Zinc fingers and homeoboxes 2 is required for diethylnitrosamine‐induced liver tumor formation in C57BL/6 mice

Abstract

Liver cancer, comprised primarily of hepatocellular carcinoma (HCC), is the third leading cause of cancer deaths worldwide and increasing in Western countries. We previously identified the transcription factor zinc fingers and homeoboxes 2 (Zhx2) as a regulator of hepatic gene expression, and many Zhx2 target genes are dysregulated in HCC. Here, we investigate HCC in Zhx2‐deficient mice using the diethylnitrosamine (DEN)–induced liver tumor model. Our study using whole‐body Zhx2 knockout (Zhx2KO) mice revealed the complete absence of liver tumors 9 and 10 months after DEN exposure. Analysis soon after DEN treatment showed no differences in expression of the DEN bioactivating enzyme cytochrome P450 2E1 (CYP2E1) and DNA polymerase delta 2, or in the numbers of phosphorylated histone variant H2AX foci between Zhx2KO and wild‐type (Zhx2wt) mice. The absence of Zhx2, therefore, did not alter DEN bioactivation or DNA damage. Zhx2KO livers showed fewer positive foci for Ki67 staining and reduced interleukin‐6 and AKT serine/threonine kinase 2 expression compared with Zhx2wt livers, suggesting that Zhx2 loss reduces liver cell proliferation and may account for reduced tumor formation. Tumors were reduced but not absent in DEN‐treated liver‐specific Zhx2 knockout mice, suggesting that Zhx2 acts in both hepatocytes and nonparenchymal cells to inhibit tumor formation. Analysis of data from the Cancer Genome Atlas and Clinical Proteomic Tumor Consortium indicated that ZHX2 messenger RNA and protein levels were significantly higher in patients with HCC and associated with clinical pathological parameters. Conclusion: In contrast to previous studies in human hepatoma cell lines and other HCC mouse models showing that Zhx2 acts as a tumor suppressor, our data indicate that Zhx2 acts as an oncogene in the DEN‐induced HCC model and is consistent with the higher ZHX2 expression in patients with HCC.

Streptomyces Bioactive Metabolites Prevent Liver Cancer through Apoptosis, Inhibiting Oxidative Stress and Inflammatory Markers in Diethylnitrosamine-Induced Hepatocellular Carcinoma

“…These increased values show the beginning of HCC in addition to liver damage. This result is in line with earlier research [ 39 , 40 ]. Notably, the Streptomyces sp.…”

Cytokine storm–based mechanisms for extrapulmonary manifestations of SARS-CoV-2 infection

“…Compared to BALB/c mice, Zhx2 hypo/hypo BALB/cJ mice developed less severe heart, liver and kidney injury and lower mortality, whereas the extent of glomerular injury was similar. The disparity between glomerular and other forms of injury is possibly related the predominantly cell membrane localization of ZHX proteins in podocytes (27,40,41), and largely nuclear expression in the heart (42), liver (43) and kidney tubular cells (27), although the use of low confidence and polyreactive antibodies to stain human tissue in a key resource (42) These studies showcase the concept of synergy between different cytokines, compartments and signaling pathways in disease pathogenesis. Cytokine depletion regimens described in this study also affect this synergy.…”

ZHX2 in health and disease

“…Interestingly, latest studies reported that ZHX2 functions as an oncogene in ccRCC (13,14) and TNBC (16). Likewise, Jiang et al reported that the whole-body knockout of Zhx2 results in reduced liver tumors in diethylnitrosamine (DEN)-induced HCC mice (52). Therefore, ZHX2 is abnormally expressed in multiple tumors and plays different roles, either acting as a tumor suppressor or oncogene in a context-dependent manner (Figure 2).…”

“…Jiang et al recently showed that whole body Zhx2 knockout (Zhx2 KO ) leads to dramatically reduced liver cancer in DEN-induced HCC mouse model, indicating the oncogenic role of ZHX2 in DENinduced liver tumor model (52). Interestingly, compared with Zhx2 KO mice, DEN induces more tumors in liver-specific Zhx2 knock-out mice (Zhx2 Dliv ) (52). These data suggest that ZHX2 expression in non-parenchymal cells plays a critical role in liver carcinogenesis.…”

“…Hu et al reported increased ZHX2 staining in HCC tissues and higher ZHX2 expression in poorly differentiated and metastasis samples, indicating that ZHX2 might promote HCC progression (53). Jiang et al recently showed that whole body Zhx2 knockout (Zhx2 KO ) leads to dramatically reduced liver cancer in DEN-induced HCC mouse model, indicating the oncogenic role of ZHX2 in DENinduced liver tumor model (52). Interestingly, compared with Zhx2 KO mice, DEN induces more tumors in liver-specific Zhx2 knock-out mice (Zhx2 Dliv ) (52).…”