Deregulation of Frizzled Receptors in Hepatocellular Carcinoma

Chan, Kristy Kwan‐Shuen; Lo, Ronald

doi:10.3390/ijms19010313

Cited by 22 publications

(17 citation statements)

References 98 publications

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“…6D), in agreement with earlier studies linking Wnt receptor (FZD7) overexpression to Wnt pathway activation in HBV-related HCC (37). Interestingly, treatment of HBV replicating DDX5 KD cells with sorafenib reduced expression of genes which act as negative effectors of Wnt activation (38), specifically Secreted Frizzled Related Protein 4 (SFRP4) and SFRP5 (Fig. 6D).…”

Section: Transcriptomic Analyses Define Dysregulated Wnt Signaling Insupporting

confidence: 91%

“…Interestingly, our results also show that sorafenib treatment of HBV replicating DDX5 KD cells suppressed expression of the negative Wnt effectors SFRP4 and SFRP5, while increasing expression of DVL1 and DVL3 ( Fig. 7) which prevent β-catenin degradation (38). Collectively, our observations support that downregulation of DDX5 is a clinically relevant player in the pathogenesis of poor prognosis HBV-associated HCCs.…”

Section: Discussionsupporting

confidence: 76%

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RNA Helicase DDX5 Negatively Regulates Wnt Signaling and Hepatocyte Reprogramming in Hepatitis B Virus-related Hepatocellular Carcinoma

Mani

Cui

Yan

et al. 2019

Preprint

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Keywords: Hepatitis B Virus, Hepatocellular Carcinoma, RNA helicase DDX5/p68, miR17~92, miR106b~25, RNA-seq, Wnt/β-catenin/ hepatocyte reprogramming/ hepatic cancer stem cell/ antagomirs Word count: 6,200 (without references) ABSTRACT Background and Aims: RNA helicase DEAD box protein 5 (DDX5) is downregulated during hepatitis B virus (HBV) replication, and associates with poor prognosis HBV-related hepatocellular carcinoma (HCC). The aim of this study is to determine the mechanism and significance of DDX5 downregulation for HBV-driven HCC. Approach & Results: We used established cellular models of HBV replication, HBV infection, as well as HBV-related liver tumors. HBV replicating DDX5 knockdown hepatocytes were analyzed by RNAseq; differentially expressed genes were validated by qRT-PCR, and bioinformatic analyses of HCCs from The Cancer Genome Atlas. Our results show reduced expression of DDX5 in HCCs of all etiologies is associated with poor survival. In HBV replicating hepatocytes, downregulation of DDX5 is mediated by miR17~92 and miR106b~25, induced by HBV infection. Increased expression of these miRNAs was quantified in HBV-associated HCCs expressing a hepatic cancer stem cell (hCSC)-like gene signature and reduced DDX5 mRNA, suggesting a role for DDX5 in hCSC formation. Interestingly, DDX5 knockdown in HBV replicating hepatocyte cell lines resulted in hepatosphere formation, sorafenib and cisplatin resistance, Wnt signaling activation and pluripotency gene expression, all characteristics of hCSCs. Moreover, DDX5 knockdown increased viral replication. RNA-seq analyses of HBV-replicating DDX5 knockdown cells, identified enhanced expression of key genes of the Wnt/β-catenin pathway, including Frizzled7 (FZD7) and Matrix Metallopeptidase7 (MMP7), indicative of Wnt signaling activation. Clinically, elevated FZD7 expression correlates with poor patient survival. Importantly, inhibitors to miR17~92 and miR106b~25 restored DDX5 levels and suppressed both Wnt/β-catenin activation and viral replication. Conclusion: DDX5 is a negative regulator of Wnt signaling and hepatocyte reprogramming in HCCs. Restoration of DDX5 levels in HBV-infected patients can exert both antitumor and antiviral effects.

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Section: Transcriptomic Analyses Define Dysregulated Wnt Signaling Insupporting

confidence: 91%

Section: Discussionsupporting

confidence: 76%

RNA Helicase DDX5 Negatively Regulates Wnt Signaling and Hepatocyte Reprogramming in Hepatitis B Virus-related Hepatocellular Carcinoma

Mani

Cui

Yan

et al. 2019

Preprint

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“…With the exception of FZD5, other FZDs, including FZD3, FZD4, FZD8, and especially FZD9, can also significantly promote LRP5/␤-catenin signaling in a ligand-independent manner. Because ectopic expression of FZDs in tumor cells is a common phenomenon (34,35), these findings may provide an alternative mechanism to comprehensively understand the molecular basis underlying tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

“…6H), implying that the endogenous canonical WNT glycoproteins were not involved in suppressing GSK3␤-AXIN-APC complexes. Therefore, we concluded that ectopic expression of Frizzled receptors (34,35), such as FZD3/4/5/9, which cause ligand-independent LRP5/6 signalosome activation, might be the putative pathological factor for the constitutive activation of WNT/␤-catenin signaling in HepG2 cells.…”

