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Iron metabolism in a mouse model of hepatocellular carcinoma

ABSTRACT: Background & Aims: Liver cancer is the sixth most frequently diagnosed type of cancer and the third leading cause of cancer-related mortality worldwide. One of the most frequently effected pathways in liver carcinoma is the p53 signalling pathway. Emerging evidence indicates that deregulation of p53 leads to several metabolic disorders that are pivotal during cancer progression. Methods: We induced chronic liver disease and subsequent liver carcinoma formation by chronic injection of CCl4 (16 weeks treatment) in p53f/f and p53LKO mice. We characterized major differences between HCC from p53f/f and HCC from p53LKO mice. In addition, we characterized differences between HCC and ICC, both from p53LKO mice. Results: We show that Conclusions: Dysregulation of Notch signaling is involved in tumor differentiation. Loss of Rbpj triggers the formation of combined HCC-iCCA which is associated by a pro-tumorigenic environment. Results: We show that all liver cancers that develop on a p53-deficient background have an iron-poor phenotype with a “low hepcidin and high Tfr1” signature, while iron deficiency at the systemic level is restricted to female mice. In addition to iron, liver tumorigenesis correlated with significant deficits of selenium, zinc and manganese, accompanied by changes in their key metabolic players. Conclusions: Our work demonstrates a pivotal role for p53 in a complex network controlling tumor development and micronutrient metabolism, locally in the liver cancers, and at a systemic level along with highlighting sex-specific differences underlying liver cancer development and the distribution of trace elements.

ORGANISM(S): Mus musculus

PROVIDER: GSE255470 | GEO | 2025/01/22

REPOSITORIES: GEO

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Project description:To model the effect of Pten loss on breast cancer, we deleted Pten using a floxed allele and the deleter lines MMTV-Cre(NLST), which targets stem/bi-potent progenitor cells, and WAP-Cre, which targets CD24-positive, pregnancy-identified stem cells/alveolar progenitors. Mammary tumors were detected in WAP-Cre:Ptenf/f females with a latency of 15.2 months. By 18 months, nearly all mice had succumbed to cancer. MMTV-Cre:Ptenf/f mice developed mammary tumors after a longer latency of 26.4 months and reduced penetrance (70%) compared to WAP-Cre:Ptenf/f mice. Tumors from both models were heterogeneous, consisting primarily of differentiated adenocarcinoma (adenomyoepithelioma; ~70%) and adenosquamous carcinoma (20-25%). In addition, a small fraction of tumors was classified as acinar and poorly differentiated adenocarcinoma (4-7%) and adenosarcoma (3-4%). To test the consequences of combined Pten and p53 gene mutation on breast cancer, we deleted both genes via MMTV-Cre or WAP-Cre. Kaplan-Meier tumor free survival curves revealed that WAP-Cre:Ptenf/f:p53f/f and MMTV-Cre:Ptenf/f:p53f/f females developed tumors with reduced latency of 11.3 and 9.8 months, compared with 15.2, 26.4, and 16.9 months for single-mutant WAP-Cre:Ptenf/f, MMTV-Cre:Ptenf/f or MMTV-Cre:p53f/f mice, respectively. In contrast to the heterogeneity of Pten tumors and small percentage of adenosarcomas in these mice, ~70% of Pten:p53 lesions were histologically classified as adeno-sacrcomatoid-like or mesenchymal-like breast cancer, with the rest exhibiting mixed mesenchymal plus adenocarcinomas and differentiated adenocarcinomas. The adeno-sacrcomatoid-like tumors expressed the mesenchymal markers vimentin, K5, SMA, N-cadherin and desmin but not ER, as well as islands of luminal-like K18 expressing cells surrounded by a layer of K14-positive cells. We used microarrays to detect differentially expressed genes in the Pten:p53 double-knock-out vs Pten or p53 single deletions Total RNA was extracted from tumors developed by double Trizol method and hybridized on Affymetrix microarrays.

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Iron metabolism in a mouse model of hepatocellular carcinoma

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