Snail controls differentiation of hepatocytes by repressing HNF4α expression

Cicchini, Carla; Filippini, Daniela; Coen, Sabrina; Marchetti, Alessandra; Cavallari, Claudio; Laudadio, Ilaria; Spagnoli, Francesca M.; Alonzi, Tonino; Tripodi, Marco

doi:10.1002/jcp.20730

Cited by 73 publications

(95 citation statements)

References 54 publications

(81 reference statements)

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“…As shown in Figure 3c, Snail overexpression caused a significant downregulation of endogenous miR-200c and -34a. Notably, TGF-b treatment, that triggers EMT and Snail expression in hepatocytes, 5,12 caused a transcriptional downregulation of these miRs in RLSCdH (Figure 3c). …”

Section: Resultsmentioning

confidence: 98%

“…pWZL RLSCdH and pWZLSnail RLSCdH cells were generated by stable transfection by Lipofectamine 2000 (Invitrogen, San Diego, CA, USA), respectively, with empty or Snail carrying pWZL-bast vectors, as described previously. 5 Cells were selected in 5 mg/ml blasticidin for a week.…”

Section: Methodsmentioning

confidence: 99%

“…4 Furthermore, we identified a simple cross-regulatory circuitry between HNF4a (master regulator of hepatocyte differentiation) and Snail (master regulator of the epithelial-to-mesenchymal transition, EMT), whose expression is mutually exclusive because of their direct reciprocal transcriptional repression. 2,5 These findings, relevant for the comprehension of the EMT and of the reverse process mesenchymal-to-epithelial transition (MET), have been demonstrated pivotal also for the maintenance of a stable epithelial phenotype. 2 Notably, EMT/MET dynamics are proposed to be relevant in the reacquisition of stem cell features from differentiated cells.…”

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confidence: 96%

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An epistatic mini-circuitry between the transcription factors Snail and HNF4α controls liver stem cell and hepatocyte features exhorting opposite regulation on stemness-inhibiting microRNAs

et al. 2011

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Preservation of the epithelial state involves the stable repression of epithelial-to-mesenchymal transition program, whereas maintenance of the stem compartment requires the inhibition of differentiation processes. A simple and direct molecular minicircuitry between master elements of these biological processes might provide the best device to keep balanced such complex phenomena. In this work, we show that in hepatic stem cell Snail, a transcriptional repressor of the hepatocyte differentiation master gene HNF4a, directly represses the expression of the epithelial microRNAs (miRs)-200c and -34a, which in turn target several stem cell genes. Notably, in differentiated hepatocytes HNF4a, previously identified as a transcriptional repressor of Cellular differentiation implies an orchestrated sequence of events guiding stem cells/precursors toward specialized cell types based on the contemporary and strictly correlated phenomena of loss of stemness and acquisition of histotypic markers and functions. The homeostasis of the stem cell compartment requires mechanisms actively counteracting differentiation; 1 similarly, the maintenance of the differentiated state involves a stable repression of elements capable to induce morphological transition and dedifferentiation. 2 The observation that a number of stem cells are restricted to a specific differentiation fate suggests that elements pivotal for the coordinated execution of the opposite processes could be tissue-specific. Considering that stem cell compartments are rare and give rise to a heterogeneous cellular population capable to reversibly shift among different states, 3 the availability of a stable stem cell line executing specific differentiation programs discloses an unique possibility to investigate mechanisms regulating alternative cellular choices. A simple and direct molecular mini-circuitry of master elements of mutually exclusive biological processes, also able to reciprocally influence their own expression, may provide the theoretically best device to trigger such complex phenomena.We previously characterized a number of stable liver stem cell lines named RLSCs (from resident liver stem cells) that spontaneously acquire an epithelial morphology and differentiate into hepatocytes (named RLSCdH from RLSC-derived hepatocytes). Notably, RLSCs were also proved to recapitulate the hepatocyte post-differentiation patterning defined as 'zonation': their spontaneous differentiation, in fact, generates periportal hepatocytes that may be induced to switch into perivenular hepatocytes by means of the convergence of Wnt signaling on the HNF4a-driven transcription. 4 Furthermore, we identified a simple cross-regulatory circuitry between HNF4a (master regulator of hepatocyte differentiation) and Snail (master regulator of the epithelial-to-mesenchymal transition, EMT), whose expression is mutually exclusive because of their direct reciprocal transcriptional repression. 2,5 These findings, relevant for the comprehension of the EMT and of the reverse process mesenchymal-...

