Acquisition of specific genetic alterations has been shown to play a pivotal role in the progression of various stages of liver cancer, and studies have proved that alteration of transforming growth factor-β (TGF-β) signaling pathway can lead to the development of gastrointestinal cancers including liver cancer. β-Spectrin (β2SP) is one of adapter proteins for Smad3/Smad4 complex formation during TGF-β signal transduction. Forty % of β2SP+/- mice develop liver cancer, and the underlying molecular mechanisms remain largely unclear. Hypothesis: Compared to wild-type (WT) mice, β2SP+/- mice had significantly higher number of inflammatory nodules in the liver and this pathological feature might be one of mechanisms contributing to liver cancer formation seen in β2SP+/- mice. Inflammation plays a crucial role at different stages of tumor development. We hypothesize that an increase in liver inflammation leads to liver cancer formation in β2SP+/- mice. We proposed to study the mechanism by which β2SP regulates liver inflammation and suppresses liver cancer development. Experimental Procedures and Results: (1) We dissected livers from 18-month-old WT and β2SP+/- mice and processed for paraffin embedding and the tissue slides were used for hematoxylin and eosin (H&E) staining. We observed inflammatory nodules in the liver of near 60% β2SP+/- mice compared to less than 5% in WT mice. (2) To identify the type of leucocytes infiltrated in the liver tissues, we carried out immunohistochemistry staining by using antibodies directly against macrophage, T-cell receptor and B-cell antigen, and found that the number of T- and B-lymphocytes in the liver was significantly higher in β2SP+/- mice than that in WT mice. (3) Microarray and quantitative real-time RT-PCR analyses indicated that hepatic expression of interleukin-1 α (IL-1α) and IL-1β mRNA was highly upregulated only in β2SP+/- mice. (4) Western blot analyses showed that STAT3 activation in the liver was higher in β2SP+/- mice than that in WT mice. Double mutant mice with β2SP+/- and liver specific deletion of STAT3 (LSTAT3-/-) had reduced inflammatory nodules and IL-1 expression compared to β2SP+/- mice, suggesting that STAT3 is one of the regulators in mediating the cross-talk between β2SP and IL-1 in the regulation of inflammatory response in liver. Conclusion: Our results suggest that hepatic expression of IL-1α and IL-1β is induced in β2SP+/- mice, which is likely due to the elevated activation of STAT3 and contributes to the increased hepatic inflammation in β2SP+/- mice.

Citation Format: Ling Lin, Hua Wang, Bin Gao, Xiuling Zhi, Aiwu Ruth He. Mechanistic analysis of liver inflammation and cancer formation in mice with heterozygous lose of β-spectrin (β2SP). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5184. doi:10.1158/1538-7445.AM2013-5184