腺苷A2B受体在促进乳腺肿瘤发生和转移的作用及机制研究

Cancer is a leading cause of death worldwide, with 8.2 million deaths in 2012. Gaining an understanding of the mechanisms of cancer progression and metastasis could lead to identification and characterization of new strategic targets for the treatment of cancer. The A2B adenosine receptor (A2BAR) is expressed in many tissues and cell types and requires higher concentration of adenosine for activation than other AR subtypes. It has become increasingly clear in recent years that A2BAR regulates a number of functions, such as angiogenesis, cytokine release. A2BAR may also play a potential role in cancer, based on a number of observations. Those reports show that increased expression of A2BAR in tumor tissues compared with normal tissues and A2BAR regulates tumor cell proliferation, apoptosis and tumor metastasis. However, most of the data are done in vitro and the detailed mechanisms are not very clear. In this study, we crossed A2B-/- mice with MMTV-PyMT mice to investigate the role of A2BAR in breast tumor initiation, progression and metastasis in vivo. Moreover, our recent finding shows that A2BAR physically interacts with α-actinin and regulates its protein expression. α-actinin are originally identified as cytoskeletal proteins which cross-link filamentous actin to establish cytoskeletal architect, function as a versatile promoter for tumorigenesis. Therefore, we hypothesized that A2BAR regulates tumorigenesis and metastasis of breast cancer through α-actinin. Our finding will provide a new mechanism of regulation of tumorigenesis and metastasis of breast cancer by A2BAR and also suggest A2BAR may constitute a novel target for therapeutic cancer intervention.

恶性肿瘤是威胁人类健康的首要顽症。揭示恶性肿瘤形成和转移的分子机制，是根治肿瘤的希望所在。A2B受体是腺苷的低亲和力结合受体，在许多病理活动中发挥着重要作用。近年来，越来越多研究显示A2B受体在肿瘤细胞中高表达并且参与肿瘤细胞的增殖、存活和迁移。但数据多基于体外实验，且作用的分子机制尚不清楚。为在体内明确A2B受体在肿瘤发生发展和转移的作用，本研究首次将乳腺癌转基因模型小鼠与A2B基因敲除小鼠杂交，在整体水平上观察敲除A2B受体对乳腺癌肿瘤形成和转移的作用。此外，我们近期研究发现A2B受体可与α辅肌动蛋白结合并影响其表达。α辅肌动蛋白是一种肌动蛋白交联蛋白，参与肿瘤的生长和转移。因此，我们假设A2B受体通过调控α辅肌动蛋白来影响乳腺肿瘤的生长和转移。本研究旨在明确A2B受体在乳腺癌肿瘤形成和转移中的重要作用并探索其作用的分子机制，为确立A2B受体作为抗肿瘤药物的新靶点提供充分的科学依据。

恶性肿瘤是威胁人类健康的首要顽症。揭示恶性肿瘤形成和转移的分子机制，是根治肿瘤的希望所在。A2B受体是腺苷的低亲和力结合受体，在许多病理活动中发挥着重要作用。近年来，越来越多研究显示A2B受体在肿瘤细胞中高表达并且参与肿瘤细胞的增殖、存活和迁移，但其作用的分子机制尚不清楚。本项目中首次研究发现A2B受体可与α辅肌动蛋白结合。 A2B 受体 C 末端的 297、 298 位置的两个氨基酸，苯丙氨酸和精氨酸，对于 A2B 受体与 α辅肌动蛋白的结合非常重要。此外，α 辅肌动蛋白能够影响 A2B 受体蛋白的稳定性从而可能影响细胞的生长和迁移。该项研究阐明了调控 A2B 受体的新分子机制，并揭示了A2B 受体在肿瘤演进中的作用分子机制。此外，该项目的另一个引申课题是发现了细胞粘附蛋白Kindlin-2可能作为乳腺肿瘤治疗的新靶点，为寻找抗肿瘤药物的新靶点提供充分的科学依据。