CD147通过COX-2/PGE2通路调控恶性黑素瘤肿瘤微环境的作用机制研究

Melanoma is one of the most immunogenic tumors. Tumor microenvironment is critical for its initiation and progression, while immune escape induced by immunosuppressive cells and anti-inflammatory cytokines hinders effective immunotherapy in melanoma. Pro-inflammatory prostaglandin E2 (PGE2), catalyzed by enzyme COX-2, plays a predominant role in cross talk between tumor cells and surrounding microenvironment through variable mechanisms. Studies showed that COX-2/PGE2 promoted immunosuppressive microenvironment by inducing Treg and MDSCs accumulation. According to our previous results, we found that, CD147, a molecule that has been studied by our research group for decades, regulated COX-2 expression tightly, which is probably through RAS/RAF/MEK/ERK signaling pathway and activation of specific downstream transcription factor. This would probably lead to more PGE2 production and secretion to the surroundings, further induce production of more anti-inflammatory cytokines, Treg and MDSCs accumulation. As a result, a more pro-tumor immunosuppressive environment would be formed, and it’s easier for tumor cells to escape from cytotoxic immune response, which benefits tumor progression, and become more resistant to immunotherapy. Our study will investigate the mechanism about regulation of COX-2/PGE2 by CD147, and the role of this axis between melanoma cell and tumor microenvironment.

恶性黑素瘤是免疫原性最强的肿瘤之一，特殊的肿瘤微环境对其发生发展非常关键，其中免疫抑制性细胞和抗炎因子介导的免疫逃逸反应更成为免疫治疗的阻碍。促炎性物质-PGE2是COX-2的主要代谢产物，并作为肿瘤细胞与周围基质细胞交互作用的“桥梁”，二者通过多种机制，即可作用于肿瘤本身，也可调节肿瘤微环境，包括诱导Treg与MDSCs的聚集。结合我们的前期实验结果，发现在恶性黑素瘤中，本课题组长期研究的CD147分子很可能通过激活RAS/RAF/MEK/ERK通路，活化特定转录因子，显著上调COX-2表达水平，促进PGE2的产生并释放至周围微环境中，从而诱导Treg、MDSCs和抗炎因子的产生与聚集，有助于形成免疫抑制性微环境，促使肿瘤细胞免疫逃逸，有利于其侵袭转移的发生及增强对免疫治疗的耐受性。本研究将揭示CD147调控COX-2/PGE2的的作用机制，阐明此信号轴对恶性黑素瘤肿瘤微环境的影响。

恶性肿瘤作为人类健康的重大威胁，其发病机制、侵袭转移及复发的机制、肿瘤微环境是攻克恶性肿瘤的几大难点和研究重点。本课题组多年以来围绕CD147分子在包括恶性黑素瘤在内的多种皮肤疾病中开展研究工作，发现其可通过影响血管生成、能量代谢、缺氧应激等方面影响黑素瘤的生物学行为。本研究着眼于黑素瘤肿瘤微环境，从CD147-COX2上游通路寻找到可以直接抑制肿瘤的关键靶点和药物-BDR4小分子抑制剂NHWD-870，可显著抑制黑素瘤细胞增殖、促进凋亡、抑制肿瘤干细胞特性。在机制方面，我们侧重于CD147信号网络在黑素瘤肿瘤微环境中的研究，并发现CD147的重要相互作用蛋白TRAF6在微环境中的肿瘤相关性成纤维细胞（cancer-associated fibroblasts, CAFs）中高表达，其表达水平高低与CAFs的增殖、迁移、侵袭能力和细胞活化水平呈正相关，并进一步证明CAFs中的TRAF6水平可显著影响黑素瘤细胞的生物学行为。这为CD147为核心的分子网络作为黑素瘤治疗靶点提供了新的理论依据。