title: Activated macrophages down-regulate expression of E-cadherin in hepatocellular carcinoma cells via NF-κB/Slug pathway.
abstract: Hepatocellular carcinomas are an aggressive malignancy mainly due to metastasis or postsurgical recurrence. Expression of E-cadherin is strongly reduced in Hepatocellular carcinoma (HCC) tissues, and its downregulation is connected to invasiveness and metastasis in hepatocellular carcinomas. The previous study showed that the supernatant from activated macrophages can downregulate the expression of E-cadherin in HCC cells. The partial known molecular mechanism is that tyrosine kinases c-Src- and EGFR phosphorylate β-catenin and E-cadherin leading to destabilization of E-cadherin/β-catenin complex. The aim of this study is to clarify other mechanism by which activated macrophages downregulate the expression of E-cadherin. We detect the expression of E-cadherin and macrophage infiltration in hepatocellular carcinoma tissues by double-staining immunohistochemistry and evaluate the relationship between macrophages and E-cadherin expression in hepatocellular carcinoma cells in vitro experiments. We found that reduced expression of E-cadherin was associated with macrophage infiltration along the border between the tumor nest and stroma in hepatocellular carcinoma tissues. Besides, protein expression of E-cadherin was significantly decreased in hepatocellular carcinoma cells co-cultured with macrophages derived from THP-1 cells. Consistently, mRNA expression of E-cadherin was also decreased in cancer cells co-cultured with THP-1-differentiated macrophages. Moreover, the downregulation of E-cadherin expression was companied by upregulation of Slug expression in cancer cells with conditional medium from THP-1-differentiated macrophage culture. The change in expression of E-cadherin and Slug was abrogated when NF-κB signaling pathway was blocked. All the findings suggested that macrophages contributed to the decreased expression of E-cadherin by NF-κB/Slug pathway in hepatocellular carcinomas.
authors.affiliation: Institute of Immunology, Shandong University School of Medicine, #44 Wenhua Xi Road, Jinan, 250012, China.
authors.forename: Xianteng
authors.initials: X
authors.lastname: Wang
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Guosheng
authors.initials: G
authors.lastname: Li
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Song
authors.forename: Shurong
authors.initials: S
authors.lastname: Wang
authors.forename: Faliang
authors.initials: F
authors.lastname: Zhu
authors.forename: Chun
authors.initials: C
authors.lastname: Guo
authors.forename: Lining
authors.initials: L
authors.lastname: Zhang
authors.forename: Yongyu
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D015536:Down-Regulation; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D000071250:Snail Family Transcription Factors; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D015820:Cadherins; D016328:NF-kappa B; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D051996:Transcription Factor RelA; D014157:Transcription Factors