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The concomitant loss of APC and HNF4? in adult hepatocytes does not contribute to hepatocarcinogenesis driven by ?-catenin activation.

ABSTRACT: BACKGROUND & AIMS:Loss of hepatocyte nuclear factor-4? (HNF4?), a critical factor driving liver development and differentiation, is frequently associated with hepatocellular carcinoma (HCC). Our recent data revealed that HNF4? level was decreased in mouse and human HCCs with activated ?-catenin signalling. In addition, increasing HNF4? level by miR-34a inhibition slowed tumour progression of ?-catenin-activated HCC in mice. METHODS:We generated a Hnf4aflox/flox/ Apcflox/flox /TTR-CreERT 2 (Hnf4a/Apc?Hep ) mouse line and evaluated the impact of Hnf4a disruption on HCC development and liver homoeostasis. RESULTS:There was no significant impact of Hnf4a disruption on tumour onset and progression in Apc?Hep model. However, we observed an unexpected phenotype in 28% of Hnf4a?Hep mice maintained in a conventional animal facility, which presented disorganized portal triads, characterized by stenosis of the portal vein and increased number and size of hepatic arteries and bile ducts. These abnormal portal structures resemble the human idiopathic non-cirrhotic portal hypertension syndrome. We correlated the presence of portal remodelling with a higher expression of protein and mRNA levels of TGF? and BMP7, a key regulator of the TGF?-dependent endothelial-to-mesenchymal transition. CONCLUSION:These data demonstrate that HNF4? does not play a major role during ?-catenin-driven HCC, thus revealing that the tumour suppressor role of HNF4? is far more complex and dependent probably on its temporal expression and tumour context. However, HNF4? loss in adult hepatocytes could induce abnormal portal structures resembling the human idiopathic non-cirrhotic portal hypertension syndrome, which may result from endothelial- and epithelial-to-mesenchymal transitions.

SUBMITTER: Sartor C

PROVIDER: S-EPMC7387933 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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The concomitant loss of APC and HNF4α in adult hepatocytes does not contribute to hepatocarcinogenesis driven by β-catenin activation.

Sartor Chiara C Bachelot Laura L Godard Cécile C Lager Franck F Renault Gilles G Gonzalez Frank J FJ Perret Christine C Gougelet Angélique A Colnot Sabine S

Liver international : official journal of the International Association for the Study of the Liver 20190224 4

<h4>Background & aims</h4>Loss of hepatocyte nuclear factor-4α (HNF4α), a critical factor driving liver development and differentiation, is frequently associated with hepatocellular carcinoma (HCC). Our recent data revealed that HNF4α level was decreased in mouse and human HCCs with activated β-catenin signalling. In addition, increasing HNF4α level by miR-34a inhibition slowed tumour progression of β-catenin-activated HCC in mice.<h4>Methods</h4>We generated a Hnf4a<sup>flox/flox/</sup> Apc<sup ...[more]

