2. Academic Validation
  3. Inhibition of dipeptidyl peptidase IV prevents high fat diet-induced liver cancer angiogenesis by downregulating chemokine ligand 2

Inhibition of dipeptidyl peptidase IV prevents high fat diet-induced liver cancer angiogenesis by downregulating chemokine ligand 2

  • Cancer Lett. 2018 Apr 28;420:26-37. doi: 10.1016/j.canlet.2018.01.064.
Chen-Jie Qin 1,  Ling-Hao Zhao 2,  Xu Zhou 3,  Hui-Lu Zhang 4,  Wen Wen 3,  Liang Tang 3,  Min Zeng 3,  Ming-Da Wang 3,  Gong-Bo Fu 3,  Shuai Huang 5,  Wei-Jian Huang 3,  Yuan Yang 6,  Zhi-Jun Bao 7,  Wei-Ping Zhou 2,  Hong-Yang Wang 8,  He-Xin Yan 9
Affiliations

Affiliations

  • 1 International Cooperation Laboratory on Signal Transduction, Easten Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China; National Center for Liver Cancer Research, Shanghai 201805, China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital, Fudan University, Shanghai 200040, China.
  • 2 National Center for Liver Cancer Research, Shanghai 201805, China; The Third Department of Easten Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China.
  • 3 International Cooperation Laboratory on Signal Transduction, Easten Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China; National Center for Liver Cancer Research, Shanghai 201805, China.
  • 4 Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China.
  • 5 Department of Tumor Minimally Invasive Surgery, Reiji Hospital, Shanghai Jiaotong University, Shanghai 200127, China.
  • 6 The Third Department of Easten Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China.
  • 7 Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital, Fudan University, Shanghai 200040, China.
  • 8 International Cooperation Laboratory on Signal Transduction, Easten Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China; National Center for Liver Cancer Research, Shanghai 201805, China. Electronic address: [email protected].
  • 9 International Cooperation Laboratory on Signal Transduction, Easten Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China; National Center for Liver Cancer Research, Shanghai 201805, China. Electronic address: [email protected].
PMID: 29409972 DOI: 10.1016/j.canlet.2018.01.064
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.

Keywords

Angiogenesis; Chemokine ligand 2; Dipeptidyl peptidase 4; Hepatocellular carcinoma; Obesity.

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