Inhibition of MALAT1 sensitizes liver cancer cells to 5-flurouracil by regulating apoptosis through IKKαNF-κB pathway

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 MALATI 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 I (ROCK1), alpha-smooth muscle actin (alpha-SMA), N-cadherin, Vimentin and TWIST. Significantly, MALATI 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-kappa B (p-NF-kappa B) was also down-regulated by MALATI silence. Importantly, suppression of IKK alpha/NF-kappa B 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 MALATI may serve as a combination with chemotherapeutic agents in liver cancer treatment. (C) 2018 Published by Elsevier Inc.