Abstract
In hepatocellular carcinomas (HCCs), the role of the cell surface protein V-set and immunoglobulin domain containing 1 (VSIG1), which is known as a specific marker of the gastric mucosa and testis, has not yet been determined. We examined VSIG1 immunohistochemical (IHC) expression in 105 consecutive samples provided by HCC patients, along with the IHC expression of three of the biomarkers known to be involved in the epithelial–mesenchymal transition (EMT): vimentin (VIM), and E- and N-cadherin (encoded by CDH1 and CDH2 genes). IHC subcellular localization of thyroid transcription factor 1 (TTF1), in which nuclear-to-cytoplasmic translocation is known to cause a lineage shift from lung to gastric-type adenocarcinoma, was also checked. The obtained data were validated using the miRNET program. In the examined HCC samples, VSIG1 expression was observed in the cytoplasm of normal hepatocytes and downregulated in 47 of the 105 HCCs (44.76%). In 29 cases (27.62%), VSIG1 was co-expressed with cytoplasmic TTF1. VSIG1 expression was positively correlated with both E-cadherin and N-cadherin and negatively correlated with VIM (p < 0.0001). The VSIG1+/E-cadherin+/N-cadherin-/VIM phenotype was seen in 13 cases (12.4%) and was characteristic of well-differentiated (G1/2) carcinomas diagnosed in pT1/2 stages. Like pulmonary carcinomas, simultaneous cytoplasmic positivity of HCC cells for VSIG1 and TTF1 may be a potential indicator of a lineage shift from conventional to gastric-type HCC. The E-cadherin/VSIG1 complex can help suppress tumor growth by limiting HCC dedifferentiation. The miRNET-based interaction between VSIG1/VIM/CDH1/CDH2 genes might be interconnected by miR-200b-3p, a central regulator of EMT which also targets VIM and VSIG1.
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Acknowledgements
We thank the colleagues from the Department of Pathology of Semmelweis University for allowing us to use the paraffin blocks from transplanted cases. The English proofreading was done by Cambridge Proofreading LLC.
Funding
Japanese MEXT S01, JSPS KAKENHI Grant Numbers JP22659072, JP24659161, JP26670187, JP16K15256, AMED Grant Numbers JP19ck0106264, JP20ck0106545, and Smoking Research Foundation.
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GS designed the study, participated in the immunoassay and statistical database interpretation, and wrote the manuscript; SH revised the paper and gave scientific approval; SJ performed the statistical assessment and design of the survival curves; SR contributed to data collection and literature review; BC performed the bioinformatic analysis and checked the UALCAN online database and gene network; KL supervised patient follow-up and performed liver transplantation; FD participated in the collection and interpretation of clinical data; JI contributed to interpretation of histopathological and immunohistochemical data, supervised the study design, and approved the final version of the manuscript. The two authors (GS and SJ) contributed equally to the paper.
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The present study was conducted after approval obtained from the ethics committees of the George Emil Palade University of Medicine, Pharmacy, Sciences and Technology located in Targu Mures, Romania, and of Semmelweis University in Budapest, Hungary.
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Supplementary file 1: Figure S1. The expression level of the main EMT genes in HCC, generated using the UALCAN online program.
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Supplementary file 2: Figure S2. Overall survival subgroup analysis of key EMT signaling genes for HCC patients, according to high or low expression level, generated using UALCAN.
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Gurzu, S., Sugimura, H., Szederjesi, J. et al. Interaction between cadherins, vimentin, and V-set and immunoglobulin domain containing 1 in gastric-type hepatocellular carcinoma. Histochem Cell Biol 156, 377–390 (2021). https://doi.org/10.1007/s00418-021-02006-8
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DOI: https://doi.org/10.1007/s00418-021-02006-8