MicroRNA-510 mediated negative regulation of Caveolin-1 in fibroblasts promotes aggressive tumor growth.
MicroRNA-510 mediated negative regulation of Caveolin-1 in fibroblasts promotes aggressive tumor growth.
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DOI：
10.3389/fimmu.2023.1116644
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发表时间：
2023
影响因子：
7.3
通讯作者：
Findlay, Victoria J.
中科院分区：
文献类型：
--
作者：
King, Brooke;Krisanits, Bradley A.;Guo, Qi J.;Blake, Bobbie;Nogueira, Lourdes M.;Jolly, Gurbani;Satterwhite, Arabia;Turner, David P.;Hoffman, Stanley;Evans-Knowell, Ashley;Findlay, Victoria J.
在美国，尽管乳腺癌死亡率最近有所下降，但黑人和白人女性乳腺癌患者的死亡率仍然存在差异，黑人女性的死亡率高出41%。现在有几项研究报告说，种族差异可以独立于社会经济和护理标准问题而存在，这表明可能涉及生物因素。肿瘤间质室caviolin -1 （Cav1）的缺失是预测包括三阴性亚型在内的乳腺癌预后不良的一种新的临床生物标志物，但Cav1缺失的机制尚不清楚。我们之前发现miR-510-5p是一种新的肿瘤细胞，并提出在患者中观察到的高水平miR-510-5p是一种导致间质Cav1丢失和更糟糕结果的新机制。通过荧光素酶、western blot和qPCR检测，Cav1被确定为miR-510-5p的直接靶点。在体外用transwell共培养法和体内用异种移植物法评估上皮细胞和成纤维细胞之间的间质串扰。我们发现Cav1是miR-510-5p的直接靶点，并且在成纤维细胞中的表达导致“激活”表型。我们认为，这在癌症差异的背景下可能是重要的，因为我们还观察到，与患有乳腺癌的白人女性相比，黑人女性中循环miR-510-5p水平升高，基质Cav1水平降低。最后，我们在体内观察到肿瘤细胞与表达癌症相关的miR-510-5p的成纤维细胞共注射时，肿瘤生长显著增加。我们提出miR-510-5p介导的成纤维细胞中Cav1的负调控是侵袭性肿瘤生长的一种新机制，可能是乳腺癌差异的驱动因素。
In the US, despite the recent decline in breast cancer deaths, a persistent mortality disparity exists between black and white women with breast cancer, with black women having a 41% higher death rate. Several studies are now reporting that racial disparities can exist independent of socioeconomic and standard of care issues, suggesting that biological factors may be involved. Caveolin-1 (Cav1) loss in the tumor stromal compartment is a novel clinical biomarker for predicting poor outcome in breast cancer including triple negative subtype, however the mechanism of Cav1 loss is unknown. We previously identified miR-510-5p as a novel oncomir and propose here that the high levels observed in patients is a novel mechanism leading to stromal Cav1 loss and worse outcomes. Cav1 was identified as a direct target of miR-510-5p through luciferase, western blot and qPCR assays. Stromal cross talk between epithelial cells and fibroblasts was assessed in vitro using transwell co-culture assays and in vivo using xenograft assays. We found that Cav1 is a direct target of miR-510-5p and that expression in fibroblasts results in an ‘activated’ phenotype. We propose that this could be important in the context of cancer disparities as we also observed increased levels of circulating miR-510-5p and reduced levels of stromal Cav1 in black women compared to white women with breast cancer. Finally, we observed a significant increase in tumor growth when tumor cells were co-injected with miR-510-5p expressing cancer associated fibroblasts in vivo. We propose that miR-510-5p mediated negative regulation of Cav1 in fibroblasts is a novel mechanism of aggressive tumor growth and may be a driver of breast cancer disparity.
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影响因子：
3.6
作者：
Mercier I;Casimiro MC;Wang C;Rosenberg AL;Quong J;Minkeu A;Allen KG;Danilo C;Sotgia F;Bonuccelli G;Jasmin JF;Xu H;Bosco E;Aronow B;Witkiewicz A;Pestell RG;Knudsen ES;Lisanti MP
通讯作者：
Lisanti MP
影响因子：
3.4
作者：
Zhang Y;Li Y;Wang Q;Zhang X;Wang D;Tang HC;Meng X;Ding X
通讯作者：
Ding X
影响因子：
5.2
作者：
Sebastian, Aimy;Hum, Nicholas R.;Loots, Gabriela G.
通讯作者：
Loots, Gabriela G.
影响因子：
4.3
作者：
Brody, Jonathan R.;Costantino, Christina L.;Witkiewicz, Agnieszka K.
通讯作者：
Witkiewicz, Agnieszka K.
影响因子：
50.3
作者：
Costa, Ana;Kieffer, Yann;Mechta-Grigoriou, Fatima
通讯作者：
Mechta-Grigoriou, Fatima