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Section: Resultsmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 96%

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An epistatic mini-circuitry between the transcription factors Snail and HNF4α controls liver stem cell and hepatocyte features exhorting opposite regulation on stemness-inhibiting microRNAs

et al. 2011

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“…Recently, RLSCs and hepatocytes derived from their differentiation (RLSCdH) permitted to identify a simple cross-regulatory circuitry between HNF4 (master regulator of hepatocyte differentiation and MET inducer) and Snail (master regulator of the EMT), whose expression is mutually exclusive due to their direct reciprocal transcriptional repression (Cicchini et al, 2006;Santangelo et al, 2011). In particular, Cicchini and co-workers showed that Snail represses the HNF4 transcription through the direct binding to its promoter (Cicchini et al, 2006) and that Snail over-expression is sufficient i) to induce EMT in hepatocytes with change of morphology, down-regulation of several epithelial adhesion molecules, reduction of proliferation and induction of matrix metalloproteinase 2 expression and, ii) most relevantly, to directly repress the transcription of the HNF4α gene.…”

Section: Molecular Mechanisms Controlling Liver Stem Cell Fatementioning

confidence: 99%

“…In particular, Cicchini and co-workers showed that Snail represses the HNF4 transcription through the direct binding to its promoter (Cicchini et al, 2006) and that Snail over-expression is sufficient i) to induce EMT in hepatocytes with change of morphology, down-regulation of several epithelial adhesion molecules, reduction of proliferation and induction of matrix metalloproteinase 2 expression and, ii) most relevantly, to directly repress the transcription of the HNF4α gene. These findings demonstrated that Snail is at the crossroads of the regulation of EMT in hepatocytes by a dual control of epithelial morphogenesis and differentiation.…”

Section: Molecular Mechanisms Controlling Liver Stem Cell Fatementioning

confidence: 99%

Hepatocytes and Progenitor - Stem Cells in Regeneration and Therapy

Amicone¹,

Citarella²,

Tripodi³

et al. 2012

Liver Regeneration

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Small Molecule‐Induced Differentiation As a Potential Therapy for Liver Cancer

et al. 2022

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Despite the efficacy demonstrated by immunotherapy recently, liver cancer still remains one of the deadliest cancers, mainly due to heterogeneity of this disease. Continuous exploration of new therapeutics is therefore necessary. Chemical-induced cell differentiation can serve as a promising approach, with its ability to consistently remodel gene expression profile and alter cell fate. Inspired by advances in stem cell and reprogramming field, here it is reported that a small molecule cocktail (SMC) consisted of: SB431542 (TGF𝜷 inhibitor), CHIR99021 (GSK3𝜷 inhibitor), BIX01294 (H3K9 methyltransferase/G9a inhibitor), and all-trans retinoic acid (ATRA), can induce differentiation of liver cancer cells including cell lines, primary cancer cells, cancer stem cells, and drug resistant cells. Treated cells lose malignant characteristics and regain hepatocyte phenotype instead. When applied in vivo, SMC induces wide range of tissue necrosis or fibrosis within the tumors, while remaining tissues begin to express hepatic nuclear factor 4𝜶 (HNF4𝜶), the hepatic nuclear marker. SMC also leads to tumor abrogation in orthotopic xenograft models and life span extension of animals. The powerful differentiation induction of SMC is exerted through modulation of Akt/mTOR/HIF1𝜶 signaling and metabolic reprogramming, as well as suppressing Snail and enhancing HNF4𝜶 expression. Together, these results highlight that chemical-induced differentiation has the potential to effectively treat liver cancer disregard of heterogeneity.

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Snail controls differentiation of hepatocytes by repressing HNF4α expression

Cited by 73 publications

References 54 publications

An epistatic mini-circuitry between the transcription factors Snail and HNF4α controls liver stem cell and hepatocyte features exhorting opposite regulation on stemness-inhibiting microRNAs

An epistatic mini-circuitry between the transcription factors Snail and HNF4α controls liver stem cell and hepatocyte features exhorting opposite regulation on stemness-inhibiting microRNAs

Hepatocytes and Progenitor - Stem Cells in Regeneration and Therapy

Small Molecule‐Induced Differentiation As a Potential Therapy for Liver Cancer

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