MicroRNA-26a suppresses tumor growth and metastasis of human hepatocellular carcinoma by targeting interleukin-6-Stat3 pathway

Abstract

Down-regulation of microRNA-26a (miR-26a) is associated with poor prognosis of hepatocellular carcinoma (HCC), but its functional mechanism in HCC remains unclear. In this study, we investigated the roles of miR-26a in tumor growth and metastasis of HCC and found that miR-26a was frequently down-regulated in HCC tissues. Down-regulation of miR-26a correlated with HCC recurrence and metastasis. Through gain-and loss-offunction studies, miR-26a was demonstrated to significantly inhibit in vitro cell proliferation, migration, and invasion. In addition, miR-26a induced G1 arrest and promoted apoptosis of HCC cells. Importantly, miR-26a suppressed in vivo tumor growth and metastasis in nude mice models bearing human HCC. Interleukin-6 (IL-6) was identified as a target of miR-26a. Knockdown of IL-6 induced effects on HCC cells similar to those induced by miR-26a. In contrast, IL-6 treatment abrogated the effects induced by miR26a up-regulation. Moreover, miR-26a dramatically suppressed expression of signal transducer and activator of transcription 3 (Stat3) target genes, including Bcl-2, Mcl-1, cyclin D1, and MMP2. IL-6 treatment antagonized this effect, while knockdown of IL-6 by IL-6 short hairpin RNA (shIL-6) induced inhibitory effects on the expression of p-Stat3 and its main target genes, similar to miR-26a. The messenger RNA and protein levels of IL-6 inversely correlated with miR-26a in HCCs. Patients with high miR-26a or low IL-6 in HCC tissues had a better prognosis with longer overall survival (OS) and time to recurrence (TTR). In multivariate analysis, miR-26a, IL-6, and their combination were demonstrated to be independent prognostic indicators for OS and TTR of HCC patients. Conclusion: miR-26a could suppress tumor growth and metastasis of HCC through IL-6-Stat3 signaling and is a novel prognostic marker and therapeutic target for HCC. (HEPATOLOGY 2013;58:158-170)

Decreased MicroRNA-26a expression causes cisplatin resistance in human non-small cell lung cancer

“…[32][33][34][35] In addition, clinical studies showed that patients with higher level of miR26a in tumor tissues have better prognosis, possibly through the role of miR-26a in inhibition of cell proliferation via targeting cyclin D2, cyclin E2, and IL-6. 36,37 Our results suggest that miR-26a acts through arresting G1-S transition to suppress A549 cell proliferation, and this effect is mediated by HMGA2-E2F1-Akt signaling pathway.…”

MicroRNA-26a/b Regulate DNA Replication Licensing, Tumorigenesis, and Prognosis by Targeting CDC6 in Lung Cancer

“…MiR26 has been shown to function as a tumor suppressor miRNA by targeting multiple genes, including EZH2 in nasopharyngeal carcinoma (35), Burkitt lymphoma (36), and lung cancer (37), IL6 in hepatocellular carcinoma (38), and CKS2 in papillary thyroid carcinoma (39). In this study, we show that miR26a and miR26b also function as tumor suppressor miRNAs in lung cancer, as miR26a and miR26b were significantly downregulated in lung cancer specimens compared with the paired normal tissues and miR26a and miR26b mimics inhibited the proliferation, migration, and invasion of lung cancer cells.…”

Programmed cell senescence: role of IL-6 in the pituitary

“…IL-6 transcript is positively regulated by Arid 5a (Masuda et al 2013), TNFα and IL-1β (Gruys et al 2005), and negatively regulated by regnase-I (Iwasaki et al 2011), bromodomain-containing protein 4 (BRD4) (Barrett et al 2014), and microRNAs (miRs) e.g. miR-26a (Yang et al 2013), miR-142 (Sun et al 2013), miR-146a (He et al 2014), miR-146b (Xiang et al 2014), miR-187 (Rossato et al 2012), miR-200s (Dou et al 2013) and miR-329 (Garg et al 2013) (Fig. 1).…”