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 p21 WAF1/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 p21 WAF1/CIP1 expression and subsequently reduced HCC incidence in Ncoa5 +/− male mice. Heterozygous deletion of the p21 WAF1/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 non-alcoholic 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 p21 WAF1/CIP1 overexpression is essential in the development of pro-tumorigenic microenvironment induced by NCOA5 deficiency and metformin prevents HCC development via alleviating p21 WAF1/CIP1 overexpression and protumorigenic microenvironment.

Metformin Actions on the Liver: Protection Mechanisms Emerging in Hepatocytes and Immune Cells against NASH-Related HCC

“…Metformin was shown to reduce the HCC incidence in this mouse model while reducing p21 expression in hepatocytes and decreasing the HPC number. Deletion of the p21 gene phenocopied metformin treatment in Ncoa5 deficient mice with regard to the reduced HPC number [ 129 ]. Thus, metformin may reduce HCC risk in the NASH condition partially by inhibiting HPC activation by reducing p21 expression in hepatocytes.…”

“…Long-term metformin treatment decreased the total intrahepatic myeloid cell number and the M2 macrophage incidence in Ncoa5 +/− mice. Metformin seems to regulate both the M1 and M2 population in the NASH condition here, and the mechanism was elusive but was implied to metformin’s repression of p21 expression in the hepatocyte [ 129 ]. In a transgenic zebrafish model of HCC driven by the expression of activated β-catenin, a high-fat diet was found to promote HCC progression.…”

“…Inhibiting the formation and recruitment of MDSCs in the liver would alleviate the immunosuppressive microenvironment that promotes tumor initiation and progression. The accumulation of MDSCs in the NASH liver of Ncoa5 +/− mice can be prevented by long-term treatment of metformin, concurrent with a reduced HCC incidence [ 129 ]. The reduction of hepatic MDSCs could be the result of suppressed chronic inflammation in the liver by metformin.…”

“…In contrast, boosting CD8 T cell expansion and cytotoxicity in the HCC stage can help with tumor clearance. In the NASH liver of the NCOA5-deficient mouse, the increase of hepatic CD8 T cells, which was more likely associated with activated and tissue-resident memory phenotypes, was prevented by long-term metformin treatment concurrent with a reduced enrichment of T cell exhaustion gene signatures in the liver transcriptome [ 129 ]. The authors suggested a mechanism related to metformin’s suppression to chronic hepatic inflammation that caused the observed reduction of T cell infiltration and exhaustion.…”

Tissue-Resident Memory T Cells in the Liver—Unique Characteristics of Local Specialists

“…The kinase inhibitor p21 promotes cell cycle arrest and has anti-proliferative functions. In this special situation, T RM cells were expanded in mice with HCC and decreased in line with HCC reduction [ 102 ]. Another study showed that T RM cells in HCC have an exhausted phenotype, e.g., shown by the expression of PD-1, LAG-3 and TIM3, especially in comparison to T RM cells, which are not in the tumor microenvironment.…”