Unique Biological Activity and Potential Role of Monomeric Laminin-γ2 as a Novel Biomarker for Hepatocellular Carcinoma: A Review

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Abstract

Laminin (Ln)-332 consists of α3, β3, and γ2 chains, which mediate epithelial cell adhesion to the basement membrane. Ln-γ2, a component of Ln-332, is frequently expressed as a monomer in the invasion front of several types of malignant tissues without simultaneous expression of Ln-α3 and/or Ln-β3 chains. Moreover, monomeric Ln-γ2 induces tumor cell proliferation and migration in vitro. These unique biological activities indicate that monomeric Ln-γ2 could be a candidate biomarker for early cancer surveillance. However, the present immune method for monomeric Ln-γ2 detection can only predict its expression, since no antibody that specifically reacts with monomeric γ2, but not with heterotrimeric γ2 chain, is commercially available. We have, therefore, developed monoclonal antibodies to specifically detect monomeric Ln-γ2, and devised a highly sensitive method to measure serum monomeric Ln-γ2 levels using a fully automated chemiluminescent immunoassay (CLIA). We evaluated its diagnostic value in sera from patients with several digestive cancers, including hepatocellular carcinoma (HCC), and found serum monomeric Ln-γ2 to be a clinically available biomarker for HCC surveillance. The combination of monomeric Ln-γ2 and prothrombin induced by Vitamin K Absence II (PIVKA-II) may be more sensitive for clinical diagnosis of HCC than any currently used combination.

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Most cited references 49

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Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer.

Akihiro Fujimoto, Mayuko Furuta, Yasushi Totoki … (2016)

Liver cancer, which is most often associated with virus infection, is prevalent worldwide, and its underlying etiology and genomic structure are heterogeneous. Here we provide a whole-genome landscape of somatic alterations in 300 liver cancers from Japanese individuals. Our comprehensive analysis identified point mutations, structural variations (STVs), and virus integrations, in noncoding and coding regions. We discovered mutational signatures related to liver carcinogenesis and recurrently mutated coding and noncoding regions, such as long intergenic noncoding RNA genes (NEAT1 and MALAT1), promoters, CTCF-binding sites, and regulatory regions. STV analysis found a significant association with replication timing and identified known (CDKN2A, CCND1, APC, and TERT) and new (ASH1L, NCOR1, and MACROD2) cancer-related genes that were recurrently affected by STVs, leading to altered expression. These results emphasize the value of whole-genome sequencing analysis in discovering cancer driver mutations and understanding comprehensive molecular profiles of liver cancer, especially with regard to STVs and noncoding mutations.

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Randomized controlled trial of screening for hepatocellular carcinoma.

Bo-Heng Zhang, Bing-Hui Yang, Zhao-You Tang (2004)

Screening for hepatocellular carcinoma (HCC) has been conducted for over 20 years, but there is no conclusive evidence that screening may reduce HCC mortality. The aim of this study was to assess the effect of screening on HCC mortality in people at increased risk. This study included 18,816 people, aged 35-59 years with hepatitis B virus infection or a history of chronic hepatitis in urban Shanghai, China. Participants were randomly allocated to a screening (9,373) or control (9,443) group. Controls received no screening and continued to use health-care facilities. Screening group participants were invited to have an AFP test and ultrasonography examination every 6 months. Screening was stopped in December 1997; by that time screening group participants had been offered five to ten times. All participants were followed up until December 1998. The primary outcome measure was HCC mortality. The screened group completed 58.2 percent of the screening offered. When the screening group was compared to the control group, the number of HCC was 86 versus 67; subclinical HCC being 52 (60.5%) versus 0; small HCC 39 (45.3%) versus 0; resection achieved 40 (46.5%) versus 5 (7.5%); 1-, 3,-, and 5-year survival rate 65.9%, 52.6%, 46.4% versus 31.2%, 7.2%, 0, respectively. Thirty-two people died from HCC in the screened group versus 54 in the control group, and the HCC mortality rate was significantly lower in the screened group than in controls, being 83.2/100,000 and 131.5/100,000, respectively, with a mortality rate ratio of 0.63 (95%CI 0.41-0.98). Our finding indicated that biannual screening reduced HCC mortality by 37%.

