B lymphocytes repress hepatic tumorigenesis but not development in Hras12V transgenic mice

Abstract

Increasing reports show noninflammation underlying HCC, challenging our understanding of the roles of the immune system in hepatocarcinogenesis. By exploring a mouse model of hepatic tumor induced by hepatocyte-specific expression of the Hras12V oncogene without obvious inflammation, we found that the proportion of B cells, but not T cells, progressively and significantly decreased in 3, 5-month-old transgenic mice (Tg) compared with non-transgenic mice. Notably, the proportions of total and activated B and T cells all significantly decreased in 9-month-old Tg with multiple massive hepatic tumors. Together with the decreased B cell proportion, serum IgG1/2 also significantly decreased in 5, 9-month-old Tg. Interestingly, homozygous Tg showed significantly higher B cell proportion and IgG2 levels, accompanied by significantly lower incidences of liver nodules but not adenomas and carcinomas compared with heterozygous Tg. Treatment of Tg with PCI-32765, a potent Bruton's tyrosine kinase (BTK) inhibitor for suppressing B cell proliferation and activation, significantly decreased the B cell proportion and IgG2 levels, accompanied by a significantly higher incidence of liver nodules, but had no effects on adenoma and carcinoma. Treatment of Tg with insulin-like growth factor 1 (IGF-1) significantly increased the B cell proportion and IgG2 levels, accompanied by a significantly lower incidence of liver nodules and carcinoma, but had no effects on adenoma. Conclusively, B cells and IgG2 may play important roles in suppressing hepatic tumorigenesis, but not development. In addition, hepatocyte-specific expression of the ras oncogene may play roles in suppressing B cells, while developed hepatic tumors suppress both B and T cells.

Metabolomic and transcriptomic profiling of hepatocellular carcinomas in Hras12V transgenic mice

“…For example, by exploring Ras‐Tg mice, we found that differences in the molecular responses to the deregulated Ras oncoprotein between females and males determine the onset of HCC, which may contribute to the striking male prevalence of HCC . In addition, we and other researchers found that B lymphocytes, FoxM1, and miR‐221 play crucial roles in HCC by using Ras‐Tg mice .…”

“…Moreover, the hyperactivation of the MEK/ERK and PI3K/AKT/mTOR signaling pathways was a marked molecular event in HCC . Reports based on the Ras‐Tg mouse demonstrate that it is a valuable model to investigate molecular mechanisms, diagnosis and therapeutic strategies, and biomarkers of hepatocarcinogenesis . For example, by exploring Ras‐Tg mice, we found that differences in the molecular responses to the deregulated Ras oncoprotein between females and males determine the onset of HCC, which may contribute to the striking male prevalence of HCC .…”

Inflammation and Liver Cancer: Molecular Mechanisms and Therapeutic Targets

“…Depletion of B cells by an anti-CD20 antibody in a syngeneic HCC mouse model or inactivation of B cells in Hras12V Tg mice using a Bruton's kinase inhibitor enhanced HCC growth. 67,68 By contrast, an Mdr2 À/À mouse model of HCC, mice treated with anti-CD20 antibody and B cell-deficient mice showed reduced inflammation-associated HCC. 69 Levels of immunoglobulin A (IgA)-producing plasma cells converted from IgM-producing B cells were increased in human NASH livers and in mouse models of NASH-promoted HCC, including HFD-fed major urinary protein-urokinase type plasminogen activator (MUP-uPA) mice and HFD-fed streptozotocin-treated mice, but not in the HFD plus DEN model of HCC.…”

Leveraging Single-Cell RNA-seq Data to Uncover the Association Between Cell Type and Chronic Liver Diseases

“…A similar phenomenon has also been observed in liver disease. In a Hras12V HCC mouse models, B cells were found to have a potential role in suppressing hepatic tumorigenesis (Wang et al, 2017), whereas in another mouse model with inflammation-associated HCC, infiltrating B cells was correlated with increased tumor aggressiveness and mortality (Faggioli et al, 2018). In addition, activated FcγRII low/− B cells from HCC tumor may also suppress host anti-tumor immune response via IL-10 signals (Ouyang et al, 2016;Jin et al, 2017).…”