ADRB2 Signaling Promotes The Tumorigenesis And Development Of Hepatocellular Carcinoma (HCC)

Primary liver cancer ranks the fifth among the most commonly seen malignancy worldwide with poor prognosis and high mortality. In the year of 2008, there were about 750,000 new cases and up to 700,000 deaths from liver cancer all around the world, which continued to increase to an estimated 780,000 new cases in 2012. Hepatocellular carcinoma (HCC) is the most common histologic type of primary liver cancer, and it accounts for between 85% and 90% of these malignancies. HCC arises from hepatocytes that comprise the parenchymal cells of the liver. The distribution of incidence of HCC is not even throughout the globe. A great proportion of cases occur in sub-Saharan Africa and Eastern Asia (>80%), and China is believed to account for approximately 50% of all cases of HCC worldwide. Conversely, North and South America, as well as Europe, have a comparatively low incidence of HCC. These marked differences can be attributed to several specific factors, among which environmental factor is an important aspect.Psychosocial state is a kind of important environmental factor. As a kind of psychosocial state that could have great influence to physiology and pathology of human body, stress is being paid more and more attention to regarding its relationship to tumor development. Recent evidence supports a longstanding hypothesis that chronic stress can influence tumor growth and progression. It has been shown that sympathetic neurotransmitters, such as catecholamines and neuropeptides, can affect both cancer cell growth and tumor vascularization. As a result, activation of the adrenergic system increases growth of various types of tumors and has been shown to mediate stress-induced augmentation of tumor progression. As a kind of ligands, catecholamines released by adrenergic system during stress exert their effects mainly through contacting and activating adrenergic receptors expressed on cell surface. Therefore, when we study the regulation of stress to tumor, we are actually trying to understand how the activatied adrenergic receptors on the surface of tumor cells regulate tumor growth and development.In the present study, we first showed that adrenaline promotes chemically induced hepatocarcinogenesis, which is completed by activating beta2-adrenergic receptor (ADRB2). And then we demonstrated that ADRB2 signaling negatively regulates autophagy, a process accomplished by interfering Beclinl/Vps34/Atg14 complex formation, which is dependent on Akt. Moreover, we also showed that ADRB2 signaling stabilizes HIF1A by inhibiting its autophagic degradation. What is more, we revealed for the first time that ADRB2 signaling inhibits sorafenib-induced autophagy and targeting ADRB2 enhances sorafenib anti-tumor effects. These findings may represent an important mechanism by which stress promotes HCC development and enhances resistance of HCC to targeted therapy, and may provide new idea and methods for clinical treatment of HCC.