Xue Chen, He Yuting, Hu Qiuyue, Yu Yan, Chen Xiaolong, Chen Jianan, Ren Fang, Li Juan, Ren Zhigang, Cui Guangying, Sun Ranran
Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China,
Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China,
Cancer Manag Res. 2018 Oct 30;10:5101-5112. doi: 10.2147/CMAR.S184381. eCollection 2018.
PIM1, a serine/threonine kinase, plays an essential role in tumorigenesis of multiple types of tumors. However, the expression pattern and functions of PIM1 in gallbladder cancer (GBC) remain largely unknown.
Immunohistochemistry, quantitative real-time PCR, and western blot analysis were performed to measure the expression of PIM1. Tissue microarray analysis was used to confirm the relationship between PIM1 expression and clinical outcomes of GBC patients. Finally, in vivo and in vitro functional studies were performed to detect the inhibition of PIM1 by RNAi or specific inhibitor in GBC cells.
We observed that PIM1 was dramatically overexpressed in GBC tissues, and its expression levels were positively related with clinical malignancies and a poor prognosis. Inhibition of PIM1 via RNAi or enzyme-specific inhibitor could suppress GBC cell proliferation, migration, and invasion both in vitro and vivo. Additionally, flow cytometry assays and cell cycle assays indicated that PIM1 inhibition promoted cell apoptosis and induced cell cycle arrest. Remarkably, inhibition of PIM1 could drive a metabolic shift from aerobic glycolysis to oxidative phosphorylation. We found that inhibition of PIM1 mechanistically reduced glucose consumption by regulating key molecules in aerobic glycolysis.
PIM1 may serve as an oncogene in GBC and be involved in the regulation of glycolysis. PIM1 is a promising therapeutic target for the treatment of human GBC.
丝氨酸/苏氨酸激酶PIM1在多种肿瘤的发生发展中起关键作用。然而，PIM1在胆囊癌（GBC）中的表达模式和功能仍不清楚。
采用免疫组织化学、定量实时PCR和蛋白质印迹分析检测PIM1的表达。利用组织芯片分析确定PIM1表达与GBC患者临床预后的关系。最后，进行体内和体外功能研究，以检测RNA干扰或特异性抑制剂对GBC细胞中PIM1的抑制作用。
我们观察到PIM1在GBC组织中显著过表达，其表达水平与临床恶性程度和不良预后呈正相关。通过RNA干扰或酶特异性抑制剂抑制PIM1可在体外和体内抑制GBC细胞的增殖、迁移和侵袭。此外，流式细胞术检测和细胞周期检测表明，抑制PIM1可促进细胞凋亡并诱导细胞周期阻滞。值得注意的是，抑制PIM1可促使代谢从有氧糖酵解转变为氧化磷酸化。我们发现抑制PIM1可通过调节有氧糖酵解中的关键分子来降低葡萄糖消耗。
PIM1可能作为GBC中的一种癌基因，参与糖酵解的调控。PIM1是治疗人类GBC的一个有前景的治疗靶点。
