Department of Thoracic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China.
Signal Transduct Target Ther. 2022 May 4;7(1):147. doi: 10.1038/s41392-022-00945-9.
The incidence of cutaneous melanoma (CM) has been increasing annually worldwide. In this study, we identify that MrgprF, a MAS related GPR family member, is decreased in cutaneous melanoma tissues and cell lines due to hypermethylation of its promoter region, and show that patients with CM expressing high levels of MrgprF exhibit an improved clinical outcome. We demonstrate that MrgprF forced expression inhibits tumor cell proliferation, migration, xenograft tumor growth, and metastasis. On the contrary, MrgprF knockdown promotes tumor cell proliferation and transformation of immortalized human keratinocyte-HaCaT cells, supporting the inhibitory role of MrgprF during tumor progression. Mechanistic studies reveal that MrgprF reduces the phosphoinositol‑3‑kinase (PI3K) complex formation between p101 and p110γ subunits, the critical step for phosphatidylinositol-(3, 4)-P2 (PIP2) conversion to phosphatidylinositol-(3, 4, 5)-P3 (PIP3), and then reduces the activation of PI3K/Akt signaling. This effect can be reversed by Akt specific agonist SC79. In addition, AMG 706, a previously documented inhibitor for endothelial cell proliferation, is identified as a potential agonist for MrgprF, and can impede tumor growth both in vitro and in vivo. Taken together, our findings suggest that MrgprF, a novel tumor suppressor in cutaneous melanoma, may be useful as a therapeutic target in the future.
皮肤黑色素瘤（CM）的发病率在全球范围内呈逐年上升趋势。在本研究中，我们发现 MAS 相关 G 蛋白偶联受体家族成员 MrgprF 由于其启动子区域的高甲基化而在皮肤黑色素瘤组织和细胞系中减少，并表明表达高水平 MrgprF 的 CM 患者表现出改善的临床结局。我们证明 MrgprF 的强制表达抑制肿瘤细胞增殖、迁移、异种移植肿瘤生长和转移。相反，MrgprF 的敲低促进了永生化人角质形成细胞-HaCaT 细胞的肿瘤细胞增殖和转化，支持 MrgprF 在肿瘤进展过程中发挥抑制作用。机制研究表明 MrgprF 减少了 p101 和 p110γ 亚基之间的磷酸肌醇-3-激酶（PI3K）复合物形成，这是磷脂酰肌醇-（3,4）-P2（PIP2）转化为磷脂酰肌醇-（3,4,5）-P3（PIP3）的关键步骤，然后减少 PI3K/Akt 信号通路的激活。这种作用可以被 Akt 特异性激动剂 SC79 逆转。此外，先前被证明可抑制内皮细胞增殖的 AMG 706 被鉴定为 MrgprF 的潜在激动剂，可在体外和体内均阻碍肿瘤生长。总之，我们的研究结果表明，MrgprF 作为皮肤黑色素瘤中的一种新型肿瘤抑制因子，可能成为未来治疗的潜在靶点。
