Hepatitis B virus X protein amplifies TGF-β promotion on HCC motility through down-regulating PPM1a

Liu, Yuan; Xu, Yong; Ma, Hao; Wang, Bo; Xu, Leiqi; Zhang, Hualin; Song, Xiaojia; Gao, Lifen; Liang, Xiaohong

doi:10.18632/oncotarget.8884

Cited by 30 publications

(30 citation statements)

References 30 publications

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“…Previous studies have reported functional crosstalk between HBx and TGF-β1 in HBV pathogenesis. For example, HBx transactivated the TGF-β1 promoter [21], interacted with Smad4 [39], and downregulated PPM1a [40], thereby amplifying TGF-β1 signaling. HBx shifted hepatocytic TGF-β1 signaling from tumor suppression to oncogenesis in the early carcinogenic process [22], and the TGF-β1 pathway may be involved in the accelerated tumor development of HBx transgenic mice after partial hepatectomy [30].…”

Section: Discussionmentioning

confidence: 99%

TGF-β1 accelerates the hepatitis B virus X-induced malignant transformation of hepatic progenitor cells by upregulating miR-199a-3p

et al. 2019

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Increasing evidence has suggested that liver cancer arises partially from transformed hepatic progenitor cells (HPCs). However, the detailed mechanisms underlying HPC transformation are poorly understood. In this study, we provide evidence linking the coexistence of hepatitis B virus X protein (HBx) and transforming growth factor beta 1 (TGF-β1) with miR-199a-3p in the malignant transformation of HPCs. The examination of liver cancer specimens demonstrated that HBx and TGF-β1 expression was positively correlated with epithelial cell adhesion molecule (EpCAM) and cluster of differentiation 90 (CD90). Importantly, EpCAM and CD90 expression was much higher in the specimens expressing both high HBx and high TGF-β1 than in those with high HBx or high TGF-β1 and the double-low-expression group. HBx and TGF-β1 double-high expression was significantly associated with poor prognosis in primary liver cancer. We also found that HBx and TGF-β1 induced the transformation of HPCs into hepatic cancer stem cells and promoted epithelial-mesenchymal transformation, which was further enhanced by concomitant HBx and TGF-β1 exposure. Moreover, activation of the c-Jun N-terminal kinase (JNK)/c-Jun pathway was involved in the malignant transformation of HPCs. miR-199a-3p was identified as a significantly upregulated microRNA in HPCs upon HBx and TGF-β1 exposure, which were shown to promote miR-199a-3p expression via c-Jun-mediated activation. Finally, we found that miR-199a-3p was responsible for the malignant transformation of HPCs. In conclusion, our results provide evidence that TGF-β1 cooperates with HBx to promote the malignant transformation of HPCs through a JNK/c-Jun/miR-199a-3p-dependent pathway. This may open new avenues for therapeutic interventions targeting the malignant transformation of HPCs in treating liver cancer.

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Section: Discussionmentioning

confidence: 99%

TGF-β1 accelerates the hepatitis B virus X-induced malignant transformation of hepatic progenitor cells by upregulating miR-199a-3p

et al. 2019

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“…39,40 HBV chronic infection is currently estimated to influence almost 240 million people, globally, of which approximately 10% have an increased risk of developing cirrhosis and HCC. 4,41 Similar to HCV, HBV also interacts with the TGF-β pathway, a phenomenon mainly mediated by HBV X protein (HBx), which may exert diverse effects on the pathogenesis of the HBV-mediated liver pathologies 7,21,42,43 (Figure 3). Evidence by Murata further supported the hypothesis that the TGF-β pathway is directly involved in liver tumorigenesis, where HBx was shown to switch the target of hepatocytic TGF-β signaling from the TGFbRI/ pSmad3C/p21 anti-tumor pathway to the JNK/pSmad3L/c-Myc tumor supportive pathway in the early stages of liver carcinogenesis.…”

Section: Hepatitis B Virusmentioning

confidence: 99%

“…7,21,44 In this respect, Liu suggested a new mechanism underlying the pathogenesis of HBV-caused HCC; HBx downmodulates protein phosphatase magnesium-dependent 1A (PPM1a) levels, resulting in overactivation of the TGF-β signaling pathway. 7 In fact, HBx was shown to promote the degradation of PPM1a, a p-Smad2/3 phosphatase required for terminating TGF-β signaling, through elevating its ubiquitination. Furthermore, Yoo showed HBx upregulates TGF-β expression by acting through the Egr transcription factors binding site.…”