PMID: 30721564

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Project description:BACKGROUND & AIMS:Shp2 is an SH2-tyrosine phosphatase acting downstream of receptor tyrosine kinases (RTKs). Most recent data demonstrated a liver tumor-suppressing role for Shp2, as ablating Shp2 in hepatocytes aggravated hepatocellular carcinoma (HCC) induced by chemical carcinogens or Pten loss. We further investigated the effect of Shp2 deficiency on liver tumorigenesis driven by classical oncoproteins c-Met (receptor for HGF), ?-catenin and PIK3CA. METHODS:We performed hydrodynamic tail vein injection of two pairs of plasmids expressing c-Met and ?N90-?-catenin (MET/CAT), or c-Met and PIK3CAH1047R (MET/PIK), into WT and Shp2hep-/- mice. We compared liver tumor loads and investigated the pathogenesis and molecular mechanisms involved using multidisciplinary approaches. RESULTS:Despite the induction of oxidative and metabolic stresses, Shp2 deletion in hepatocytes suppressed hepatocarcinogenesis driven by overexpression of oncoproteins MET/CAT or MET/PIK. Shp2 loss inhibited proliferative signaling from c-Met, Wnt/?-catenin, Ras/Erk and PI3K/Akt pathways, but triggered cell senescence following exogenous expression of the oncogenes. CONCLUSIONS:Shp2, acting downstream of RTKs, is positively required for hepatocyte-intrinsic tumorigenic signaling from these oncoproteins, even if Shp2 deficiency induces a tumor-promoting hepatic microenvironment. These data suggest a new and more effective therapeutic strategy for HCCs driven by oncogenic RTKs and other upstream molecules, by inhibiting Shp2 and also suppressing any tumor-enhancing stromal factors produced because of Shp2 inhibition. LAY SUMMARY:Primary liver cancer is a malignant disease with poor prognosis, largely because there are limited systemic therapies available. We show here that a cytoplasmic tyrosine phosphatase Shp2 is required for liver tumorigenesis. This tumorigenesis is driven by two oncoproteins that are implicated in human liver cancer. This, together with our previous studies, uncovers the complexity of liver tumorigenesis, by elucidating the pro- and anti-tumor effects of Shp2 in mouse models. This data can be used to guide new therapies.

Project description:BACKGROUND:The role and mechanism of the nicotinamide adenine dinucleotide (NAD+) salvage pathway in cancer cell proliferation is poorly understood. Nicotinamide phosphoribosyltransferase (NAMPT), which converts nicotinamide into NAD+, is the rate-limiting enzyme in the NAD+ salvage pathway. Here, we assessed the role of NAMPT in the proliferation of colorectal cancer. METHODS:Real-time PCR, immunohistochemistry, western blotting, and analyses of datasets from Oncomine and Gene Expression Omnibus were conducted to assess the expression of NAMPT at the mRNA and protein levels in colorectal cancer. The Kaplan Meier plotter online tool was used to evaluate the prognostic role of NAMPT. Knockdown of NAMPT was performed to assess the role of NAMPT in colorectal cancer cell proliferation and tumorigenesis both in vitro and in vivo. Overexpression of NAMPT was used to evaluate impact of NAMPT on colorectal cancer cell proliferation in vitro. NAD+ quantitation, immunofluorescence, dual luciferase assay and western blot were used to explore the mechanism of colorectal cancer proliferation. Transwell migration and invasion assays were conducted to assess the role of NAMPT in cell migration and invasion abilities of colorectal cancer cells. RESULTS:Our study indicated that the inhibition of NAMPT decreased proliferation capacity of colorectal cancer cells both in vitro and in vivo. Conversely, overexpression of NAMPT could promote cell proliferation in vitro. NAMPT inhibition induced ?-catenin degradation by increasing Axin expression levels; this resulted in the inhibition of Wnt/?-catenin signaling and cell proliferation in colorectal cancer. The addition of nicotinamide mononucleotide, the enzymatic product of NAMPT, effectively reversed ?-catenin protein degradation and inhibited growth. Similarly, the knockdown of Axin also decreased the cell death induced by the inhibition of NAMPT. In addition, we showed that colorectal cancer tissues harbored significantly higher levels of NAMPT than the levels harbored by paired normal tissues, especially in colorectal cancer stages I and II. And the overexpression of NAMPT was associated with unfavorable survival results. CONCLUSIONS:Our findings reveal that NAMPT plays an important role in colorectal cancer proliferation via Wnt/?-catenin pathway, which could have vital implications for the diagnosis, prognosis and treatment of colorectal cancer.

Dataset Information

The concomitant loss of APC and HNF4? in adult hepatocytes does not contribute to hepatocarcinogenesis driven by ?-catenin activation.

Publications

The concomitant loss of APC and HNF4α in adult hepatocytes does not contribute to hepatocarcinogenesis driven by β-catenin activation.

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