抑郁作为乳腺癌风险因素中的机制研究

Depression is of concern as a risk factor for breast cancer, but its detailed mechanism and involved signal pathway are not revealed. Our survey showed that depression has a strong correlation with breast cancer. Depression is accompanied by immunoregulatory abnormalities and inflammatory response activation. Reports and our study had shown that the levels of Interleukin 6 (IL-6), which is one of the inflammatory factors, are significantly increased in depressed patients. We found that the expression of acetyltransferase ARD1 was positively regulated by IL-6 in a dose-dependent manner and was also increased in clinical breast cancer specimens from depressed patients. Our previous studies have confirmed that ARD1 promotes breast cancer development. In this research, we will elucidate the regulation of ARD1 by IL-6 and the role of depression in breast cancer development with cell model, animal model and depression-related breast cancer clinical specimens; we hope to reveal how depression affects immunological system, which ensues IL6 altering ARD1 expression and promotes cancer development in corresponding signal pathways. It will be helpful for comprehensive understanding of the role of ARD1 in depression and breast cancer, which will provide the basis for understanding depression as a risk factor for breast cancer and new clues for breast cancer development and possible intervention targets.

抑郁作为乳腺癌的风险因素备受关注，但具体的机制和相关信号通路揭示不多。我们进行了抑郁与乳腺癌的临床问卷调查，显示两者有较强相关性。抑郁伴随着免疫调节异常和炎症反应系统活化。文献报道及我们的检测都显示，抑郁病人炎性因子IL-6水平显著增高。我们发现，乙酰基转移酶ARD1的表达以剂量依赖的方式受到IL-6的正调控，并且在乳腺癌临床标本中抑郁患者的ARD1表达量更高。我们过去的研究证实ARD1促进了乳腺癌的发生发展。本课题拟利用抑郁相关乳腺癌临床标本、动物模型和细胞模型，研究IL-6对ARD1的调控机制及其在抑郁作为乳腺癌风险因素中的作用，以期揭示抑郁通过影响免疫系统，使得IL-6改变ARD1表达水平，在相应的信号转导途径介导下发挥促癌作用的机制，有助于更全面的认识ARD1在抑郁与乳腺癌中发挥的作用，为理解抑郁作为乳腺癌风险因素提供依据，也为认识乳腺癌的发病原因和寻找可能的干预靶点提供新的线索。

长久以来，抑郁作为乳腺癌的风险因素备受关注。大量的回顾性研究让我们相信，抑郁提高了乳腺癌的罹患风险，但具体的机制和相关信号通路揭示不多。抑郁伴随着免疫调节异常和炎症反应系统活化。文献报道及我们的检测都显示，抑郁病人炎性因子IL-6水平显著增高。我们发现，乙酰基转移酶ARD1的表达以剂量依赖的方式受到IL-6的正调控，并且在乳腺癌临床标本中抑郁患者的ARD1表达量更高。同时我们也证实了ARD1对乳腺癌的促进作用。因此我们推测抑郁提高了IL6的水平，而IL6又促进了ARD1的表达，从而推动了乳腺癌进程。本项目基于初步实验的线索，进一步研究IL6和ARD1在抑郁提高乳腺癌罹患风险进程中的调控作用及其机制，明确相关信号通路及ARD1的转录因子。我们将抑郁的乳腺癌病人临床组织标本和血清、乳腺癌细胞模型和小鼠抑郁乳腺癌移植瘤模型作为研究材料。通过临床相关性调查和小鼠乳腺癌移植瘤模型证实，抑郁提高了乳腺癌的罹患风险。通过测定抑郁病人和动物模型血清中IL6的水平，进一步确定抑郁提高了IL6水平。而抑郁乳腺癌移植瘤模型显示，IL-6在抑郁提高乳腺癌罹患风险中发挥促进作用。通过检测临床和动物模型组织标本中ARD1的表达以及细胞加入浓度梯度IL6后ARD1的蛋白水平，证实了IL6对ARD1的正调控作用。通过临床标本检测、细胞实验和乳腺癌移植瘤模型证实，ARD1能够促进乳腺癌的发展进程。检悬浮芯片和转录组测序富集分析初步显示，HIF1ɑ介导了IL6对ARD1的表达调控。从我们的研究结果可以看出，IL6促进ARD1的表达，在抑郁提高乳腺癌发生中的作用是有据可循的。本研究揭示了抑郁提高IL6水平，从而促进ARD1蛋白表达，进而提高乳腺癌发生、发展和恶化的风险。为理解ARD1在肿瘤中的不同角色提供依据，也为深入认识抑郁在乳腺癌发生中的作用增加理论支持，也有助于寻找临床上预防和缓解相关疾病的可能性。