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Cell Mol Gastroenterol Hepatol. 2018 Sep 11;7(1):115-134. doi: 10.1016/j.jcmgh.2018.08.008. eCollection 2019.

Dipeptidyl Peptidase 4 Inhibitors Reduce Hepatocellular Carcinoma by Activating Lymphocyte Chemotaxis in Mice.

Author information

1
Department of Hepatology and Gastroenterology, Kawasaki Medical School, Kurashiki, Japan.
2
Department of Biochemistry, Kawasaki Medical School, Kurashiki, Japan.
3
Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
4
Department of Internal Medicine I, Kawasaki Medical School General Medical Center, Okayama, Japan.
5
Pharmaceutical Research Laboratories, Sanwa Kagaku Kenkyusho Co, Ltd, Mie, Japan.
6
Department of Hepatology and Gastroenterology, Kawasaki Medical School, Kurashiki, Japan. Electronic address: khino@med.kawasaki-m.ac.jp.

Abstract

Background & Aims:

CD26, a multifunctional transmembrane glycoprotein, is expressed in various cancers and functions as dipeptidyl peptidase 4 (DPP4). We investigated whether CD26 expression is associated with hepatocellular carcinoma (HCC) progression and whether DPP4 inhibitors exert antitumor effects against HCC.

Methods:

CD26 expression was examined in 41 surgically resected HCC specimens. The effects of DPP4 inhibitors on HCC were examined by using HCC cell lines (Huh-7 and Li-7), xenograft tumors in nude mice, and a nonalcoholic steatohepatitis-related HCC mouse model.

Results:

CD26 expression in HCC specimens was associated with increased serum DPP4 activity, as well as a more advanced stage, less tumor immunity, and poorer prognosis in HCC patients. The HCC cell lines and xenograft tumors exhibited CD26 expression and DPP4 activity. The DPP4 inhibitors did not exhibit antitumor effects in vitro, but natural killer (NK) and/or T-cell tumor accumulation suppressed growth of xenograft tumor and HCC in vivo. The antitumor effects of DPP4 inhibitors were abolished by the depletion of NK cells or the neutralization of CXCR3, a chemokine receptor on NK cells. EZ-TAXIScan, an optical horizontal chemotaxis apparatus, identified enhanced NK and T-cell chemotaxis by DPP4 inhibitors ex vivo in the presence of Huh-7 cells and the chemokine CXCL10, which binds to CXCR3. The DPP4 inhibitors prevented the biologically active form of CXCL10 from being truncated by Huh-7 cell DPP4 activity. DPP4 inhibitors also suppressed tumor angiogenesis.

Conclusions:

These results provide a rationale for verifying whether DPP4 inhibitors clinically inhibit the progression of HCC or augment the antitumor effects of molecular-targeting drugs or immunotherapies against HCC.

KEYWORDS:

CCK-8, Cell Counting Kit 8; CD26; CXCL10; DM, diabetes mellitus; DPP4, dipeptidyl peptidase 4; FBS, fetal bovine serum; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HPLC, high-performance liquid chromatography; IC50, inhibitory concentration of 50%; Ig, immunoglobulin; LDH, lactate dehydrogenase; MICA, MHC class I polypeptide-related sequence A; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NK Cell; NK, natural killer; PBMC, peripheral blood mononuclear cell; PBS, phosphate-buffered saline; PTH, phenylthiohydantoin; SDS-PAGE, sodium dodecyl sulfate–polyacrylamide gel electrophoresis; T Cell; TAXIScan; Tumor Immunity; anti-ASGM, anti-asialo GM1 antisera

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