Department of Pathology and Forensics, Dalian Medical University, No.9 West Section, Lvshun South Road, Dalian 116044, China; Department of Clinical Medicine, Grade 2013, Dalian Medical University, No. 9 West Section, Lvshun South Road, Dalian 116044, China.
Teaching Laboratory of Morphology, Dalian Medical University, No.9 West Section, Lvshun South Road, Dalian 116044, China.
Chem Biol Interact. 2017 Nov 1;277:33-42. doi: 10.1016/j.cbi.2017.08.014. Epub 2017 Aug 24.
MicroRNAs (miRNAs) play an important role in regulating cancer stem cell (CSC). Previous studies have shown that microRNA-221/222 (miR-221/222) cluster are involved in the propagation of breast cancer stem cell (BCSC), however, the underlying molecular mechanisms are still not fully understood. In this study, we found that miR-221/222 were overexpressed in highly aggressive breast cancer MDA-MB-231 cells, that are enriched in markers for epithelial-mesenchymal transition (EMT) and BCSCs, than in MCF-7 cells. Phosphatase and tensin homolog (PTEN) was confirmed to be the target of miR-221/222 in breast cancer cells. MiR-221/222 enhanced breast cancer cell growth, migration and invasion by downregulating PTEN. Importantly, both ectopic expression of miR-221/222 and PTEN knockdown increased the mammosphere formation capacity and the expression of the stemness marker ALDH1. MiR-221/222 lentivirus vector infected MCF-7 cells produced larger subcutaneous tumors, while shRNA vector of PTEN showed similar trend. Along with the downregulation of PTEN caused by miR-221/222 in the breast cancer cells and the xenograft tumor tissues, Akt phosphorylation (p-Akt), NF-κB p65 and phosphorylated p65 (p-p65), and cyclooxygenase-2 (COX-2) were all overexpressed compared to the negative control. Taken together, our findings indicate that miR-221/222 play a critical role in the propagation of BCSCs and tumor growth possibly through targeting PTEN, which in turn activating the Akt/NF-κB/COX-2 pathway. MiR-221/222 might represent the potential target of breast cancer therapy.
微小 RNA（miRNAs）在调节癌症干细胞（CSC）方面发挥着重要作用。先前的研究表明，miR-221/222 簇参与了乳腺癌干细胞（BCSC）的增殖，然而，其潜在的分子机制仍不完全清楚。在这项研究中，我们发现 miR-221/222 在高度侵袭性乳腺癌 MDA-MB-231 细胞中过度表达，这些细胞富含上皮-间充质转化（EMT）和 BCSC 标志物，而 MCF-7 细胞中则没有。磷酸酶和张力蛋白同源物（PTEN）被证实是乳腺癌细胞中 miR-221/222 的靶标。miR-221/222 通过下调 PTEN 增强了乳腺癌细胞的生长、迁移和侵袭能力。重要的是，miR-221/222 的过表达和 PTEN 的敲低均增加了乳腺球形成能力和干细胞标志物 ALDH1 的表达。miR-221/222 慢病毒载体感染 MCF-7 细胞产生的皮下肿瘤较大，而 PTEN 的 shRNA 载体则表现出相似的趋势。随着 miR-221/222 在乳腺癌细胞及其异种移植肿瘤组织中对 PTEN 的下调，Akt 磷酸化（p-Akt）、NF-κB p65 和磷酸化 p65（p-p65）以及环氧化酶-2（COX-2）的表达均高于阴性对照。综上所述，我们的研究结果表明，miR-221/222 通过靶向 PTEN 发挥关键作用，从而激活 Akt/NF-κB/COX-2 通路，促进 BCSC 的增殖和肿瘤生长。miR-221/222 可能成为乳腺癌治疗的潜在靶点。
