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Cache Domain Containing 1 Is a Novel Marker of Non-Alcoholic Steatohepatitis-Associated Hepatocarcinogenesis

Department of Molecular Pathology, Graduate School of Medicine, Osaka City University, Abeno-ku 1-4-3 Asahi-machi, Osaka 545-8585, Japan
Department of Biochemistry, Faculty of Medicine, Chiang Mai University, 110 Inthawarorot Rd., Sri Phum, Muang, Chiang Mai 50200, Thailand
Author to whom correspondence should be addressed.
Academic Editor: Yoshitaka Hippo
Cancers 2021, 13(6), 1216;
Received: 29 January 2021 / Revised: 25 February 2021 / Accepted: 3 March 2021 / Published: 10 March 2021
(This article belongs to the Special Issue Carcinogenesis Model)
The aim of the present study was to discover novel early molecular biomarkers of liver neoplasms which arise in non-alcoholic steatohepatitis (NASH) Stelic Animal Model (STAM) mice. Significant increase of lipid deposits, hepatocyte ballooning, fibrosis, and incidences and multiplicities of hepatocellular adenomas and carcinomas were detected in the livers of 18-week-old STAM mice. From the results of proteome analysis of STAM mice hepatocellular carcinomas, significant elevation of a novel protein, cache domain-containing 1 (CACHD1) was found. Furthermore, we observed CACHD1-positive foci in STAM mice livers, which number, area, and cell proliferation index within the foci were significantly elevated. Results of immunohistochemical and in vitro functional analysis indicated that CACHD1 may become a useful early biomarker and potential molecular target in NASH-associated hepatocarcinogenesis, which is involved in control of cell proliferation, autophagy and apoptosis.
In the present study, potential molecular biomarkers of NASH hepatocarcinogenesis were investigated using the STAM mice NASH model, characterized by impaired insulin secretion and development of insulin resistance. In this model, 2-days-old C57BL/6N mice were subjected to a single subcutaneous (s.c.) injection of 200 μg streptozotocin (STZ) to induce diabetes mellitus (DM). Four weeks later, mice were administered high-fat diet (HFD) HFD-60 for 14 weeks (STAM group), or fed control diet (STZ group). Eighteen-week-old mice were euthanized to allow macroscopic, microscopic, histopathological, immunohistochemical and proteome analyses. The administration of HFD to STZ-treated mice induced significant fat accumulation and fibrosis development in the liver, which progressed to NASH, and rise of hepatocellular adenomas (HCAs) and carcinomas (HCCs). In 18-week-old animals, a significant increase in the incidence and multiplicity of HCAs and HCCs was found. On the basis of results of proteome analysis of STAM mice HCCs, a novel highly elevated protein in HCCs, cache domain-containing 1 (CACHD1), was chosen as a potential NASH-HCC biomarker candidate. Immunohistochemical assessment demonstrated that STAM mice liver basophilic, eosinophilic and mixed-type altered foci, HCAs and HCCs were strongly positive for CACHD1. The number and area of CACHD1-positive foci, and cell proliferation index in the area of foci in mice of the STAM group were significantly increased compared to that of STZ group. In vitro siRNA knockdown of CACHD1 in human Huh7 and HepG2 liver cancer cell lines resulted in significant inhibition of cell survival and proliferation. Analysis of the proteome of knockdown cells indicated that apoptosis and autophagy processes could be activated. From these results, CACHD1 is an early NASH-associated biomarker of liver preneoplastic and neoplastic lesions, and a potential target protein in DM/NASH-associated hepatocarcinogenesis. View Full-Text
Keywords: CACHD1; hepatocarcinogenesis; NASH; HCC; STAM mice CACHD1; hepatocarcinogenesis; NASH; HCC; STAM mice
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MDPI and ACS Style

Kakehashi, A.; Chariyakornkul, A.; Suzuki, S.; Khuanphram, N.; Tatsumi, K.; Yamano, S.; Fujioka, M.; Gi, M.; Wongpoomchai, R.; Wanibuchi, H. Cache Domain Containing 1 Is a Novel Marker of Non-Alcoholic Steatohepatitis-Associated Hepatocarcinogenesis. Cancers 2021, 13, 1216.

AMA Style

Kakehashi A, Chariyakornkul A, Suzuki S, Khuanphram N, Tatsumi K, Yamano S, Fujioka M, Gi M, Wongpoomchai R, Wanibuchi H. Cache Domain Containing 1 Is a Novel Marker of Non-Alcoholic Steatohepatitis-Associated Hepatocarcinogenesis. Cancers. 2021; 13(6):1216.

Chicago/Turabian Style

Kakehashi, Anna, Arpamas Chariyakornkul, Shugo Suzuki, Napaporn Khuanphram, Kumiko Tatsumi, Shotaro Yamano, Masaki Fujioka, Min Gi, Rawiwan Wongpoomchai, and Hideki Wanibuchi. 2021. "Cache Domain Containing 1 Is a Novel Marker of Non-Alcoholic Steatohepatitis-Associated Hepatocarcinogenesis" Cancers 13, no. 6: 1216.

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