Jafari Naser, Chen Andrew, Kolla Manohar, Pompa Isabella R, Qiu Yuhan, Yu Rebecca, Llevenes Pablo, Ennis Christina S, Mori Joakin, Mahdaviani Kiana, Halpin Meredith, Gignac Gretchen A, Heaphy Christopher M, Monti Stefano, Denis Gerald V
Boston University-Boston Medical Center Cancer Center, Boston University School of Medicine, Boston, MA, 02118, USA.
Department of Medicine, Computational Biomedicine Section, Boston University School of Medicine, Boston, MA, 02118, USA.
Adv Cancer Biol Metastasis. 2022 Dec;6. doi: 10.1016/j.adcanc.2022.100073. Epub 2022 Nov 4.
Comorbid Type 2 diabetes (T2D), a metabolic complication of obesity, associates with worse cancer outcomes for prostate, breast, head and neck, colorectal and several other solid tumors. However, the molecular mechanisms remain poorly understood. Emerging evidence shows that exosomes carry miRNAs in blood that encode the metabolic status of originating tissues and deliver their cargo to target tissues to modulate expression of critical genes. Exosomal communication potentially connects abnormal metabolism to cancer progression. Here, we hypothesized that T2D plasma exosomes induce epithelial-mesenchymal transition (EMT) and immune checkpoints in prostate cancer cells. We demonstrate that plasma exosomes from subjects with T2D induce EMT features in prostate cancer cells and upregulate the checkpoint genes and . We demonstrate that specific exosomal miRNAs that are differentially abundant in plasma of T2D adults compared to nondiabetic controls (miR374a-5p, miR-93-5p and let-7b-3p) are delivered to cancer cells, thereby regulating critical target genes. We build on our previous reports showing BRD4 controls migration and dissemination of castration-resistant prostate cancer, and transcription of key EMT genes, to show that T2D exosomes require BRD4 to drive EMT and immune ligand expression. We validate our findings with gene set enrichment analysis of human prostate tumor tissue in TGCA genomic data. These results suggest novel, non-invasive approaches to evaluate and potentially block progression of prostate and other cancers in patients with comorbid T2D.
2型糖尿病（T2D）作为肥胖的一种代谢并发症，与前列腺癌、乳腺癌、头颈癌、结直肠癌及其他几种实体瘤的不良癌症预后相关。然而，其分子机制仍知之甚少。新出现的证据表明，外泌体在血液中携带编码起源组织代谢状态的微小RNA（miRNA），并将其货物递送至靶组织以调节关键基因的表达。外泌体通讯可能将异常代谢与癌症进展联系起来。在此，我们假设T2D血浆外泌体可诱导前列腺癌细胞发生上皮-间质转化（EMT）和免疫检查点。我们证明，来自T2D患者的血浆外泌体可诱导前列腺癌细胞出现EMT特征，并上调检查点基因 和 。我们证明，与非糖尿病对照组相比，T2D成年人血浆中差异丰富的特定外泌体miRNA（miR374a-5p、miR-93-5p和let-7b-3p）被递送至癌细胞，从而调节关键靶基因。我们基于之前的报告展开研究，这些报告显示BRD4控制去势抵抗性前列腺癌的迁移和扩散以及关键EMT基因的转录，结果表明T2D外泌体需要BRD4来驱动EMT和免疫配体表达。我们通过对TGCA基因组数据中的人类前列腺肿瘤组织进行基因集富集分析来验证我们的发现。这些结果提示了评估并潜在阻断合并T2D患者前列腺癌及其他癌症进展的新型非侵入性方法。
