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.
Highlights
Throughput Reaction time Narrow *1 Low High > > 2.5 h Wide *2 High min 30 min*1: Note that dynamic range of enzyme-linked immunosorbent assay (ELISA) is 15–4000 pg/mL *2, and chemiluminescent immunoassay (CLIA) is 10–20,000 pg/mL.6
We evaluated the serum monomeric Ln-γ2 level evaluated the serum monomeric Ln-γ2 level in serum specimens of patients with digestive cancers, in serum specimens of patients with digestive cancers, using CLIA, and found it to be a promising using CLIA, and found it to be a promising biomarker for early detection of hepatocellular carcinoma biomarker for early detection of hepatocellular carcinoma (HCC), as described below
Monomeric Ln-γ2 was identified as a biomarker, which is expressed on the cancer invasionMonomeric front
Summary
Extracellular matrix (ECM) proteins in basement membranes (BMs), such as collagen and laminin, play an important role in cell-cell adhesion to maintain epithelial structures in vitro [1]. Immobilization epithelial cellsthat ontomany the underlying [5] It has of been reported proteases BMs are involved in the processing of each Ln-332. Giannelli et al reported for the first time that proteolytic processing of the γ2 chain of Ln-332 stimulates mammary epithelial cell motility [7]. Ln-332 trimer is crucial to convert its static form to a migratory form, since proteolytic Ln-γ2 fragment, fragment, Domain III, acts as an EGF-receptor (EGFR) ligand and promotes cell motility [8,9]. Proteolytic processing of γ2 chain converts Ln-332 function from static adhesion functions (red arrows). 1B,C are modified from Koshikawa et al [8], and Shenk et al [9]
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