Tao Sifeng, He Haifei, Chen Qiang
Department of Surgical Oncology, Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou, 310009, China.
J Transl Med. 2015 Apr 25;13:131. doi: 10.1186/s12967-015-0489-x.
HOTAIR plays an important role in the regulation of cancer cell proliferation and cancer invasion in breast cancer. The up-regulation of HOTAIR has been reported in both estrogen receptor (ER) positive and triple-negative (TN) breast cancer. It has been reported that HOTAIR is regulated by estrogen (E2) via ERs in ER-positive breast cancer. However, it is unknown how HOTAIR is regulated in TN breast cancer. In this study, we found that HOTAIR was increased in the peripheral blood mononuclear cells and cancer tissues from breast cancer patients, and was especially higher in patients with metastatic breast cancer. In addition, we found that estrogen promoted HOTAIR through its receptor GPER and estrogen-induced breast cancer cell migration was reversed by deleting HOTAIR in TN breast cancer cells MDA-MB-231and BT549. Furthermore, we identified that E2-GPER induces the level of HOTAIR through the suppression of miR-148a. miR-148a level was negatively correlated with HOTAIR level in breast cancer patients. After the mutation of the predicted miR-148a binding sites in HOTAIR, miR-148a had no effect on HOTAIR. In conclusion, our findings offer important new insights into the ability of estrogenic GPER signaling to increase the HOTAIR level by inhibiting miR-148a in breast cancer.
HOTAIR在乳腺癌细胞增殖和侵袭调控中发挥重要作用。雌激素受体（ER）阳性和三阴性（TN）乳腺癌中均有HOTAIR上调的报道。据报道，在ER阳性乳腺癌中，HOTAIR受雌激素（E2）通过ERs调控。然而，TN乳腺癌中HOTAIR如何调控尚不清楚。在本研究中，我们发现乳腺癌患者外周血单个核细胞和癌组织中HOTAIR增加，且转移性乳腺癌患者中尤其更高。此外，我们发现雌激素通过其受体GPER促进HOTAIR，在TN乳腺癌细胞MDA-MB-231和BT549中敲除HOTAIR可逆转雌激素诱导的乳腺癌细胞迁移。此外，我们确定E2-GPER通过抑制miR-148a诱导HOTAIR水平。乳腺癌患者中miR-148a水平与HOTAIR水平呈负相关。HOTAIR中预测的miR-148a结合位点突变后，miR-148a对HOTAIR无影响。总之，我们的研究结果为雌激素GPER信号通路通过抑制乳腺癌中miR-148a来提高HOTAIR水平的能力提供了重要的新见解。
