| Hepatocellular carcinoma(HCC)is the fifth most prevalent tumor type and the second leading cause of cancer deaths worldwide.Despite advances in diagnosis and treatment,prognosis for patients with HCC remains extremely poor.Its mortality rate is comparable to the incidence rate in most countries due to the high rate of recurrence and lack of effective molecular markers for monitoring and treatment.It is widely accepted that ongoing inflammation in the liver is the characteristic feature and an influential factor for the initiation,promotion,and progression of HCC.Most HCCs develop in the context of severe liver fibrosis and cirrhosis,following years of chronic liver inflammation induced by viral infections,chemicals,autoimmunity,and/or metabolic diseases.Currently,cancer prevention or anti-cancer therapy targeting inflammation-related molecules has been widely applied for some tumors.In particular,long-term intake of non-steroidal anti-inflammatory drugs has been shown to reduce the risk of colorectal cancer by targeting COX1/2.However,for HCC,a typically inflammation-related malignant tumor,inflammation-targeted therapy is still lacking.The use of Sorafenib,theonly targeted drug in HCC,is suggested for advanced HCC although its precise target sites have yet to been characterized.Therefore,further studies to explore the molecules link between inflammation and HCC are essential for the identification of novel monitoring and therapeutic targets for this dreadful disease.Oxidative stress and inflammation are complementary in the pathogenesis of many diseases.Chronic inflammation results in the accumulation of reactive oxygen species(ROS),and increased oxidative stress leads to further inflammation in turn.Paraoxonase(PON)proteins have been reported to play a vital role in preventing oxidative stress and inhibiting inflammation.The PON gene family consists of three members,PON1,PON2,and PON3,located adjacent to each other on chromosome 7q21.3-q22.1 in humans and shares high levels of homology in amino acid and nucleotide sequences.The expression and specific activities of PON genes were found to negatively correlate with several inflammatory disorders,such as cardiovascular diseases,type-2 diabetes,and inflammatory bowel disease.However,their roles in cancer are rarely evaluated,and despite being mainly expressed in the liver,the effect of PONs in the development and progression of HCC has not been discovered.PON3 is the most recently identified and least studied among the three PON genes.Like PON1,PON3 is primarily expressed in the liver,and to a much lesser extent in the kidney.In contrast,PON2 is ubiquitously expressed in tissues.Similar to PON2,PON3’s antioxidant and anti-inflammatory activities were thought to take place mainly at the cellular level,namely in hepatocytes.Moreover,Draganovet al.found that rabbit serum PON3 had a significantly more pronounced antioxidant effect when compared to serum PON1.Moreover,analysis of our previously acquired microarray data(GSE54238)showed a remarkable PON3 downregulation as HCC progresses.All these characteristics of PON3 revealed that it might play a vital role in HCC progression.Therefore,in this study,we focused on the expression,clinical significance,and function of PON3 in HCC.In the present study,we discovered significant downregulation of PON3 in HCC tissues at both m RNA and protein levels.We found that downregulation of PON3 was associated with several malignant characteristics of HCC.Prognostic analysis indicated that PON3 downregulation predicted poor post-surgical recurrence-free survival(RFS)and overall survival(OS)for patients with HCC,especially at early-stage HCC(TNM stage I).Moreover,a multivariate analysis revealed that PON3 downregulation was an independent risk factor for RFS and OS after surgery.Subcutaneous tumor growth assays demonstrated that downregulation of PON3 promoted tumor growth in vivo,while the opposite effect was observed in cell lines with PON3 overexpression.Using gain-and loss-of-function experiments in vitro,we discovered that the tumor growth inhibitory property of PON3 was mediated by its regulation of cell proliferation and cell cycle,but not cell apoptosis.A gene microarray study using stable PON3 knockdown cell lines showed that downregulation of PON3 elevated a pool of pro-proliferative genes.This may contribute to the molecular mechanism behind PON3 regulation of cell proliferation. |
