Inhibition of dipeptidyl peptidase IV prevents high fat diet-induced liver cancer angiogenesis by downregulating chemokine ligand 2. (28th April 2018)

• Record Type: Journal Article
• Authors: Qin, Chen-Jie; Zhao, Ling-Hao; Zhou, Xu; Zhang, Hui-Lu; Wen, Wen; Tang, Liang; Zeng, Min; Wang, Ming-Da; Fu, Gong-Bo; Huang, Shuai; Huang, Wei-Jian; Yang, Yuan; Bao, Zhi-Jun; Zhou, Wei-Ping; Wang, Hong-Yang; Yan, He-Xin
• Is Part Of: Cancer letters. Volume 420(2018)
• Page Start: 26
• Page End: 37
• Publication Date: 2018-04-28
• Subjects: Dipeptidyl peptidase 4 -- Obesity -- Angiogenesis -- Chemokine ligand 2 -- Hepatocellular carcinoma; HCC hepatocellular carcinoma -- DPP4 dipeptidyl peptidase-4 -- CCL2 chemokine ligand-2 -- HMGB-1 high mobility group box-1 -- CXCL-10 chemokine ligand-10 -- NS normal saline -- Vil vildagliptin -- HFD high-fat diet -- LFD low-fat diet; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.01.064
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Obesity is a major risk factor for hepatocellular carcinoma (HCC) and is typically accompanied by higher levels of serum dipeptidyl peptidase 4 (DPP4). However, the role of DPP4 in obesity-promoted HCC is unclear. Here, we found that consumption of a high-fat diet (HFD) promoted HCC cell proliferation and metastasis and led to poor survival in a carcinogen-induced model of HCC in rats. Notably, genetic ablation of DPP4 or treatment with a DPP4 inhibitor (vildagliptin) prevented HFD-induced HCC. Moreover, HFD-induced DPP4 activity facilitated angiogenesis and cancer cell metastasis in vitro and in vivo, and vildagliptin prevented tumor progression by mediating the pro-angiogenic role of chemokine ligand 2 (CCL2). Loss of DPP4 effectively reversed HFD-induced CCL2 production and angiogenesis, indicating that the DPP4/CCL2/angiogenesis cascade had key roles in HFD-associated HCC progression. Furthermore, concomitant changes in serum DPP4 and CCL2 were observed in 210 patients with HCC, and high serum DPP4 activity was associated with poor clinical prognosis. These results revealed a link between obesity-related high serum DPP4 activity and HCC progression. Inhibition of DPP4 may represent a novel therapeutic intervention for patients with HCC. Highlights: Both genetic ablation and pharmacological inhibition of DPP4 prevented HFD-induced cancer vascularization and metastasis. Tumor promotion effect of DPP4 was mediated by CCL2. The concomitant changes of serum DPP4 and CCL2 were noted in liver cancer patients. High serum DPP4 activity was closely associated with poor clinical prognosis.