Endocrinology and Metabolism Department, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.
Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.
Int J Oncol. 2019 Mar;54(3):1033-1042. doi: 10.3892/ijo.2019.4679. Epub 2019 Jan 8.
Tamoxifen is the gold standard for breast cancer endocrinotherapy. However, drug resistance remains a major limiting factor of tamoxifen treatment. Long non‑coding (lnc) RNA serves an important role in drug resistance; however, the molecular mechanisms of tamoxifen resistance in breast cancer endocrinotherapy are largely unclear. lncRNA urothelial cancer associated 1 (lncRNA UCA1, UCA1) has been proven to be dysregulated in human breast cancer and promotes cancer progression. In the present study, it was demonstrated that UCA1 was significantly upregulated in breast cancer tissues compared with healthy tissues. Furthermore, the expression level of UCA1 was significantly greater in tamoxifen‑resistant breast cancer cells (LCC2 and LCC9) when compared with those in the tamoxifen‑sensitive breast cancer cells (MCF‑7 and T47D). UCA1 silencing in LLC2 and LLC9 cells increased tamoxifen drug sensitivity by promoting cell apoptosis and arresting the cell cycle at the G2/M phase. Notably, the induced overexpression of UCA1 in MCF‑7 and T47D cells decreased the drug sensitivity of tamoxifen. The molecular mechanism involved in UCA1‑induced tamoxifen‑resistance was also investigated. It was identified that UCA1 was physically associated with the enhancer of zeste homolog 2 (EZH2), which suppressed the expression of p21 through histone methylation (H3K27me3) on the p21 promoter. In addition, it was demonstrated that UCA1 expression was paralleled to the phosphorylation of CAMP responsive element binding protein (CREB) and AKT. When LCC2 cells were treated with the phosphoinositide 3‑kinase (PI3K)/protein kinase B (AKT) signaling pathway inhibitor LY294002, the phosphorylation levels of CREB and AKT were significantly downregulated. Taken together, it was concluded that UCA1 regulates the EZH2/p21 axis and the PI3K/AKT signaling pathway in breast cancer, and may be a potential therapeutic target for solving tamoxifen resistance.
他莫昔芬是乳腺癌内分泌治疗的金标准。然而，药物耐药性仍是他莫昔芬治疗的主要限制因素。长链非编码 RNA（lncRNA）在耐药性中发挥重要作用；然而，乳腺癌内分泌治疗中他莫昔芬耐药的分子机制在很大程度上尚不清楚。lncRNA 尿路上皮癌相关 1（lncRNA UCA1，UCA1）已被证明在人类乳腺癌中失调，并促进癌症进展。在本研究中，与健康组织相比，UCA1 在乳腺癌组织中显著上调。此外，与他莫昔芬敏感乳腺癌细胞（MCF-7 和 T47D）相比，UCA1 在他莫昔芬耐药乳腺癌细胞（LCC2 和 LCC9）中的表达水平显著更高。在 LLC2 和 LLC9 细胞中沉默 UCA1 可通过促进细胞凋亡和将细胞周期阻滞在 G2/M 期来增加他莫昔芬药物敏感性。值得注意的是，在 MCF-7 和 T47D 细胞中诱导 UCA1 过表达会降低他莫昔芬的药物敏感性。还研究了 UCA1 诱导的他莫昔芬耐药的分子机制。确定 UCA1 与增强子结合蛋白 2（EZH2）物理结合，通过组蛋白甲基化（H3K27me3）抑制 p21 启动子上的 p21 表达。此外，还表明 UCA1 的表达与环磷酸腺苷反应元件结合蛋白（CREB）和 AKT 的磷酸化平行。当 LCC2 细胞用磷酸肌醇 3-激酶（PI3K）/蛋白激酶 B（AKT）信号通路抑制剂 LY294002 处理时，CREB 和 AKT 的磷酸化水平显著下调。综上所述，UCA1 调节乳腺癌中的 EZH2/p21 轴和 PI3K/AKT 信号通路，可能是解决他莫昔芬耐药的潜在治疗靶点。