Section: Hepatitis B Virusmentioning

confidence: 99%

“…surprising that its loss of regulation can contribute to a broad range of pathologies such as cancer. 6,7 In this regard, the present review focuses on describing the modulation of this pivotal pathway by either tumor-caused or tumor-associated viruses. It first outlines the key aspects of the TGF-β pathway, before focusing on the existing literature on the subject of viral interference with TGF-β signaling.…”

mentioning

confidence: 99%

“…43 -upregulated signaling through PPM1a downmodulation. 7 -upregulated TGF-β expression by acting through the Egr transcription factors binding site. 45 -stabilized SMADs complex by interacting with SMAD4.…”

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confidence: 99%

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Viruses as key modulators of the TGF‐β pathway; a double‐edged sword involved in cancer

Mirzaei

Faghihloo

2018

Reviews in Medical Virology

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Transforming growth factor-β (TGF-β) signaling pathway is a key network in cell signaling that controls vital processes such as proliferation, differentiation, apoptosis, epithelial-mesenchymal transition, and migration, thus acting as a double-edged sword in normal development and diseases, in particular organ fibrosis, vascular disorders, and cancer. Early in tumorigenesis, the pathway exerts anti-tumor effects through suppressing cell cycle and inducing apoptosis, while during late stages, it functions as a tumor promoter by enhancing tumor invasiveness and metastasis. This signaling pathway can be perturbed by environmental and genetic factors such as microbial interference and mutation, respectively. In this way, the present review describes the modulation of the TGF-β pathway by oncogenic human viral pathogens and other viruses. The main mechanisms by which viruses interferes with TGF-β signaling seems to be through (1) the alteration of either TGF-β protein expression or activation, (2) the modulation of the TGF-β receptors or SMADs factors (by interfering with their levels and functions), (3) the alteration of none-SMAD pathways, and (4) indirect interaction with the pathway by the modulation of transcriptional co-activator/repressor and regulators of the pathway. Given the axial role of this pathway in tumorigenesis, it can be regarded as an attractive target for cancer therapy. Hence, further investigations on this subject may represent molecular targets among either TGF-β signaling molecules or viral factors for the treatment and management of viral infection consequences such as cancer.

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Tripartite motif protein 52 (TRIM52) promoted fibrosis in LX‐2 cells through PPM1A‐mediated Smad2/3 pathway

Zhang

Lan

et al. 2019

Cell Biology International

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To investigate the roles of tripartite motif containing 52 (TRIM52) in human hepatic fibrosis in vitro, human hepatic stellate cell line LX‐2 cells were transfected with hepatitis B virus (HBV) replicon to establish HBV‐induced fibrosis in LX‐2 cells, and then treated with small interfering RNA‐mediated knockdown of TRIM52 (siTRIM52). LX‐2 cells without HBV replicon transfection were treated with lentiviruses‐mediated overexpression of TRIM52 and phosphatase magnesium dependent 1A (PPM1A). Fibrosis response of LX‐2 cells were assessed by the production of hydroxyproline (Hyp) and collagen I/III, as well as protein levels of α‐smooth muscle actin (α‐SMA). PPM1A and phosphorylated (p)‐Smad2/3 were measured to assess the mechanism. The correlation between TRIM52 and PPM1A was determined using co‐immunoprecipitation, and whether and how TRIM52 regulated the degradation of PPM1A were determined by ubiquitination assay. Our data confirmed HBV‐induced fibrogenesis of LX‐2 cells, as evidenced by significant increase in Hyp and collagen I/III and α‐SMA, which was associated with reduction of PPM1A and elevation of transforming growth factor‐β (TGF‐β), p‐Smad2/3, and p‐Smad3L. However, those changes induced by HBV were significantly attenuated with additional siTRIM52 treatment. Similar to HBV, overexpression of TRIM52 exerted promoted effect in the fibrosis of LX‐2 cells. Interestingly, TRIM52 induced the fibrogenesis of LX‐2 cells and the activation of TGF‐β/Smad pathway were significantly reversed by PPM1A overexpression. Furthermore, our data confirmed TRIM52 as a deubiquitinase that influenced the accumulation of PPM1A protein, and subsequently regulated the fibrogenesis of LX‐2 cells. TRIM52 was a fibrosis promoter in hepatic fibrosis in vitro, likely through PPM1A‐mediated TGF‐β/Smad pathway.

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Hepatitis B virus X protein amplifies TGF-β promotion on HCC motility through down-regulating PPM1a

Cited by 30 publications

References 30 publications

TGF-β1 accelerates the hepatitis B virus X-induced malignant transformation of hepatic progenitor cells by upregulating miR-199a-3p

TGF-β1 accelerates the hepatitis B virus X-induced malignant transformation of hepatic progenitor cells by upregulating miR-199a-3p

Viruses as key modulators of the TGF‐β pathway; a double‐edged sword involved in cancer

Tripartite motif protein 52 (TRIM52) promoted fibrosis in LX‐2 cells through PPM1A‐mediated Smad2/3 pathway

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