Abstract 2932: CD59 facilitates tumor progression through activating TGF-β/Smad signaling pathway in hepatocellular carcinoma

Abstract

Abstract Little success has been achieved in the exploitation of effective interventions against hepatocellular carcinoma (HCC) pathogenesis. To determine the crucial regulators in this process, CD59 was identified from the lung metastasis screening mice models that we previously reported. It is well known that CD59, belonging to membrane-bound complement regulatory proteins (mCRPs), acts as a suppressor of the formation of the membrane attack complex to enable tumor cells to escape from complement surveillance. Apart from that, our work identified CD59 as a potential oncogenic driver in hepatocarcinogenesis and metastasis. Specifically, CD59 was considerably upregulated in HCC tissues. High expression of CD59 was associated with poor overall survival and disease-free survival. Functional studies demonstrated that CD59 knockdown inhibited proliferation, cell cycle and apoptosis resistance of HCC cells, impaired their tumorigenic and metastasis capacities in vitro and in vivo, whereas overexpression of CD59 exhibited opposite cell phenotypes. Mechanistically, CD59 competitively binds to aminoacyl tRNA synthetase complex interacting multifunctional protein 1 (AIMP1), resulting in the disassociation of AIMP1 from Smad-specific E3 ubiquitin protein ligase 2 (Smurf2) and the continuous interaction between Smurf2 and Smad7, thus accelerating the ubiquitin-mediated degradation of Smad7. By contrast, loss of CD59 promoted excessive Smad7 formation, leading to the abolishment of Smad2/3 phosphorylation and subsequent nuclear translocation, therefore inhibiting hepatocarcinogenesis and metastasis. Overall, our findings indicated that CD59 facilitated HCC pathogenesis via modulating TGF-β signaling, apart from disturbing the complement-dependent cytotoxicity. CD59 may be an effective prognostic biomarker and potential therapeutic target for HCC. Citation Format: Tian Lan, Hong Wu. CD59 facilitates tumor progression through activating TGF-β/Smad signaling pathway in hepatocellular carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2932.