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 Hnf4a-null (Hnf4ΔH) 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 (Gyg1)), cell adhesion and migration (activated leukocyte cell adhesion molecule (Alcam)), tumorigenesis and tumor progression (Rap2b and epiregulin (Ereg)), protein SUMOylation (Sumo2), epigenetic regulation (Setd5 and Cullin 4B (Cln4b)), and the epithelial-mesenchymal transition (moesin (Msn)) was up-regulated in Hnf4aH 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 Gyg1, Setd5, Sumo2, Cln4b, and Rap2b are miR-194 targets, whereas Ereg, Alcam, and Msn 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.
| Original language | English |
|---|---|
| Pages (from-to) | 10574-10585 |
| Number of pages | 12 |
| Journal | Journal of Biological Chemistry |
| Volume | 292 |
| Issue number | 25 |
| DOIs | |
| Publication status | Published - 2017 |
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ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology
Cite this
An HNF4α–microRNA-194/192 signaling axis maintains hepatic cell function. / Morimoto, Aoi; Kannari, Mana; Tsuchida, Yuichi; Sasaki, Shota; Saito, Chinatsu; Matsuta, Tsuyoshi; Maeda, Tsukasa; Akiyama, Megumi; Nakamura, Takahiro; Sakaguchi, Masakiyo; Nameki, Nobukazu; Gonzalez, Frank J.; Inoue, Yusuke.
In: Journal of Biological Chemistry, Vol. 292, No. 25, 2017, p. 10574-10585.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - An HNF4α–microRNA-194/192 signaling axis maintains hepatic cell function
AU - Morimoto, Aoi
AU - Kannari, Mana
AU - Tsuchida, Yuichi
AU - Sasaki, Shota
AU - Saito, Chinatsu
AU - Matsuta, Tsuyoshi
AU - Maeda, Tsukasa
AU - Akiyama, Megumi
AU - Nakamura, Takahiro
AU - Sakaguchi, Masakiyo
AU - Nameki, Nobukazu
AU - Gonzalez, Frank J.
AU - Inoue, Yusuke
PY - 2017
Y1 - 2017
N2 - 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 Hnf4a-null (Hnf4ΔH) 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 (Gyg1)), cell adhesion and migration (activated leukocyte cell adhesion molecule (Alcam)), tumorigenesis and tumor progression (Rap2b and epiregulin (Ereg)), protein SUMOylation (Sumo2), epigenetic regulation (Setd5 and Cullin 4B (Cln4b)), and the epithelial-mesenchymal transition (moesin (Msn)) was up-regulated in Hnf4aH 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 Gyg1, Setd5, Sumo2, Cln4b, and Rap2b are miR-194 targets, whereas Ereg, Alcam, and Msn 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.
AB - 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 Hnf4a-null (Hnf4ΔH) 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 (Gyg1)), cell adhesion and migration (activated leukocyte cell adhesion molecule (Alcam)), tumorigenesis and tumor progression (Rap2b and epiregulin (Ereg)), protein SUMOylation (Sumo2), epigenetic regulation (Setd5 and Cullin 4B (Cln4b)), and the epithelial-mesenchymal transition (moesin (Msn)) was up-regulated in Hnf4aH 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 Gyg1, Setd5, Sumo2, Cln4b, and Rap2b are miR-194 targets, whereas Ereg, Alcam, and Msn 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.
UR - http://www.scopus.com/inward/record.url?scp=85021656934&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85021656934&partnerID=8YFLogxK
U2 - 10.1074/jbc.M117.785592
DO - 10.1074/jbc.M117.785592
M3 - Article
C2 - 28465351
AN - SCOPUS:85021656934
VL - 292
SP - 10574
EP - 10585
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 25
ER -