Abstract 3828: Tumor promoting effects of sulforaphane on diethylnitrosamine-induced murine hepatocarcinogenesis

Abstract

Abstract Nuclear factor erythroid 2-related factor 2 (NRF2) is a key transcription factor involved in protection against initiation of carcinogenesis in normal cells. Notably, recent studies have demonstrated that mutation of the gene encoding this transcription factor causes its overactivation in various types of human malignancies. The aberrant activation of NRF2 is considered to accelerate the proliferation and progression of cancer cells. However, the exact function of NRF2 in the stage of pre-malignancy remains still largely unresolved. The differential effects of NRF2 on multi-stage carcinogenesis have raised a concern about the validity of NRF2 activators for chemoprevention. In the present study, a well-known NRF2 activating chemopreventive phytochemical, sulforaphane (SFN), was daily injected intraperitonally (25 mg/kg) for 3 months to male C57BL/6 mice at 6 months after single intraperitoneal administration of a hepatocarcinogen, diethylnitrosamine (DEN). The relative fold changes of liver weight, tumor growth, and the number and the size of hepatomas measured at 9 months after DEN administration were significantly higher in SFN-treated mice than that in vehicle-treated mice. Moreover, the expression of NRF2, its target protein NAD(P)H:quinone oxidoreductase 1 (NQO1), and the cell proliferation marker proliferating cell nuclear antigen (PCNA) and the DNA damage marker gamma-histone 2A family member X (γH2AX) was markedly elevated in SFN-treated mice compared with that in vehicle-treated mice as assessed by the Western blot assay. Immunohistochemistry and Immunofluorescence staining data further verified higher expression of NRF2 and PCNA in SFN-treated mice. These results suggest that once HCC is initiated, SFN stimulates the progression of DEN-induced HCC via activation of NRF2, rather than exerting a cancer chemopreventive effect. RNA sequencing analysis with liver tumors from DEN-treated mice revealed the B-raf V637E mutation (4/7). We speculate that mutation of B-raf proto-oncogene may contribute, at least in part, to activation of oncogenic NRF2 in DEN-induced murine carcinogenesis. The effects of SFN on DEN-induced mutation spectrum is under investigation. This study was supported by the Global Core Research Center (GCRC) Grant (No. 2011-003-0001) from the National Research Foundation (NRF) of Republic of Korea. Citation Format: Jie Zheng, Do-Hee Kim, Xi Zhu Fang, Seong Hoon Kim, Soma Saeidi, Su-Jung Kim, Young-Joon Surh. Tumor promoting effects of sulforaphane on diethylnitrosamine-induced murine hepatocarcinogenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3828.