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Surveillance programme of cirrhotic patients for early diagnosis and treatment of hepatocellular carcinoma: a cost effectiveness analysis.

G Zironi, M. Zanetti, L Gramantieri … (2001)

Hepatocellular carcinoma (HCC) is a major cause of death in cirrhotic patients. This neoplasm is associated with liver cirrhosis (LC) in more than 90% of cases. Early diagnosis and treatment of HCC are expected to improve survival of patients. To assess the cost effectiveness of a surveillance programme of patients with LC for the early diagnosis and treatment of HCC. A cohort of 313 Italian patients with LC were enrolled in the surveillance programme between March 1989 and November 1991. In the same period, 104 consecutive patients with incidentally detected HCC were referred to our centre and served as a control group. Surveillance was based on ultrasonography (US) and alpha fetoprotein (AFP) determinations repeated at six month intervals. Risk factors for HCC were assessed by multivariate analysis (Cox model). Outcome measures analysed were: (1) number and size of tumours; (2) eligibility for treatment; and (3) survival of patients. Economic issues were: (1) overall cost of surveillance programme; (2) cost per treatable HCC; and (3) cost per year of life saved (if any). Costs were assessed according to charges for procedures at our university hospital. Surveillance lasted a mean of 56 (31) months (range 6-100). During the follow up, 61 patients (19.5%) developed HCC (unifocal at US in 49 cases), with an incidence of 4.1% per year of follow up. AFP, Child-Pugh classes B and C, and male sex were detected as independent risk factors for developing HCC. Only 42 (68.9%) of 61 liver tumours were treated by surgical resection, orthotopic liver transplantation, or local therapy. The cumulative survival rate of the 61 patients with liver tumours detected in the surveillance programme was significantly longer than that of controls (p=0.02) and multivariate analysis showed an association between surveillance and survival. The overall cost of the surveillance programme was US$753 226, the cost per treatable HCC was US$17 934, and the cost for year of life saved was US$112 993. Our surveillance policy of patients with LC requires a large number of resources and offers little benefit in terms of patient survival. The decision whether to adopt a surveillance policy towards HCC should rely on the prevalence of the disease in the population and on the resources of a particular country.

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Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 08 January 2019

Publication date Collection: January 2019

Volume: 20

Issue: 1

Electronic Location Identifier: 226

Affiliations

[1 ]Division of Gastroenterology and Hepatology, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan; h2kiyokawa@ 123456marianna-u.ac.jp (H.K.); fitoh@ 123456marianna-u.ac.jp (F.I.)

[2 ]Division of Cancer Cell Research, Kanagawa Cancer Center Research Institute, Yokohama 241-8515, Japan; Masatoshi.Nakagawa@ 123456abbott.com

[3 ]Diagnostics Division, Abbott Japan Co., Ltd., Chiba 270-2214, Japan; Eisaku.Yoshida@ 123456abbott.com (E.Y.); Tohru.Yoshimura@ 123456abbott.com (T.Y.)

[4 ]Division of Cancer Cell Research, The Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; mseiki@ 123456ims.u-tokyo.ac.jp

[5 ]Faculty of Medicine, Institute of Medical, Pharmaceutical & Health Science, Kanazawa University, Takara-machi, Kanazawa 920-0934, Japan

Author notes

[* ]Correspondence: hyasuda@ 123456marianna-u.ac.jp (H.Y.); nkoshi-tky@ 123456umin.ac.jp (N.K.); Tel.: +81-44-977-8111 (H.Y.); +81-045-520-2222 (N.K.)

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Hiroshi Yasuda https://orcid.org/0000-0003-4547-5213

Hirofumi Kiyokawa https://orcid.org/0000-0002-7418-7977

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Publisher ID: ijms-20-00226

DOI: 10.3390/ijms20010226

PMC ID: 6337480

PubMed ID: 30626121

SO-VID: 9b44dec7-cd11-4134-8f4a-07a752104cd6

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Unique Biological Activity and Potential Role of Monomeric Laminin-γ2 as a Novel Biomarker for Hepatocellular Carcinoma: A Review

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Higher order chromatin architecture

Most cited references 49

Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer.

Randomized controlled trial of screening for hepatocellular carcinoma.

Surveillance programme of cirrhotic patients for early diagnosis and treatment of hepatocellular carcinoma: a cost effectiveness analysis.

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