Department of Medical Laboratory Science, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui, China.
Department of Molecular and Cellular Biology, University of Connecticut, Storrs, Connecticut, USA.
J Biochem Mol Toxicol. 2022 Nov;36(11):e23176. doi: 10.1002/jbt.23176. Epub 2022 Aug 15.
The current study was set out to investigate the mechanism by which silenced long noncoding RNA (lncRNA) colon cancer-associated transcript 2 (CCAT2) modulates the cell growth, migration, invasion, and drug sensitivity of breast cancer (BC) cells to 5-fluorouracil (5-Fu) with the involvement of miR-145 and p53. First, high CCAT2 expression was presented in BC cells and tissues. Subsequently, the links between CCAT2 expression and BC clinicopathological features were analyzed. Highly-expressed CCAT2 was linked to lymph node metastasis, positive progesterone receptor, estrogen receptor, and Ki-67 of BC cells. Then, the gain- and loss-of-function approaches were performed to measure the regulatory role of CCAT2 in the biological processes of BC cells. Silencing of CCAT2 suppressed in vitro cell growth, proliferation, invasion, migration abilities, and epithelial-mesenchymal transformation, increased cell apoptosis, and enhanced drug sensitivity of BC cells. Silencing of CCAT2 upregulated miR-145, which was poorly expressed in drug-resistant BC cells. p53 can bind to the miR-145 promoter region and increase miR-145 expression. Upregulation of miR-145 induced by silencing of CCAT2 can be invalidated by p53-siRNA. To conclude, p53-induced activation of miR-145 could be inhibited by CCAT2, while overexpression of CCAT2 could improve the drug resistance of BC cells to 5-Fu.
本研究旨在探讨沉默长链非编码 RNA（lncRNA）结肠癌相关转录物 2（CCAT2）通过 miR-145 和 p53 调节乳腺癌（BC）细胞对 5-氟尿嘧啶（5-Fu）的细胞生长、迁移、侵袭和药物敏感性的机制。首先，CCAT2 在 BC 细胞和组织中高表达。随后，分析了 CCAT2 表达与 BC 临床病理特征的关系。高表达的 CCAT2 与 BC 细胞的淋巴结转移、孕激素受体、雌激素受体和 Ki-67 阳性有关。然后，采用增益和缺失功能方法来测量 CCAT2 在 BC 细胞生物学过程中的调节作用。沉默 CCAT2 抑制了 BC 细胞的体外生长、增殖、侵袭、迁移能力和上皮间质转化，增加了细胞凋亡，并增强了 BC 细胞对药物的敏感性。沉默 CCAT2 上调了 miR-145，而 miR-145 在耐药性 BC 细胞中表达较低。p53 可以结合 miR-145 启动子区域并增加 miR-145 的表达。沉默 CCAT2 诱导的 miR-145 上调可以通过 p53-siRNA 无效化。总之，CCAT2 可以抑制 p53 诱导的 miR-145 激活，而过表达 CCAT2 可以提高 BC 细胞对 5-Fu 的耐药性。
