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NCOA5 deficiency promotes a unique liver protumorigenic microenvironment through p21WAF1/CIP1 overexpression, which is reversed by metformin

Abstract

Prevention and treatment options for hepatocellular carcinoma (HCC) are presently limited, underscoring the necessity for further elucidating molecular mechanisms underlying HCC development and identifying new prevention and therapeutic targets. Here, we demonstrate a unique protumorigenic niche in the livers of Ncoa5+/ mouse model of HCC, which is characterized by altered expression of a subset of genes including p21WAF1/CIP1 and proinflammatory cytokine genes, increased putative hepatic progenitors, and expansions of activated and tissue-resident memory (TRM) CD8+ T lymphocytes, myeloid-derived suppressor cells (MDSCs), and alternatively activated M2 macrophages. Importantly, prophylactic metformin treatment reversed these characteristics including aberrant p21WAF1/CIP1 expression and subsequently reduced HCC incidence in Ncoa5+/− male mice. Heterozygous deletion of the p21WAF1/CIP1 gene alleviated the key features associated with the protumorigenic niche in the livers of Ncoa5+/− male mice. Moreover, transcriptomic analysis reveals that preneoplastic livers of Ncoa5+/− mice are similar to the livers of nonalcoholic steatohepatitis patients as well as the adjacent noncancerous liver tissues of a subset of HCC patients with a relatively poor prognosis. Together, our results suggest that p21WAF1/CIP1 overexpression is essential in the development of protumorigenic microenvironment induced by NCOA5 deficiency and metformin prevents HCC development via alleviating p21WAF1/CIP1 overexpression and protumorigenic microenvironment.

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Fig. 1: Dysregulated genes expression and increased putative HPCs in preneoplastic livers of Ncoa5+/− male mouse.
Fig. 2: Frequency, absolute numbers, and subsets of CD8+ T cells in livers of Ncoa5+⁄− mice.
Fig. 3: Frequency and absolute numbers of MDSCs, macrophages and M2 macrophages in livers of Ncoa5+⁄− mice.
Fig. 4: Effects of metformin on the characteristics of precancerous livers and HCC incidence in Ncoa5+/− male mice.
Fig. 5: Effects of metformin on dysregulated genes, cytoplasmic p21WAF1/CIP1-positive hepatocytes and HPCs in Ncoa5+/− male mouse liver.
Fig. 6: Effect of heterozygous deletion of p21 gene on the livers of Ncoa5+/− male mice.
Fig. 7: Association of CDKN1A/p21WAF1/CIP1 expression and Ncoa5 gene set with HCC Patients and NASH patients.

Data availability

The RNA sequencing data have been deposited in NCBI’s Gene Expression Omnibus and are accessible through GEO Series accession number GSE110524. All other data that support the findings of this study are available within the article and its supplementary information files or from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by the grants (R01 CA188305 and R21 CA185021) of National Cancer Institute to HX and a NIH-NCI K22 award (5K22CA18814802) to RD. MW was supported by a NIH F32 student training fellowship (5 T32 GM 92715-3). XL was partially supported by a fellowship from Integrated Hospital of Traditional Chinese Medicine, Southern Medical University. The authors thank J. Rennhack and E. Andrechek for sharing expertise in RNA-seq data analysis; E. Andrechek for manuscript comments; and members of the HX lab for helpful discussions. The results reported here are partially based on data generated by the TCGA Research Network: http://cancergenome.nih.gov, which we also gratefully acknowledge.

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Correspondence to Hua Xiao.

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Williams, M., Liu, X., Zhang, Y. et al. NCOA5 deficiency promotes a unique liver protumorigenic microenvironment through p21WAF1/CIP1 overexpression, which is reversed by metformin. Oncogene 39, 3821–3836 (2020). https://doi.org/10.1038/s41388-020-1256-x

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