Department of Breast Disease, The First Affiliated Hospital of Nanjing Medical University.
Department of Breast Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
Anticancer Drugs. 2022 Feb 1;33(2):178-190. doi: 10.1097/CAD.0000000000001253.
Breast cancer is an aggressive malignancy with high morbidity in females worldwide. Extensive studies reveal that long noncoding RNAs (lncRNAs) are abnormally expressed and act as key regulators in various cancers, including breast cancer. In this work, we investigated the role and regulatory mechanism of lncRNA prostate cancer-associated transcript 6 (PCAT6) in breast cancer progression. Our findings revealed that PCAT6 was overexpressed in breast cancer tissues and cell lines. Furthermore, elevation of PCAT6 reflected an adverse prognosis of patients. Functional experiments indicated that PCAT6 knockdown hampered cell proliferation, facilitated apoptosis and cell cycle arrest in vitro, and inhibited tumor growth in vivo. We also found that the transcription factor SP1 could bind to the PCAT6 promoter and promoted its expression. Subsequently, it was verified that PCAT6 was a molecular sponge for microRNA-326 (miR-326), and the leucine-rich repeat containing the eight family member E (LRRC8E) was a direct target of miR-326. Rescue assays revealed that LRRC8E overexpression attenuated the suppressive effect of PCAT6 knockdown on cellular progression of breast cancer. In summary, this study demonstrated that SP1-activated PCAT6 promoted the malignant behaviors of breast cancer cells by regulating the miR-326/LRRC8E axis.
乳腺癌是一种具有高发病率的侵袭性恶性肿瘤，在全球女性中较为常见。大量研究表明，长链非编码 RNA（lncRNA）在包括乳腺癌在内的各种癌症中异常表达，并作为关键调节因子发挥作用。在这项工作中，我们研究了 lncRNA 前列腺癌相关转录物 6（PCAT6）在乳腺癌进展中的作用和调节机制。我们的研究结果表明，PCAT6 在乳腺癌组织和细胞系中表达上调。此外，PCAT6 的升高反映了患者预后不良。功能实验表明，PCAT6 敲低可抑制体外细胞增殖，促进细胞凋亡和细胞周期停滞，并抑制体内肿瘤生长。我们还发现转录因子 SP1 可以与 PCAT6 启动子结合并促进其表达。随后，验证了 PCAT6 是 microRNA-326（miR-326）的分子海绵，富含亮氨酸重复的八个家族成员 E（LRRC8E）是 miR-326 的直接靶标。挽救实验表明，LRRC8E 的过表达减弱了 PCAT6 敲低对乳腺癌细胞进展的抑制作用。总之，这项研究表明，SP1 激活的 PCAT6 通过调节 miR-326/LRRC8E 轴促进了乳腺癌细胞的恶性行为。
