Regulatory Effects and Mechanism of Adenovirus-Mediated PTEN Gene on Hepatic Stellate Cells

An, Junyan; Zheng, Libo; Xie, Shurui; Yin, Fengrong; Huo, Xiaoxia; Guo, Jun; Zhang, Xiaolan

doi:10.1007/s10620-015-3976-2

Cited by 11 publications

(13 citation statements)

References 41 publications

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“…The role of PTEN in liver fibrosis has been well documented [19,31,44,45]. PTEN can dephosphorylate PIP3 to PIP2, which can antagonize the PI3kinase signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Adiponectin inhibits hepatic stellate cell activation by targeting the PTEN/AKT pathway

Kumar¹,

Raeman²,

Chopyk³

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Adiponectin inhibits hepatic stellate cell (HSC) activation and subsequent development of liver fibrosis via multiple mechanisms. Phosphatase and tensin homolog deletion 10 (PTEN) plays a crucial role in suppression of HSC activation, but its regulation by adiponectin is not fully understood. Here, we investigated the effect of adiponectin on PTEN in LX-2 cells, a human cell line and examined the underlying molecular mechanisms involved in adiponectin-mediated upregulation of PTEN activity during fibrosis. PTEN expression was found to be significantly reduced in the livers of mice treated with CCl4, whereas its expression was rescued by adiponectin treatment. The DNA methylation proteins DNMT1, DNMT3A, and DNMT3B are all highly expressed in activated primary HSCs compared to quiescent HSCs, and thus represent additional regulatory targets during liver fibrogenesis. Expression of DNMT proteins was significantly induced in the presence of fibrotic stimuli; however, only DNMT3B expression was reduced in the presence of adiponectin. Adiponectin-induced suppression of DNMT3B was found to be mediated by enhanced miR-29b expression. Furthermore, PTEN expression was significantly increased by overexpression of miR-29b, whereas its expression was markedly reduced by a miR-29b inhibitor in LX-2 cells. These findings suggest that adiponectin-induced upregulation of miR-29b can suppress DNMT3B transcription in LX-2 cells, thus resulting in reduced methylation of PTEN CpG islands and ultimately suppressing the PI3K/AKT pathway. Together, these data suggest a possible new explanation for the inhibitory effect of adiponectin on HSC activation and liver fibrogenesis.

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“…The role of PTEN in liver fibrosis has been well documented [19,31,44,45]. PTEN can dephosphorylate PIP3 to PIP2, which can antagonize the PI3kinase signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Adiponectin inhibits hepatic stellate cell activation by targeting the PTEN/AKT pathway

Kumar¹,

Raeman²,

Chopyk³

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…The expression of p‐AKT was concomitantly reduced by the miR‐1273g‐3p inhibitor, indicating that PTEN/AKT signaling is regulated by miR‐1273g‐3p. It is well established that PTEN is a negative regulator of this pathway . AKT, a core component of canonical PTEN/AKT signaling, is an important regulator of cellular proliferation and differentiation.…”

Section: Discussionmentioning

confidence: 99%

miR‐1273g‐3p modulates activation and apoptosis of hepatic stellate cells by directly targeting PTEN in HCV‐related liver fibrosis

Niu

et al. 2016

FEBS Letters

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MicroRNA (miRNA) play a pivotal role in the development of liver fibrosis. However, the functions of miRNA in hepatitis C virus (HCV)‐related liver fibrosis remain unclear. In this study, we systematically analyzed the microarray data of the serum miRNA in patients with HCV‐induced hepatic fibrosis. Among 41 dysregulated miRNA, miR‐1273g‐3p was the most significantly upregulated miRNA and correlated with the stage of liver fibrosis. Overexpression of miR‐1273g‐3p could inhibit translation of PTEN, increase the expression of α‐SMA, Col1A1, and reduce apoptosis in HSCs. Hence, we conclude that miR‐1273g‐3p might affect the activation and apoptosis of HSCs by directly targeting PTEN in HCV‐related liver fibrosis.

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“…164 Overexpression of PTEN reduces fibroblast activation, viability, caspase-3 activity, cell-cycle arrest in the G0/G1 and G2/M phases and suppression of PI3K/AKT and FAK/ERK signaling pathways. 165 PTEN also regulates M2 macrophage polarization through activation of PI3K/AKT/ STAT6, with its loss yielding more profibrotic M2 macrophages. 166 There is a wealth of literature documenting the critical role of PTEN loss in fibrogenesis.…”

Section: Ptenmentioning

confidence: 99%

Cancer driver mutations in endometriosis: Variations on the major theme of fibrogenesis

Guo

2018

Reprod Medicine & Biology

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BackgroundOne recent study reports cancer driver mutations in deep endometriosis, but its biological/clinical significance remains unclear. Since the natural history of endometriosis is essentially gradual progression toward fibrosis, it is thus hypothesized that the six driver genes reported to be mutated in endometriosis (the RP set) may play important roles in fibrogenesis but not necessarily malignant transformation.MethodsExtensive PubMed search to see whether RP and another set of driver genes not yet reported (NR) to be mutated in endometriosis have any roles in fibrogenesis. All studies reporting on the role of fibrogenesis of the genes in both RP and NR sets were retrieved and evaluated in this review.ResultsAll six RP genes were involved in various aspects of fibrogenesis as compared with only three NR genes. These nine genes can be anchored in networks linking with their upstream and downstream genes that are known to be aberrantly expressed in endometriosis, piecing together seemingly unrelated findings.ConclusionsGiven that somatic driver mutations can and do occur frequently in physiologically normal tissues, it is argued that these mutations in endometriosis are not necessarily synonymous with malignancy or premalignancy, but the result of enormous pressure for fibrogenesis.

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Regulatory Effects and Mechanism of Adenovirus-Mediated PTEN Gene on Hepatic Stellate Cells

Abstract: These data have shown that gene therapy using the recombinant adenovirus encoding wild-type PTEN inhibits proliferation and induces apoptosis of HSCs, which is a potential treatment option for hepatic fibrosis.

Cited by 11 publications

References 41 publications

Adiponectin inhibits hepatic stellate cell activation by targeting the PTEN/AKT pathway

Adiponectin inhibits hepatic stellate cell activation by targeting the PTEN/AKT pathway

miR‐1273g‐3p modulates activation and apoptosis of hepatic stellate cells by directly targeting PTEN in HCV‐related liver fibrosis

Cancer driver mutations in endometriosis: Variations on the major theme of fibrogenesis

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