Abstract
The SET protein is a potent inhibitor of protein phosphatase 2A (PP2A). Here, we report the oncogenic role of SET in hepatocarcinogenesis, clinical aggressiveness and anti-hepatocellular carcinoma (HCC) therapeutics. By analyzing samples obtained from 147 HCC patients, we found that SET overexpression was detected specifically in 30.6% HCC tumor samples, and was significantly associated with worse clinical features and high p-Akt expression in HCC tumors. Co-expression of SET and Akt predicted shorter post-operative recurrence-free survival in this cohort (P=0.045). Furthermore, SET was significantly associated with cell growth and hepatosphere formation. To elucidate the anti-HCC potential of targeting SET, we generated a novel SET antagonist, EMQA (N(4)-(3-ethynylphenyl)-6,7-dimethoxy-N(2)-(4-phenoxyphenyl) quinazoline-2,4-diamine). EMQA enhanced PP2A activity via disrupting SET-PP2Ac (catalytic domain of PP2A) binding in HCC cells, which restored PP2A-mediated p-Akt downregulation and promoted HCC cell death. In HCC cells or recombinant proteins expressing the N- and C- truncated forms of SET, only the C-terminal SET was required for EMQA targeting. Furthermore, combining sorafenib and EMQA showed good synergism in inhibiting HCC survival. Our findings suggested the oncogenic role of SET and the adverse prognostic value of SET overexpression in HCC. This alteration defines a subgroup of HCC patients who could benefit from SET antagonists, such as EMQA.
Highlights
IntroductionHepatocellular carcinoma (HCC) is the fifth most prevalent cancer and the third leading cause of cancer-related death worldwide.[1]
Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and the third leading cause of cancer-related death worldwide.[1]According to the latest GLOBOCAN survey, about 782 000 new HCC cases were diagnosed in 2012, and 746 000 patients died of this disease within the same year.[2]
To understand the clinical relevance of SET, we investigated the expression of SET protein by immunohistochemistry in a large set comprising 147 HCC patients with paired samples collected from the tumor tissue and adjacent normal tissue (Figures 1a–c)
Summary
Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and the third leading cause of cancer-related death worldwide.[1]. According to the latest GLOBOCAN survey, about 782 000 new HCC cases were diagnosed in 2012, and 746 000 patients died of this disease within the same year.[2] The comparable numbers of annual death to incidence reflect the shortage of treatments to improve outcomes for HCC patients. Reversible protein phosphorylation, antagonistically regulated by protein kinases and phosphatases, is one of the major mechanisms of transmitting signals and regulating protein functions within cells; and deregulation of this process is a central mechanism involved in carcinogenesis.[5,6] Previously, the protein phosphatase 2A (PP2A) was found to have a critical role in cell transformation by negatively regulating many oncogenic signal pathways.[7,8,9,10,11] Importantly, inactivation of PP2A by aberrant expression levels of the PP2A inhibitors is a highly recurrent and relevant event in human cancers.[6,11,12,13,14] In previous report, a potent inhibitor of PP2A, the SET protein, is overexpressed in some human malignant diseases, like leukemia and colon cancer.[15,16,17,18] SET has been described to interact with several
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