A Feedback Loop Between the Liver-Enriched Transcription Factor Network and Mir-122 Controls Hepatocyte Differentiation

Laudadio, Ilaria; Manfroid, Isabelle; Achouri, Younès; Schmidt, Dominic; Wilson, Michael D.; Cordi, Sabine; Thorrez, Lieven; Knoops, Laurent; Jacquemin, Patrick; Schuit, Frans; Pierreux, Christophe E.; Odom, Duncan T.; Peers, Bernard; Lemaigre, Frédéric P.

doi:10.1053/j.gastro.2011.09.001

Cited by 158 publications

(152 citation statements)

References 43 publications

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“…Significantly, miR-122 was also found to stimulate HNF6 expression. Thus miR-122 and HNF6 establish a positive feedback loop involved in directing hepatocyte differentiation and liver development (Laudadio et al, 2012). Together, the most abundant liver-specific microRNA miR-122, and liver-enriched transcription factors scription factors such as HNFs, have an integral role in liver development and function.…”

Section: Mir-122 In Liver Developmentmentioning

confidence: 99%

MiR-122 in hepatic function and liver diseases

et al. 2012

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Section: Mir-122 In Liver Developmentmentioning

confidence: 99%

MiR-122 in hepatic function and liver diseases

et al. 2012

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“…During liver development, complex regulatory cascades of hepatic transcription factors control hepatocyte maturation (22,23), and the regulatory circuit formed by cross-regulation of hepatocyte nuclear factor (HNF)-4α, HNF-1α, HNF-6 and upstream stimulatory factor (USF)-1 plays a pivotal role in hepatocyte maturation and functional formation (24)(25)(26). HNF-4α, the core of the regulatory circuit, 2 and Hui Xiao is believed to be a controller and marker of mature hepatocytes (27,28).…”

Section: Introductionmentioning

confidence: 99%

“…USF-1, which competes with the oncogene c-Myc for the E-box regulatory element, is another downstream target of HNF-4α that plays crucial roles in the maturation and formation of functional hepatocytes (31,32). USF-1 can activate HNF-6, which is another important transcription factor for hepatocyte maturation that has been found to regulate HNF-4α (23,33). Therefore, HNF-4α, HNF-1α, HNF-6 and USF-1 form a positive feedback loop that drives hepatocyte maturation in liver development ( Figure 1A).…”

Section: Introductionmentioning

confidence: 99%

Developmental Stage-Specific Hepatocytes Induce Maturation of HepG2 Cells by Rebuilding the Regulatory Circuit

Liu

Zong

et al. 2015

Mol Med

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On the basis of their characteristics, we presume that developmental stage-specific hepatocytes should have the ability to induce maturation of hepatoma cells. A regulatory circuit formed by hepatocyte nuclear factor (HNF)-4α, HNF-1α, HNF-6 and the upstream stimulatory factor (USF-1) play a key role in the maturation of embryonic hepatocytes; however, it is unclear whether the regulatory circuit mediates the embryonic induction of hepatoma cell maturation. In this study, 12.5-d to 15.5-d mouse embryonic hepatocytes or their medium were used to coculture or treat HepG2 cells, and the induced maturation was evaluated in vitro and in vivo. In the induced HepG2 cells, the components of the regulatory circuit were detected, their cross-regulation was evaluated and HNF-4α RNA interference was performed. We found that 13.5-d to 14.5-d embryonic hepatocytes could induce HepG2 cell maturation, demonstrated by morphological changes, increased maturation markers and decreased c-Myc and α-fetoprotein (AFP) in vitro. The majority of HepG2 tumors were eliminated by 13.5-d embryonic induction in vivo. All components of the regulatory circuit were upregulated and the binding of HNF-4α, HNF-1α, HNF-6 and USF-1 to their target sites was promoted to rebuild the regulatory circuit in the induced HepG2 cells. Moreover, RNA interference targeting HNF-4α, which is the core of the regulatory circuit, attenuated the induced maturation of HepG2 cells with downregulation of the regulatory circuit. These results revealed that developmental stage-specific hepatocytes could induce the maturation of HepG2 cells by rebuilding the regulatory circuit. is believed to be a controller and marker of mature hepatocytes (27,28). As a downstream target of HNF-4α, HNF-1α is also essential for hepatocyte maturation (29,30). USF-1, which competes with the oncogene c-Myc for the E-box regulatory element, is another downstream target of HNF-4α that plays crucial roles in the maturation and formation of functional hepatocytes (31,32). USF-1 can activate HNF-6, which is another important transcription factor for hepatocyte maturation that has been found to regulate 33). Therefore, HNF-4α, HNF-1α, HNF-6 and USF-1 form a positive feedback loop that drives hepatocyte maturation in liver development ( Figure 1A). Because the transcription factor binding sites are generally believed to scatter within 10 kb upstream of the transcriptional start site (34), the 10-kb gene promoters were all analyzed. On the basis of previous reports (25), the predicted binding sites of HNF-4α HNF-1α, HNF-6 and USF-1 were identified, respectively ( Figure 1B). It remains unknown whether developmental stage-specific hepatocytes rebuild the regulatory circuit to induce the maturation of HepG2 cells.In this study, HepG2 cells were cocultured with mouse embryonic hepatocytes at gestation of 12.5-15.5 d, because the mouse hepatocytes differentiated at 12.5 d, and the liver structure became firmly established between 12 and 15 d of gestation (35)(36)(37). The induced maturation of HepG2 cel...

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“…For example, it is necessary that activin A-mediated DE formation is enhanced by the forced combined expression of RNAs, including miRNA (miR) 181, miR222, miR196a, miR196b, miR333-5p and let-7e. It was previously reported that a positive feedback loop between miR122 and hepatocyte nuclear factor 6 (HNF6) regulates proper hepatocyte-specific gene expression (33). During the process of liver differentiation and maturation, hepatoblasts exhibit morphological changes, such as epithelial-to-mesenchymal transition (EMT).…”

Section: Mirnas In Liver Development and Homeostasismentioning

confidence: 99%

Function and clinical potential of microRNAs in hepatocellular carcinoma

et al. 2015

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Abstract. MicroRNAs (miRNAs) are small non-coding RNAs involved in the initiation and progression of several types of human cancer, including hepatocellular carcinoma (HCC), which is one of the most common types of cancer and the third leading cause of cancer-related mortality worldwide. Mounting evidence has demonstrated that miRNAs play a vital role in HCC, hepatitis, alcoholic liver disease, liver cell development and the metabolic functions of the liver. The aim of the present review was to summarize the most recent findings on the functions of miRNAs in the liver and discuss their potential roles in the diagnosis, prognosis and treatment of HCC.

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A Feedback Loop Between the Liver-Enriched Transcription Factor Network and Mir-122 Controls Hepatocyte Differentiation

Cited by 158 publications

References 43 publications

MiR-122 in hepatic function and liver diseases

MiR-122 in hepatic function and liver diseases

Developmental Stage-Specific Hepatocytes Induce Maturation of HepG2 Cells by Rebuilding the Regulatory Circuit

Function and clinical potential of microRNAs in hepatocellular carcinoma

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