National Laboratory CIB (LNCIB), AREA Science Park, 34149, Trieste, Italy.
Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Hönggerberg, 8093, Zurich, Switzerland.
Cell Death Differ. 2018 Jul;25(7):1224-1238. doi: 10.1038/s41418-018-0088-5. Epub 2018 Mar 22.
The tumor suppressor DAB2IP contributes to modulate the network of information established between cancer cells and tumor microenvironment. Epigenetic and post-transcriptional inactivation of this protein is commonly observed in multiple human malignancies, and can potentially favor progression of tumors driven by a variety of genetic mutations. Performing a high-throughput screening of a large collection of human microRNA mimics, we identified miR-149-3p as a negative post-transcriptional modulator of DAB2IP. By efficiently downregulating DAB2IP, this miRNA enhances cancer cell motility and invasiveness, facilitating activation of NF-kB signaling and promoting expression of pro-inflammatory and pro-angiogenic factors. In addition, we found that miR-149-3p secreted by prostate cancer cells induces DAB2IP downregulation in recipient vascular endothelial cells, stimulating their proliferation and motility, thus potentially remodeling the tumor microenvironment. Finally, we found that inhibition of endogenous miR-149-3p restores DAB2IP activity and efficiently reduces tumor growth and dissemination of malignant cells. These observations suggest that miR-149-3p can promote cancer progression via coordinated inhibition of DAB2IP in tumor cells and in stromal cells.
肿瘤抑制因子 DAB2IP 有助于调节癌细胞与肿瘤微环境之间建立的信息网络。这种蛋白的表观遗传和转录后失活在多种人类恶性肿瘤中很常见，并且可能有利于多种基因突变驱动的肿瘤的进展。通过对大量人类 microRNA 模拟物进行高通量筛选，我们鉴定出 miR-149-3p 是 DAB2IP 的负转录后调节因子。通过有效地下调 DAB2IP，这种 miRNA 增强了癌细胞的迁移和侵袭能力，促进了 NF-kB 信号的激活，并促进了促炎和促血管生成因子的表达。此外，我们发现前列腺癌细胞分泌的 miR-149-3p 诱导受体血管内皮细胞中 DAB2IP 的下调，刺激它们的增殖和迁移，从而潜在地重塑肿瘤微环境。最后，我们发现抑制内源性 miR-149-3p 可恢复 DAB2IP 的活性，并有效地减少肿瘤生长和恶性细胞的扩散。这些观察结果表明，miR-149-3p 可以通过协调抑制肿瘤细胞和基质细胞中的 DAB2IP 来促进癌症进展。
