Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality. Short-term prognosis of patients with HCC has improved recently due to advances in early diagnosis and treatment, but long-term prognosis is still unsatisfactory. Therefore, obtaining a further understanding of the molecular carcinogenic mechanisms and the unique pathogenic biology of HCC is important. The most characteristic process in hepatocarcinogenesis is underlying chronic liver injury, which leads to repeated cycles of hepatocyte death, inflammation, and compensatory proliferation and subsequently provides a mitogenic and mutagenic environment leading to the development of HCC. Recent in vivo studies have shown that the stress-activated mitogen-activated protein kinase (MAPK) cascade converging on c-Jun NH2-terminal kinase (JNK) and p38 plays a central role in these processes, and it has attracted considerable attention as a therapeutic target. However, JNK and p38 have complex functions and a wide range of cellular effects. In addition, crosstalk with each other and the nuclear factor-kappaB pathway further complicate these functions. A full understanding is essential to bring these observations into clinical settings. In this paper, we discuss the latest findings regarding the mechanisms of liver injury and hepatocarcinogenesis focusing on the role of the stress-activated MAPK pathway. 1. Introduction Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer mortality worldwide [1]. The age-adjusted incidence rate of HCC varies geographically, with high rates in East Asia and moderate rates in Europe, North/South America, and Oceania. In addition, a definite increase in HCC incidence has recently been reported in Europe and North America [2]. Although the etiology of background liver disease varies geographically, chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection is the main cause of HCC in most areas. Other major etiologies include alcoholic hepatitis, hemochromatosis, and nonalcoholic steatohepatitis (NASH) [1, 3]. Accumulating evidence indicates that a sustained inflammatory reaction in the liver is the major contributing factor to the development of HCC. For example, in chronic hepatitis C, the host immune responses to HCV are often not strong enough to completely clear the infection, resulting in chronic stimulation of an antigen-specific immune response [4]. Hepatocyte damage is induced by the continued expression of cytokines and recruitment of activated inflammatory cells to the liver,
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