An HNF4α–microRNA-194/192 signaling axis maintains hepatic cell function

Abstract

Hepatocyte nuclear factor 4α (HNF4α) controls the expression of liver-specific protein-coding genes. However, some microRNAs are also modulated by HNF4α, and it is not known whether they are direct targets of HNF4α and whether they influence hepatic function. In this study, we found that HNF4α regulates microRNAs, indicated by marked down-regulation of miR-194 and miR-192 (miR-194/192) in liver-specific -null () mice. Transactivation of the shared miR-194/192 promoter was dependent on HNF4α expression, indicating that miR-194/192 is a target gene of HNF4α. Screening of potential mRNAs targeted by miR-194/192 revealed that expression of genes involved in glucose metabolism (glycogenin 1 ()), cell adhesion and migration (activated leukocyte cell adhesion molecule ()), tumorigenesis and tumor progression ( and epiregulin ()), protein SUMOylation (), epigenetic regulation ( and Cullin 4B ()), and the epithelial-mesenchymal transition (moesin ()) was up-regulated in mice. Moreover, we also found that miR-194/192 binds the 3'-UTR of these mRNAs. siRNA knockdown of HNF4α suppressed miR-194/192 expression in human hepatocellular carcinoma (HCC) cells and resulted in up-regulation of their mRNA targets. Inhibition and overexpression experiments with miR-194/192 revealed that, ,, , and are miR-194 targets, whereas ,, and are miR-192 targets. These findings reveal a novel HNF4α network controlled by miR-194/192 that may play a critical role in maintaining the hepatocyte-differentiated state by inhibiting expression of genes involved in dedifferentiation and tumorigenesis. These insights may contribute to the development of diagnostic markers for early HCC detection, and targeting of the miR-194/192 pathway could be useful for managing HCC.

A miR‐194/PTBP1/CCND3 axis regulates tumor growth in human hepatocellular carcinoma

“…Accordingly, miR-194 abundance was reduced and inversely correlated with that of PTBP1 in HCC tissues and in GEO and TCGA cohorts. This is consistent with earlier studies demonstrating that miR-194 functions as a tumor suppressor in HCC [45][46][47][48][49]. These studies revealed that the expression of miR-194 is reduced in HCC tissues and that these HCC show aggressive clinicopathological phenotypes with high proliferation, increased tumor size and metastasis, poor prognosis, and reduced overall and disease-free survival, suggesting that miR-194 is a tumor suppressor and a prognostic factor for HCC.…”

Identification of the genomic region under epigenetic regulation during non‐alcoholic fatty liver disease progression

“…The MIR192 / 194–2 genes are involved in the pathway of cancer. Hepatocyte nuclear factor 4α regulates expression of MIR192 and MIR194–2 . NUPR1 is induced by stress or mitochondrial dysfunction, and plays an important role in the growth and migration of human tumor cells .…”

Hepatocyte Nuclear Factor 4 Alpha Activation Is Essential for Termination of Liver Regeneration in Mice

“…Hepatocyte nuclear factor 4 alpha (HNF4α) is considered the master regulator of hepatocyte differentiation because of its essential role in embryonic development, stabilizing the hepatic transcription factor network and maintaining hepatocyte function . HNF4α regulates genes involved in xenobiotic metabolism, carbohydrate metabolism, fatty acid metabolism, bile acid synthesis, blood coagulation, and ureagenesis .…”

“…H epatocyte nuclear factor 4 alpha (HNF4α) is considered the master regulator of hepatocyte differentiation because of its essential role in embryonic development, (1,2) stabilizing the hepatic transcription factor network (3) and maintaining hepatocyte function. (4) HNF4α regulates genes involved in xenobiotic metabolism, carbohydrate metabolism, fatty acid metabolism, bile acid synthesis, blood coagulation, and ureagenesis. (5) Expression of HNF4α induces hepatocyte-like characteristics in induced pluripotent stem cells, (6) and forced expression of HNF4α induces differentiation and decrease cancer Abbreviations: AAV8, adeno-associated virus serotype 8; AKR1B7, aldo-keto reductase family 1, member B7; AKT, protein kinase A; ALAS2, 5′-aminolevulinate synthase 2; APOA2, apolipoprotein A2; APOB, apolipoprotein B; AUC, area under the curve; CCND1, cyclin D1; CDK4, cyclin-dependent kinase 4; CDKN3, cyclin-dependent kinase inhibitor 3; CLDN1, claudin 1; CYP2C37, cytochrome P450, family 2. subfamily C, polypeptide 37; DIO1, iodothyronine deiodinase 1; Dox, doxycycline; ECT2, epithelial cell transforming 2; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; EGR1, early growth response 1; EP300, E1A-binding protein P300; ERK1/2, extracellular signal-regulated kinases 1 and 2; Esrra, estrogen receptor; F12, coagulation factor XII; GSK-3, glycogen synthase kinase 3 beta; HCCs, hepatocellular carcinomas; HMGB1, high mobility group box 1; HNF1A, hepatocyte nuclear factor 1 homeobox A; HNF4, hepatocyte nuclear factor 4 alpha; HNF4A, hepatocyte nuclear factor 4 alpha; IPA, Ingenuity Pathway Analysis; IRF, interferon regulatory factor; KO, knockout; LR, liver regeneration; c-MET, MET proto-oncogene; MYC, MYC proto-oncogene, BHLH transcription factor; NFIX, nuclear factor I X-type; PCNA, proliferating cell nuclear antigen; PH, partial hepatectomy; PP2, pyrazolo pyrimidine type 2; PPARGC1A (PGC1A), peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PTMs, posttranslational modifications; RNA-Seq, RNA sequencing; SMAD, small mothers against decapentaplegic; SNAI2, snail family transcriptional repressor 2; SREBF, sterol-regulatory element-binding transcription factor; TGF, transforming growth factor beta; UGT2B1, UDP glucuronosyltransferase 2 family, polypeptide B1; WT, wild type.…”