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Introduction
Hepatocellular carcinoma (HCC) is the fifth most common form of cancer and the most aggressive and frequently diagnosed malignancy of the liver. HCC is responsible for more than 600,000 deaths annually in the world. The main risk factors of HCC include hepatitis B virus infection, hepatitis C virus infection, alcohol abuse and tobacco. Recent data indicate that the mortality of primary liver cancer in China is increasing (1). Surgical resection has been considered the classical treatment, but only a small proportion of patients are diagnosed in time to have the chance for surgery. Therefore, there is a critical need for effective approaches for HCC treatment, especially in intermediate-stage and end-stage.
The signal transducer and activator of transcription (STAT) protein family have been shown to play an important role in tumor cell survival and proliferation (2). Among them, constitutive activation of STAT3 has been detected in a wide number of human cancer cell lines and primary tumors, including 50% of HCC (3,4). STAT3 can be activated by certain cytokines such as interleukin-6 (IL-6) (5), leukemia inhibitory factor (LIF) (6) and interferon-α (IFN-α) (7). Among these inflammation factors inducing STAT3 phosphorylation, IL-6 is regarded as one of the most vital cytokines in the studies published in the past few years. Patients with HCC show elevated levels of IL-6 in their serum compared with those with liver cirrhosis or healthy individuals (8). The homodimerization of the IL-6 triggers a signaling cascade of phosphorylation of Janus kinases 2 (JAK2) and a downstream effector STAT3, followed by reciprocal dimerization of the Tyr705 phosphorylated STAT3 (9). Then, the STAT3 downstream target genes are activated, including Bcl-xl, Bcl-2 and survivin (10,11). It has been shown that aberrant activation of IL-6/JAK2/STAT3 signaling pathway plays an important role in pathogenesis and progress of liver cancer (12). However, there is still no JAK2/STAT3 inhibitors approved to be used clinically for the treatment or prevention of HCC.
Ursolic acid (UA) is natural triterpenoid compound found in plants, herbs and other kinds of food. It has been identified to play noteworthy role in anti-inflammatory, hepatoprotective and antiallergic activities. It suppresses cell proliferation of various types of cancer, including multiple myeloma (13), colon (14), breast (15), pancreatic (16) and prostate cancer (17) by inhibiting the STAT3 signaling...