miR-22 gene therapy treats HCC by promoting anti-tumor immunity and enhancing metabolism.

MicroRNA-22 (miR-22) can be induced by beneficial metabolites that have metabolic and immune effects, including retinoic acids, bile acids, vitamin D3, and short-chain fatty acids. The tumor suppressor effects of miR-22 have been suggested, but whether miR-22 treats orthotopic hepatocellular carcinoma (HCC) is not established. The role of miR-22 in regulating tumor immunity is also poorly understood. Our data showed that miR-22 delivered by adeno-associated virus serotype 8 effectively treated HCC. Compared with FDA-approved lenvatinib, miR-22 produced better survival outcomes without noticeable toxicity. miR-22 silenced hypoxia-inducible factor 1 (HIF1α) and enhanced retinoic acid signaling in both hepatocytes and T cells. Moreover, miR-22 treatment improved metabolism and reduced inflammation. In the liver, miR-22 reduced the abundance of IL17-producing T cells and inhibited IL17 signaling by reducing the occupancy of HIF1α in the Rorc and Il17a genes. Conversely, increasing IL17 signaling ameliorated the anti-HCC effect of miR-22. Additionally, miR-22 expanded cytotoxic T cells and reduced regulatory T cells (Treg). Moreover, depleting cytotoxic T cells also abolished the anti-HCC effects of miR-22. In patients, miR-22 high HCC had upregulated metabolic pathways and reduced IL17 pro-inflammatory signaling compared with miR-22 low HCC. Together, miR-22 gene therapy can be a novel option for HCC treatment.

Accelerated partial hepatectomy-induced liver cell proliferation is associated with liver injury in Nur77 knockout mice.

Nur77, encoded by Nr4a1 (alias Nur77), plays roles in cell death, survival, and inflammation. To study the role of Nur77 in liver regeneration, wild-type (WT) and Nur77 knockout (KO) mice were subjected to standard two-thirds partial hepatectomy (PH). Nur77 mRNA and protein levels were markedly induced at 1 hour after PH in WT livers, coinciding with ERK1/2 activation. Surprisingly, Nur77 KO mice exhibited a higher liver-to-body weight ratio than WT mice at 24, 48, and 72 hours after PH. Nur77 KO livers exhibited increase in Ki-67-positive hepatocytes at 24 hours, with early induction of cell-cycle genes. Despite accelerated regeneration, Nur77 KO livers paradoxically incurred necrosis, hepatocyte apoptosis, elevated serum alanine aminotransferase activity, and Kupffer cell accumulation. Microarray analysis revealed up-regulation of genes modulating inflammation, cell proliferation, and apoptosis but down-regulation (due to Nur77 deficiency) of glucose and lipid homeostasis genes. Levels of proinflammatory cytokines IL-6, IL-12, IL-23, and CCL2 were increased and levels of anti-inflammatory IL-10 were decreased, compared with WT. Activated NF-κB and STAT3 and mRNA levels of target genes Myc and Bcl2l1 were elevated in Nur77 KO livers. Overall, Nur77 appears essential for regulating early signaling of liver regeneration by modulating cytokine-mediated inflammatory, apoptotic, and energy mobilization processes. The accelerated liver regeneration observed in Nur77 KO mice is likely due to a compensatory effect caused by injury.

Targeting stroma and tumor, silencing galectin 1 treats orthotopic mouse hepatocellular carcinoma.

This study examines inhibiting galectin 1 (Gal1) as a treatment option for hepatocellular carcinoma (HCC). Gal1 has immunosuppressive and cancer-promoting roles. Our data showed that Gal1 was highly expressed in human and mouse HCC. The levels of Gal1 positively correlated with the stages of human HCC and negatively with survival. The roles of Gal1 in HCC were studied using overexpression (OE) or silencing using Igals1 siRNA delivered by AAV9. Prior to HCC initiation induced by RAS and AKT mutations, lgals1-OE and silencing had opposite impacts on tumor load. The treatment effect of lgals1 siRNA was further demonstrated by intersecting HCC at different time points when the tumor load had already reached 9% or even 42% of the body weight. Comparing spatial transcriptomic profiles of Gal1 silenced and OE HCC, inhibiting matrix formation and recognition of foreign antigen in CD45+ cell-enriched areas located at tumor-margin likely contributed to the anti-HCC effects of Gal1 silencing. Within the tumors, silencing Gal1 inhibited translational initiation, elongation, and termination. Furthermore, Gal1 silencing increased immune cells as well as expanded cytotoxic T cells within the tumor, and the anti-HCC effect of lgals1 siRNA was CD8-dependent. Overall, Gal1 silencing has a promising potential for HCC treatment.

MiR-22 as a metabolic silencer and liver tumor suppressor.

With obesity rate consistently increasing, a strong relationship between obesity and fatty liver disease has been discovered. More than 90% of bariatric surgery patients also have non-alcoholic fatty liver diseases (NAFLDs). NAFLD and non-alcoholic steatohepatitis (NASH), which are the hepatic manifestations of metabolic syndrome, can lead to liver carcinogenesis. Unfortunately, there is no effective medicine that can be used to treat NASH or liver cancer. Thus, it is critically important to understand the mechanism underlying the development of these diseases. Extensive evidence suggests that microRNA 22 (miR-22) can be a diagnostic marker for liver diseases as well as a treatment target. This review paper focuses on the roles of miR-22 in metabolism, steatosis, and liver carcinogenesis. Literature search is limited based on the publications included in the PubMed database in the recent 10 years.

The Expression of Cancer-Related Genes in Aging Mouse Liver is RXRα and Gender Dependent.

BACKGROUND: Previous reports have demonstrated that gene expression profiles are modified in several tissue types including liver during the aging process and that such alterations might impact on the development and advancement of certain diseases. To understand the affect of aging on liver cancer, we have studied the expression pattern of cancer-related genes in aging mouse livers. Retinoid x receptor α (RXRα) is a transcription factor that is highly expressed in the liver. RXRα-regulated pathways are implicated in liver detoxification and carcinogenesis. In addition, liver cancer incidence is higher in males than in females. Thus, we have also studied the effects of hepatic RXRα and gender on regulating those cancer-related genes in aging mouse livers. RESULTS: Hepatic cancer-related gene expression patterns were compared between old (24-month-old) and young mature (6-month-old) wild type as well as hepatocyte RXRα-deficient C57BL/6J mice in both genders. cDNA microarray was performed and quantitative reverse transcription-polymerase chain reaction assays were employed to validate part of our results. In aged male mouse liver, genes associated with apoptosis, metastasis, cell cycle transition, and DNA repair showed changes in expression levels. In female aged mouse liver, the most notable variations were found in genes that are related to the immune system. In addition, the expression pattern is RXRα dependent. CONCLUSIONS: Our results suggested that specific sets of genes, which are regulated by gender and RXRα, might contribute to the increase in liver cancer incidence observed with age.