Guo Jiefang, Hao Jun, Jiang Hongxue, Jin Jing, Wu Hongyu, Jin Zhendong, Li Zhaoshen
Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Department of Pancreatic Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Cancer Lett. 2017 Feb 1;386:161-167. doi: 10.1016/j.canlet.2016.08.018. Epub 2016 Oct 15.
Pancreatic cancer has the worst prognosis among all cancers and novel markers and therapeutic targets are desperately needed for this terribly deadly disease. Proteasome activator subunit 3 (PSME3) is highly involved in the initiation and progression of many human cancers. However, the potential effect of PSME3 on pancreatic cancer remains largely unknown. In the present study, we first found that PSME3 was significantly upregulated in pancreatic cancer cells and tissues at both mRNA and protein levels using qRT-PCR, western blot analysis, Oncomine data mining and immunohistochemical analysis. High PSME3 expression was positively correlated with tumor size and pM stage, and was significantly correlated with poor prognosis in pancreatic cancer patients revealed by Kaplan-Meier analysis. Gene set enrichment analysis demonstrated that the gene sets related to cell proliferation and metastasis were positively correlated with elevated PSME3 expression. Consistently, silencing of PSME3 suppressed cell proliferation and invasive capacity of pancreatic cancer. Mechanistically, PSME3 inhibited the degradation of c-Myc and thus enhanced glycolysis, which ultimately led to the oncogenic effects of PSME3 on pancreatic cancer. Collectively, our data suggest that PSME3 plays oncogenic roles in pancreatic cancer by inhibiting c-Myc degradation to promote glycolysis, and could serve as a novel therapeutic target for pancreatic cancer treatment.
在所有癌症中，胰腺癌的预后最差，对于这种极其致命的疾病，迫切需要新的标志物和治疗靶点。蛋白酶体激活亚基3（PSME3）高度参与多种人类癌症的发生和发展。然而，PSME3对胰腺癌的潜在影响在很大程度上仍不清楚。在本研究中，我们首先使用qRT-PCR、蛋白质印迹分析、Oncomine数据挖掘和免疫组织化学分析发现，PSME3在胰腺癌细胞和组织中的mRNA和蛋白质水平均显著上调。PSME3高表达与肿瘤大小和pM分期呈正相关，Kaplan-Meier分析显示，PSME3高表达与胰腺癌患者的不良预后显著相关。基因集富集分析表明，与细胞增殖和转移相关的基因集与PSME3表达升高呈正相关。同样，沉默PSME3可抑制胰腺癌细胞的增殖和侵袭能力。机制上，PSME3抑制c-Myc的降解，从而增强糖酵解，最终导致PSME3对胰腺癌的致癌作用。总体而言，我们的数据表明，PSME3通过抑制c-Myc降解促进糖酵解在胰腺癌中发挥致癌作用，并可作为胰腺癌治疗的新靶点。
