Renalase Expression by Melanoma and Tumor-Associated Macrophages Promotes Tumor Growth through a STAT3-Mediated Mechanism.
Renalase Expression by Melanoma and Tumor-Associated Macrophages Promotes Tumor Growth through a STAT3-Mediated Mechanism.
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DOI：
10.1158/0008-5472.can-15-1524
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发表时间：
2016-07-01
期刊：
影响因子：
11.2
通讯作者：
Desir GV
中科院分区：
文献类型：
--
作者：
Hollander L;Guo X;Velazquez H;Chang J;Safirstein R;Kluger H;Cha C;Desir GV
为了维持其增殖，癌细胞克服了抑制其生长、促进衰老和细胞死亡的负面作用信号。肾酶(Renalase，RNLS)是一种分泌型黄素蛋白，在缺血和毒性损伤后发挥生存因子的作用，通过血浆钙通道PMCA4b激活PI3K/AKT和MAPK通路。我们发现，在原发性黑色素瘤和CD163+肿瘤相关巨噬细胞()中，RNLS的表达显著增加。在临床标本中，RNLS在肿瘤中的表达与疾病特异性生存呈负相关，提示RNLS具有致病作用。在小鼠异种移植实验中，通过RNAi、阻断抗体或RNLS衍生的抑制肽来减弱RNLS降低黑色素瘤细胞的存活，并且抗RNLS治疗在体内阻止了肿瘤的生长。机制研究表明，肿瘤细胞的凋亡增加与p38MAPK介导的Bax激活有关，而细胞生长停滞的增加与细胞周期抑制物p21的表达增加有关。总体而言，我们的结果证实了分泌性黄素蛋白RNLS在促进黑色素瘤细胞生长和肿瘤微环境中CD163+的作用，对黑色素瘤的治疗具有潜在的治疗意义。
To sustain their proliferation cancer cells overcome negative-acting signals that restrain their growth and promote senescence and cell death. Renalase (RNLS) is a secreted flavoprotein that functions as a survival factor after ischemic and toxic injury, signaling through the plasma calcium channel PMCA4b to activate the PI3K/AKT and MAPK pathways. We show that RNLS expression is increased markedly in primary melanomas and CD163+ tumor associated macrophages (TAM). In clinical specimens, RNLS expression in the tumor correlated inversely with disease-specific survival, suggesting a pathogenic role for RNLS. Attenuation of RNLS by RNAi, blocking antibodies or an RNLS-derived inhibitory peptide decreased melanoma cell survival, and anti-RNLS therapy blocked tumor growth in vivo in murine xenograft assays. Mechanistic investigations showed that increased apoptosis in tumor cells was temporally related to p38 MAPK-mediated Bax activation and that increased cell growth arrest was associated with elevated expression of the cell cycle inhibitor p21. Overall, our results established a role for the secreted flavoprotein RNLS in promoting melanoma cell growth and CD163+ TAM in the tumor microenvironment, with potential therapeutic implications for the management of melanoma.