Department of Hepatobiliary Surgery, China-Japan Union Hospital of Jilin University, No.126, Xiantan Street, Changchun, 130033, China.
Department of Breast Surgery, China-Japan Union Hospital of Jilin University, No.126, Xiantan Street, Changchun, 130033, China.
Biochem Biophys Res Commun. 2018 Jun 18;501(1):33-40. doi: 10.1016/j.bbrc.2018.04.116. Epub 2018 May 7.
Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is involved in tumor cell growth process. However, its role and molecular mechanism in liver cancer is still not fully understood. In this study, we found that MALAT1 was significantly expressed in liver cancer cell lines. And knockdown of MALAT1 suppressed proliferation, migration and invasion of HepG2 cells, accompanied with decrease of Rho-associated coiled-coil-forming protein kinase 1 (ROCK1), α-smooth muscle actin (α-SMA), N-cadherin, Vimentin and TWIST. Significantly, MALAT1 deletion sensitized HepG2 cells to 5-FU-induced cell cycle arrest in G1 phase, as evidenced by the significant reduction in Cyclin D1 and CDK4 and increase in p53, p21 and p27 protein levels. In addition, MALAT1 knockdown triggered 5-FU induced apoptosis in HepG2 cells by inducing intrinsic apoptosis-related signals, including Cyto-c, Apaf-1, cleaved Caspase-9/-7/-3 and poly (ADP-ribose) polymerase (PARP). Furthermore, phosphorylated nuclear factor-κB (p-NF-κB) was also down-regulated by MALAT1 silence. Importantly, suppression of IKKα/NF-κB significantly elevated apoptosis and reduced liver cancer cell viability in MALAT1-knockdown cells with 5-FU incubation. The nude mice transplantation model also confirmed the promoted sensitivity of MALAT1-silenced HepG2 cells to 5-FU by blocking tumor cell proliferation and inducing apoptosis. Therefore, our data supplied a potential mechanism by which knockdown of MALAT1 might play an important role in augmenting sensitivity of HepG2 cells to 5-FU in therapeutic approaches, demonstrating suppressing of MALAT1 may serve as a combination with chemotherapeutic agents in liver cancer treatment.
转移相关肺腺癌转录物 1（MALAT1）参与肿瘤细胞的生长过程。然而，其在肝癌中的作用和分子机制尚不完全清楚。在本研究中，我们发现 MALAT1 在肝癌细胞系中表达显著上调。敲低 MALAT1 抑制 HepG2 细胞的增殖、迁移和侵袭，同时 Rho 相关卷曲螺旋形成蛋白激酶 1（ROCK1）、α-平滑肌肌动蛋白（α-SMA）、N-钙黏蛋白、波形蛋白和 TWIST 的表达下调。重要的是，MALAT1 缺失使 HepG2 细胞对 5-FU 诱导的细胞周期 G1 期阻滞更加敏感，Cyclin D1 和 CDK4 的表达显著降低，p53、p21 和 p27 蛋白水平升高。此外，MALAT1 敲低通过诱导细胞色素 C、凋亡蛋白酶激活因子 1（Apaf-1）、cleaved Caspase-9/-7/-3 和多聚（ADP-核糖）聚合酶（PARP）等内在凋亡相关信号，触发 5-FU 诱导的 HepG2 细胞凋亡。此外，MALAT1 沉默还下调磷酸化核因子-κB（p-NF-κB）。重要的是，抑制 IKKα/NF-κB 可显著增加 MALAT1 敲低的 HepG2 细胞在 5-FU 孵育下的凋亡，并降低肝癌细胞活力。裸鼠移植模型也证实了通过阻断肿瘤细胞增殖和诱导凋亡，MALAT1 沉默可增强 MALAT1 沉默的 HepG2 细胞对 5-FU 的敏感性。因此，我们的数据提供了一个潜在的机制，即敲低 MALAT1 可能在增强 HepG2 细胞对 5-FU 的敏感性方面发挥重要作用，表明抑制 MALAT1 可能在肝癌治疗中与化疗药物联合使用。
