Chang S C, Choo W Q W, Toh H C, Ding J L
Department of Biological Sciences, National University of Singapore , 117543, Singapore.
Department of Biological Sciences, National University of Singapore, 117543, Singapore; NUS Graduate School for Integrative Science and Engineering, National University of Singapore, 117543, Singapore.
Cell Death Discov. 2015 Sep 28;1:15032. doi: 10.1038/cddiscovery.2015.32. eCollection 2015.
Hepatocellular carcinoma (HCC) is a deadly cancer because of its commonly late diagnosis and limited treatment options. SAG (sensitive to apoptosis gene)-dependent UPS (ubiquitin-proteasome system) is a key switch between immune-mediated apoptosis and overactivation-mediated protumorigenesis, prompting us to hypothesize that SAG-UPS modulates chronic inflammation-induced tumorigenesis. Here, we investigated the molecular mechanism by which SAG-UPS regulates death/survival of liver cancer cells. By retrospective studies, we found reciprocal expressions of anti-/proapoptotic factors: SAG/SARM and SAG/Noxa in human primary HCC tissues - the antiapoptotic SAG was significantly upregulated whereas the proapoptotic SARM and Noxa were markedly downregulated, suggesting their involvement in hepatocarcinogenesis. Upregulated SAG-UPS effectively manipulates the levels of high-molecular-weight ubiquitinated SARM and Noxa in carcinoma tissues compared with corresponding normal tissues. SAG-overexpressing HCC cell lines display reduced SARM and Noxa (but not Bcl-2, Bax and Bcl-xL), suggesting that SARM and Noxa are specific substrates of SAG-dependent ubiquitination. SARM overexpression activated caspase-3 and caspase-9, reducing cell viability. SAG knockdown significantly elevated apoptosis with increased cytosolic cytochrome c, confirming SAG-mediated antiapoptosis in HCC. SAG overexpression stimulated protumorigenic cytokines, IL-1β, IL-6 and TNF, but not antitumorigenic IL-12p40 and anti-inflammatory IL-10. This is consistent with higher proinflammatory cytokines (IL-1β, IL-6 and TNF) in hepatoma compared with healthy tissues. Altogether, early stage-upregulated SAG-UPS exacerbates hepatocarcinogenesis progression, through: (1) ubiquitination-mediated degradation of proapoptotic SARM and Noxa; and (2) production of protumorigenic cytokines that induce a protumorigenic microenvironment, conferring survival advantage to HCC cells. Thus, we propose SAG-UPS to be an early diagnostic marker for HCC, and a potential target for therapeutics development.
肝细胞癌（HCC）是一种致命的癌症，因为其通常诊断较晚且治疗选择有限。依赖于凋亡敏感基因（SAG）的泛素-蛋白酶体系统（UPS）是免疫介导的凋亡与过度激活介导的促肿瘤发生之间的关键开关，这促使我们推测SAG-UPS调节慢性炎症诱导的肿瘤发生。在此，我们研究了SAG-UPS调节肝癌细胞死亡/存活的分子机制。通过回顾性研究，我们发现抗凋亡/促凋亡因子在人原发性肝癌组织中的相互表达：SAG/SARM和SAG/Noxa——抗凋亡的SAG显著上调，而促凋亡的SARM和Noxa明显下调，表明它们参与了肝癌发生。与相应的正常组织相比，上调的SAG-UPS有效调控癌组织中高分子量泛素化的SARM和Noxa水平。过表达SAG的肝癌细胞系显示SARM和Noxa减少（但Bcl-2、Bax和Bcl-xL未减少），表明SARM和Noxa是SAG依赖性泛素化的特异性底物。SARM过表达激活了caspase-3和caspase-9，降低了细胞活力。敲低SAG显著增加凋亡并使胞质细胞色素c增加，证实了SAG在肝癌中介导的抗凋亡作用。SAG过表达刺激促肿瘤细胞因子IL-1β、IL-6和TNF，但不刺激抗肿瘤的IL-12p40和抗炎的IL-10。这与肝癌组织中比健康组织更高的促炎细胞因子（IL-1β、IL-6和TNF）一致。总之，早期上调的SAG-UPS通过以下方式加剧肝癌发生进程：（1）泛素化介导的促凋亡SARM和Noxa降解；（2）产生促肿瘤细胞因子，诱导促肿瘤微环境，赋予肝癌细胞生存优势。因此，我们提出SAG-UPS可作为肝癌的早期诊断标志物，以及治疗药物开发的潜在靶点。
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