Hepatocyte nuclear factor-4α reverses malignancy of hepatocellular carcinoma through regulating miR-134 in the DLK1-DIO3 region

Abstract

Hepatocyte nuclear factor-4a (HNF4a) is a dominant transcriptional regulator of hepatocyte differentiation and hepatocellular carcinogenesis. There is striking suppression of hepatocellular carcinoma (HCC) by HNF4a, although the mechanisms by which HNF4a reverses HCC malignancy are largely unknown. Herein, we demonstrate that HNF4a administration to HCC cells resulted in elevated levels of 28 mature microRNAs (miRNAs) from the miR-379-656 cluster, which is located in the delta-like 1 homolog (DLK1) -iodothyronine deiodinase 3 (DIO3) locus on human chromosome 14q32. Consistent with the reduction of HNF4a, these miRNAs were down-regulated in human HCC tissue. HNF4a regulated the transcription of the miR-379-656 cluster by directly binding to its response element in the DLK1-DIO3 region. Interestingly, several miRNAs in this cluster inhibited proliferation and metastasis of HCC cells in vitro. As a representative miRNA in this cluster, miR-134 exerted a dramatically suppressive effect on HCC malignancy by down-regulating the oncoprotein, KRAS. Moreover, miR-134 markedly diminished HCC tumorigenicity and displayed a significant antitumor effect in vivo. In addition, inhibition of endogenous miR-134 partially reversed the suppressive effects of HNF4a on KRAS expression and HCC malignancy. Furthermore, a positive correlation between HNF4a and miR-134 levels was observed during hepatocarcinogenesis in rats, and decreases in miR-134 levels were significantly associated with the aggressive behavior of human HCCs. Conclusion: Our data highlight the importance of the miR-379-656 cluster in the inhibitory effect of HNF4a on HCC, and suggest that regulation of the HNF4a-miRNA cascade may have beneficial effects in the treatment of HCC. (HEPATOLOGY 2013;58:1964-1976 H epatocyte nuclear factor-4a (HNF4a), a member of the nuclear hormone receptor superfamily, is essential for the differentiation of the hepatic lineage and for maintaining the function of mature hepatocytes.1-3 Loss of HNF4a expression is a critical event in the progression of hepatocellular carcinoma (HCC) and is inversely associated with HCC differentiation status.4,5 A previous study from this laboratory demonstrated that up-regulating HNF4a could reverse the malignant phenotypes of HCC by inducing redifferentiation of HCC cells to hepatocytes. 6 We also demonstrated that HNF4a administration could attenuate liver fibrosis and block hepatocarcinogenesis in rats. 7,8 Interestingly, a recent study by others reported that transient inhibition of HNF4a could initiate hepatocellular oncogenesis

Decreased miR-134 expression and its tumor-suppressive function in human osteosarcoma

“…Yin et al (2013) confirmed decreased miRNA-134 expression in HCC tissues and its association with more aggressive pathological features, including liver cirrhosis, high levels of α-fetoprotein, large tumor size, advanced tumor stage, presence of tumor microsatellites, and absence of tumor encapsulation (Yin et al, 2013). Overexpression of miR-134 in HCC cells arrested cell growth and decreased cell migration and invasion by downregulating the oncoprotein KRAS.…”

“…Recently, miR-134 has been implicated in the pathogenesis of several types of tumors and plays dual roles in different tumors. It is significantly increased in head and neck squamous-cell carcinoma (HNSCC) and acts as a potential oncogene (Liu et al, 2014), while it is downregulated and acts as a candidate tumor suppressor in gastrointestinal stromal tumors (GISTs) (Haller et al, 2010), gliomas (Lages et al, 2011), non-small cell lung cancer (Li et al, 2012), hepatocellular carcinoma (Yin et al, 2013), and prostate cancer (Wang et al, 2011). However, very little is currently known about the links of miR-134 dysregulation to clinicopathological characteristics of osteosarcoma, and the functional attributes of miR-134 associated with osteosarcoma progression remain elusive.…”

MicroRNA-134 targets KRAS to suppress breast cancer cell proliferation, migration and invasion

“…miR-134 was first identified as a brain-specific miRNA located at 14q32 (25); it was observed to be localized in the synapto-dendritic compartment of hippocampal neurons and involved in the regulation of the neuronal microstructure (26). Previous studies have indicated that miR-134 was involved in several physiological and pathological processes; Han et al (27) identified that miR-134 has a crucial role in the translation-dependent guidance of nerve growth cones.…”

Effects of targeted modulation of miR-762 on expression of the IFITM5 gene in Saos-2 cells

“…MiRNAs play essential roles in diverse biological processes, including cell proliferation, differentiation, apoptosis, and tumor oncogenesis (4)(5)(6). Recently, numerous studies have revealed that miRNAs play critical roles in osteoblast differentiation.…”