DKK1‐CKAP4 signal axis promotes hepatocellular carcinoma aggressiveness

Kosuke Iguchi; Ryota Sada; Shinji Matsumoto; Hirokazu Kimura; Yoh Zen; Masayuki Akita; Hidetoshi Gon; Takumi Fukumoto; Akira Kikuchi

doi:10.1111/cas.15743

journal article Open Access Mar 09, 2023

DKK1‐CKAP4 signal axis promotes hepatocellular carcinoma aggressiveness

Kosuke Iguchi Ryota Sada Shinji Matsumoto

Hirokazu Kimura Yoh Zen

Masayuki Akita Hidetoshi Gon Takumi Fukumoto Akira Kikuchi

Cancer Science Vol. 114 No. 5 pp. 2063-2077 · Wiley

View at Publisher Save 10.1111/cas.15743

Abstract

AbstractHepatocellular carcinoma (HCC) is the most prevalent malignant liver neoplasm. Despite the advances in diagnosis and treatment, the prognosis of HCC patients remains poor. Cytoskeleton‐associated membrane protein 4 (CKAP4) is a receptor of the glycosylated secretory protein Dickkopf‐1 (DKK1), and the DKK1‐CKAP4 axis is activated in pancreatic, lung, and esophageal cancer cells. Expression of DKK1 and CKAP4 has been examined in HCC in independent studies that yielded contradictory results. In this study, the relationship between the DKK1‐CKAP4 axis and HCC was comprehensively examined. In 412 HCC cases, patients whose tumors were positive for both DKK1 and CKAP4 had a poor prognosis compared to those who were positive for only one of these markers or negative for both. Deletion of either DKK1 or CKAP4 inhibited HCC cell growth. In contrast to WT DKK1, DKK1 lacking the CKAP4 binding region did not rescue the phenotypes caused by DKK1 depletion, suggesting that binding of DKK1 to CKAP4 is required for HCC cell proliferation. Anti‐CKAP4 Ab inhibited HCC growth, and its antitumor effect was clearly enhanced when combined with lenvatinib, a multikinase inhibitor. These results indicate that simultaneous expression of DKK1 and CKAP4 is involved in the aggressiveness of HCC, and that the combination of anti‐CKAP4 Ab and other therapeutics including lenvatinib could represent a promising strategy for treating advanced HCC.

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Details

Published: Mar 09, 2023
Vol/Issue: 114(5)
Pages: 2063-2077
License: View

Authors

K

Kosuke Iguchi

Department of Molecular Biology and Biochemistry, Graduate School of Medicine Osaka University Suita Japan; Department of Surgery, Division of Hepato‐Biliary‐Pancreatic Surgery Kobe University Graduate School of Medicine Kobe Japan

R

Ryota Sada

Department of Molecular Biology and Biochemistry, Graduate School of Medicine Osaka University Suita Japan; Institute for Open and Transdisciplinary Research Initiatives (OTRI) Osaka University Suita Japan

S

Shinji Matsumoto

Department of Molecular Biology and Biochemistry, Graduate School of Medicine Osaka University Suita Japan; Institute for Open and Transdisciplinary Research Initiatives (OTRI) Osaka University Suita Japan

H

Hirokazu Kimura

Department of Molecular Biology and Biochemistry, Graduate School of Medicine Osaka University Suita Japan; The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology The Johns Hopkins University School of Medicine Baltimore Maryland USA

Y

Yoh Zen

Division of Diagnostic Pathology Kobe University Graduate School of Medicine Kobe Japan

M

Masayuki Akita

Department of Surgery, Division of Hepato‐Biliary‐Pancreatic Surgery Kobe University Graduate School of Medicine Kobe Japan

H

Hidetoshi Gon

Department of Surgery, Division of Hepato‐Biliary‐Pancreatic Surgery Kobe University Graduate School of Medicine Kobe Japan

T

Takumi Fukumoto

Department of Surgery, Division of Hepato‐Biliary‐Pancreatic Surgery Kobe University Graduate School of Medicine Kobe Japan

A

Akira Kikuchi

Department of Molecular Biology and Biochemistry, Graduate School of Medicine Osaka University Suita Japan; Center of Infectious Disease Education and Research (CiDER) Osaka University Suita Japan

Cite This Article

Kosuke Iguchi, Ryota Sada, Shinji Matsumoto, et al. (2023). DKK1‐CKAP4 signal axis promotes hepatocellular carcinoma aggressiveness. Cancer Science, 114(5), 2063-2077. https://doi.org/10.1111/cas.15743

DKK1‐CKAP4 signal axis promotes hepatocellular carcinoma aggressiveness

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