Section: Ligand-independent Fzd-lrp5/6 Signaling May Be Involved In Tmentioning

confidence: 92%

Oligomerization of Frizzled and LRP5/6 protein initiates intracellular signaling for the canonical WNT/β-catenin pathway

Yue

Yang

et al. 2018

Journal of Biological Chemistry

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Edited by Xiao-Fan WangUpon binding to the canonical WNT glycoproteins, Frizzled family receptors (FZDs) and low-density lipoprotein receptorrelated protein 5/6 (LRP5/6) undergo a series of polymerizations on the cell surface that elicit canonical WNT/␤-catenin signaling. The hyperactivation of WNT/␤-catenin signaling is the major cause of tumorigenesis, but the mechanism in tumors such as hepatoma remains unclear. Here, we observed that WNT3A manifested the hyperactivity in ␤-catenindependent signaling after binding to FZD's competitive inhibitory molecule secreted Frizzled-related protein 2 (SFRP2). To understand the mechanism of FZDs in the presence of SFRP2, we explored how FZDs can bind and activate the LRP5/6 signalosome independently of WNT glycoproteins. Our findings further revealed that oligomerizations of FZDs and LRP5/6 can integrate the cytoplasmic protein Dishevelled into the LRP5/6 signalosome, resulting in a robust activation of ligand-independent ␤-catenin signaling. We propose that besides WNT-bridged FZD-WNT-LRP5/6 protein complexes, the homo-and hetero-oligomerizations of WNT receptors may contribute to the formation of the LRP5/6 signalosome on the cell surface. Of note, we identified four highly expressed FZDs in the hepatoma cell line HepG2, all of which significantly promoted ligand-independent LRP5/␤catenin signaling. As FZDs are ectopically expressed in numerous tumors, our findings may provide a new perspective on tumor pathologies. Furthermore, the results in our study suggest that the composition and stoichiometry of FZDs and LRP5/6 within the LRP5/6 signalosome may tune the selection of bound WNT glycoproteins and configure downstream WNT/ ␤-catenin signaling.

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“…Overactivation of the WNT pathway is associated with a number of human malignancies, including (but not limited to) cancers of lungs, ovaries, breast, skin, brain and intestinal tract (Clevers and Nusse, 2012). In some subsets of these cancers, different FZD receptors are overexpressed, leading to an amplification of the WNT signal (Chan and Lo, 2018;Ueno et al, 2013). Importantly, pan-WNT inhibitory therapies cause toxic side effects, due to the importance of WNT signaling in other tissues, such as the maintenance of the intestinal epithelium (Korinek et al, 1998;Schepers and Clevers, 2012;van Es et al, 2012).…”

Section: Wnt-fzd Co-receptors In Regenerative Medicine and Cancermentioning

confidence: 99%

EGFR confers exquisite specificity of Wnt9a-Fzd9b signaling in hematopoietic stem cell development

Grainger

Nguyen

Richter

et al. 2018

Preprint

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SummaryThe mechanisms of Wnt-Frizzled (Fzd) signaling selectivity and their biological implications remain unclear. We demonstrate for the first time that the epidermal growth factor receptor (EGFR) is required as a co-factor for Wnt signaling. Using genetic studies in zebrafish, paired with in vitro cell biology and biochemistry, we have determined that Fzd9b signals specifically with Wnt9a in vivo and in vitro to elicit β-catenin dependent Wnt signals that regulate hematopoietic stem and progenitor cell (HSPC) development in the dorsal aorta. This requirement is conserved in the derivation of HSPCs from human embryonic stem cells. Wnt9a-Fzd9b specificity requires two intracellular domains in Fzd9b, which interact with EGFR as a required co-factor to promote signal transduction. EGFR phosphorylates one tyrosine residue on Fzd9b, a requirement for the Wnt signal. These findings indicate that Wnt signaling interactions can be exquisitely specific and inform protocols for derivation of HSPCs in vitro.HighlightsAn in vitro signaling screen identifies Fzd9b as a Wnt9a-specific receptor.Fzd9b and Wnt9a regulate hematopoietic stem cell development as a cognate pair.WNT9A and FZD9 are required for HSPC derivation from human pluripotent cells in vitro.EGFR confers specificity to Wnt9a-Fzd9b signaling in zebrafish and human cells.

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Deregulation of Frizzled Receptors in Hepatocellular Carcinoma

Cited by 22 publications

References 98 publications

RNA Helicase DDX5 Negatively Regulates Wnt Signaling and Hepatocyte Reprogramming in Hepatitis B Virus-related Hepatocellular Carcinoma

RNA Helicase DDX5 Negatively Regulates Wnt Signaling and Hepatocyte Reprogramming in Hepatitis B Virus-related Hepatocellular Carcinoma

Oligomerization of Frizzled and LRP5/6 protein initiates intracellular signaling for the canonical WNT/β-catenin pathway

EGFR confers exquisite specificity of Wnt9a-Fzd9b signaling in hematopoietic stem cell development

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