CEACAM1 Long Cytoplasmic Domain Isoform is Associated with Invasion and Recurrence of Hepatocellular Carcinoma

Abstract

Background The two isoforms of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), 1 with a long cytoplasmic domain (CEACAM1-L) and 1 with a short (CEACAM1-S), are involved in different signaling pathways. β2-spectrin (β2SP) is an adaptor protein that plays critical roles in the proper control of Smad access to activate receptors involved in regulation of TGF-β signaling. In this study, we examined the association between CEACAM1 isoform balance and hepatocellular carcinoma (HCC) malignant potential and investigated the possibility of a molecular interaction between CEACAM1 and β2SP. Methods Immunohistochemical analysis was carried out with CEACAM1-L or CEACAM1-S antibodies on 154 HCC tissues to correlate with the factors of malignancy. Invasion assay was performed for the effect of CEACAM1 expression on HCC cell lines. Moreover, immunohistochemical analysis and immunoprecipitation analysis were performed to investigate the association between CEACAM1 isoform balance and β2SP. Results In immunohistochemical analysis, CEACAM1-L expression dominance was a risk factor for HCC recurrence (p = 0.04) and was significantly associated with a shorter survival compared with CEACAM1-S expression dominance. Invasion assay indicated that CEACAM1-4L-transfected HLF and PLC/PRF/5 cells showed significantly increased invasion (p<0.0001) and CEACAM1-4S-transfected HLF cells showed significantly decreased invasion. Immunohistochemical analysis of β2SP suggested that the HCCs with CEACAM1-L-dominant expression were more strongly stained with β2SP than the HCCs with CEACAM1-S-dominant expression (p = 0.013), and coprecipitation assays indicated that CEACAM1-L could bind to β2SP. Conclusions CEACAM1-L may enhance the HCC invasiveness through an interaction with β2SP and subsequent effects on TGF-β signaling.

Identification and validation of alternative splicing isoforms as novel biomarker candidates in hepatocellular carcinoma

“…However, research on the genome scale indicated that the different CEACAM1 isoforms had divergent roles during tumorigenesis. CEACAM1-L (CEACAM1 long cytoplasmic domain isoform) is a risk factor for HCC recurrence and its overexpression is involved in tumor cell invasion and metastasis (30). More specifically, in this study, we demonstrated that exon 7 of CEACAM1 was the critical hub of the functional differences between the CEACAM1 isoforms.…”

“…Patients with increased inclusion levels of CEACAM1 exon 7 in HCC samples had significantly shorter survival times. Exon 7 is located on the 3'terminal of the CEACAM1 transcript, although it does not encode the immunoglobulin-like domain, the inclusion or exclusion of which may influence the subcellular location of the protein, which could remodel the tumorigenicity of CEACAM1 isoforms (30)(31)(32).…”

CEACAM1 Is Associated With the Suppression of Natural Killer Cell Function in Patients With Chronic Hepatitis C

“…Based on these results, the elevated CEACAM1 levels observed in patients with CHC might be associated with impaired cytotoxicity of NK cells. A previous report used immunohistochemical analysis to reveal that liver CEACAM1 expression correlated with the progression of HCC . We examined serum CEACAM1 levels in patients with HCC (Supporting Tables and ).…”

“…A previous report used immunohistochemical analysis to reveal that liver CEACAM1 expression correlated with the progression of HCC. (15) We examined serum CEACAM1 levels in patients with HCC (Supporting Tables S1 and S2). The median serum level (100.8 ng/mL) in HCC patients was significantly higher than that in CHC patients (Fig.…”

“…CEACAM1 is associated with inflammation, angiogenesis, and immune response to cancer and infections . CEACAM1 expression in the liver is associated with disease progression of HCC . However, the role of CEACAM1 in CHC is not completely understood.…”