Apoptosis Research Group, School of Life Sciences, Faculty of Natural Sciences, Keele University, Huxley Building, Keele ST5 5BG, U.K.
Biosci Rep. 2018 Jul 6;38(4). doi: 10.1042/BSR20180704. Print 2018 Aug 31.
The long noncoding RNA myocardial infarction associated transcript (MIAT) is involved in a number of diseases, including myocardial infarction and diabetic retinopathy. Emerging evidence suggests that MIAT expression levels are increased in different type of cancers, including breast cancer. In the present study, we further evaluated the role of MIAT in breast cancer and investigated the consequences of its silencing on breast cancer response to chemotherapeutic agents. Expression levels of MIAT mRNA in breast cancer were determined using TissueScan™ Breast Cancer cDNA Arrays. Breast cancer cell lines were transfected with MIAT specific siRNAs, with silencing confirmed using RT-qPCR and the effects on breast cancer cell survival and response to different apoptotic stimuli determined. MIAT transcript levels were significantly elevated in breast cancer samples. Such increase was specific to the early stages of the disease, ER, PR +ve, HER -ve, and triple negative breast cancer samples. Silencing of MIAT induced growth arrest and increased basal apoptosis. Reduced levels of MIAT augmented the apoptotic response of breast cancer cells to a wide range of apoptotic stimuli. Our results also showed that MIAT down-regulation was associated with a decrease in OCT4 mRNA, suggesting the existence of a MIAT/OCT4 regulatory loop, similar to that observed in malignant mature B cells. Taken together with the recent demonstration of oncogene characteristics, our observations suggest that MIAT plays an important role in breast tumorigenesis. Strategies to decrease MIAT expression levels may improve sensitivity to therapy in breast cancer by enhancing the apoptotic responses to conventional chemotherapies.
长链非编码 RNA 心肌梗死相关转录物（MIAT）与许多疾病有关，包括心肌梗死和糖尿病性视网膜病变。新出现的证据表明，MIAT 的表达水平在不同类型的癌症中升高，包括乳腺癌。在本研究中，我们进一步评估了 MIAT 在乳腺癌中的作用，并研究了其沉默对乳腺癌对化疗药物反应的影响。使用 TissueScan™乳腺癌 cDNA 阵列确定乳腺癌中 MIAT mRNA 的表达水平。用 MIAT 特异性 siRNA 转染乳腺癌细胞系，通过 RT-qPCR 证实沉默，并确定对乳腺癌细胞存活和对不同凋亡刺激物反应的影响。MIAT 转录物水平在乳腺癌样本中显著升高。这种增加是疾病早期、ER、PR +ve、HER -ve 和三阴性乳腺癌样本特有的。MIAT 的沉默诱导了生长停滞和基础凋亡增加。MIAT 水平的降低增强了乳腺癌细胞对广泛的凋亡刺激物的凋亡反应。我们的研究结果还表明，MIAT 下调与 OCT4 mRNA 的减少有关，这表明存在 MIAT/OCT4 调节环，类似于在恶性成熟 B 细胞中观察到的调节环。结合最近关于癌基因特征的研究结果，我们的观察结果表明，MIAT 在乳腺癌的发生中起着重要作用。降低 MIAT 表达水平的策略可能通过增强对常规化疗的凋亡反应来提高乳腺癌的治疗敏感性。
