Liver cancer is a major contributor to the world’s cancer burden, with more than 800,000 new cases and 700,000 death each year. Hepatocellular carcinoma (HCC), a principal histologic type of liver cancer, represents more than 75% of primary liver cancers. Due to the aging and population growth, the global incidence of HCC increased by 75% between 1990 and 2015, with the highest incident, mortality and years of life lost in east Asia. The worldwide risk factors of HCC is heterogeneous. Hepatitis B virus (HBV) is the leading cause of incident cases of HCC in Africa and East Asia, while alcoholic liver disease (ALD) and hepatitis C (HCV) are the most common risk factor for HCC in the USA. Prognosis of HCC is poor all around the world, resulting in a rough equivalent of incidence and mortality rates. For early-stage HCC, radiofrequency ablation or surgical resection remains the main treatment. However, up to 75% of patients undergoing surgery experience recurrence within 5 years. Over the last decade, targeted therapy (sorafenib) has become the major systemic strategy which can significantly improve the overall survival for patients with unresectable HCC. However, the adverse effects of sorafenib, such as diarrhea, hypertension, and hand-foot skin reaction (HFSR), as well as its low bioavailability limit its clinical application[8, 9]. Therefore, there is an urgent need to explore potential drug candidates for HCC.
Alike many carcinomas, HCC has multiple genomic mutations. The prevalent mutations locate at TERT promoters, such as TP53, CTNNB1, AXIN1 and CDKN2A[10, 11]. In most cases of HCC (>90%), telomerase activation, relating to TERT promoter mutations, is necessary for malignant transformation and tumor progression[12, 13]. Of these, CTNNB1 mutations frequently activate the Wnt/β-catenin pathway, particularly in patients with HBV uninfection and well-differentiated tumors (11–37% of HCC cases) [14, 15]. By contrast, inactivation of p53 caused by TP53 mutations particularly appears in cases related to HBV infection and aflatoxin B1 exposure[16–18]. As a tumor suppressor, TP53 encodes p53 transcriptional factor to prevent tumor development through permanently suppression of cell proliferation by cell cycle arrest and facilitation of cell death by apoptosis. However, TP53 mutation or deletion occurs in nearly a half of human cancers, while tumors carrying wild-type TP53 usually get rid of the p53 defense mechanism via interaction with negative regulators, such as MDM2 and MDM4[20, 21]. Thus, reactivation of p53 becomes a potential strategy for cancer treatment[22–25] For instance, a p53-MDM2 inhibitor, RG7388, activates p53 signaling pathway by selectively blocking p53-MDM2 binding, exhibiting encouraging anti-cancer efficacy in several different clinical trials[26, 27].
Green tea, derived from leaves of Camellia sinensis, was originally used as medicine in ancient China. Meanwhile, it was one of the most prevalent beverages worldwide for centuries. In recent decades, green tea’s health benefits have been extensively studied, including anti-inflammation, cardiovascular-protection, anti-obesity, anti-cancer, and hepato-protection[28–32]. A large prospective cohort study on 164681 adult Chinese men has concluded that 10 g or more green tea consumption per day decreased the mortality from cancers, indicating an anti-cancer efficacy of green tea. As the main pigment of tea, theabrownin (TB) possesses regulatory effects in improving metabolism of glucose and serum lipids[34–36]. Our previous studies have discovered TB’s pro-apoptotic effects on human carcinoma cells and sarcoma cells both through a p53-mediated mechanism[37, 38]. To date, the efficacy of TB on human HCC cells with different p53 genotypes remains unclear. To fill this gap, this study adopted HCC cell lines, including SK-Hep-1 (p53-WT), HepG2 (p53-WT) and Huh7 (p53-mut), to evaluate TBʹs effects and the p53-related mechanism.