title: Redifferentiation and ZO-1 reexpression in liver-metastasized colorectal cancer: possible association with epidermal growth factor receptor-induced tyrosine phosphorylation of ZO-1.
abstract: Tubular gland structures of colorectal cancer (CRC) have been demonstrated to undergo dedifferentiation at the primary site, and then the gland structures are re-formed in the liver metastases. In this study, we examined the degree of differentiation of the gland structure of 48 cases of CRCs (24 cases with synchronous liver metastasis, 24 cases without metastasis) by the modified Gleason grading system. We also investigated the role of ZO-1, one of the tight junction proteins, in the morphological changes, i.e., dedifferentiation and redifferentiation, of CRCs at the primary site and liver metastases. Liver-metastasized CRCs (2.47+/-0.37) showed a lower score in the modified Gleason grading system than the corresponding primary tumors (3.28+/-0.36) did, i.e., the tumor cells had undergone redifferentiation at liver metastases. ZO-1 was expressed at the apical cell borders of normal colorectal epithelium, the luminal side of which has tubular gland structures. In comparison with this normal epithelium, the ZO-1 expression level was frequently reduced in primary CRC with liver metastasis (20.8%) and ZO-1 was reexpressed in liver metastasized cancers (79.2%). Furthermore, it was demonstrated by an immunoprecipitation-western blotting analysis on 5 cases of CRC with liver metastasis that ZO-1 bound to epidermal growth factor receptor (EGFR) irrespective of the phosphorylation status of EGFR, and that EGFR associated ZO-1 was highly tyrosine-phosphorylated only in the primary CRC, but was dephosphorylated in the liver-metastasized cancers. Our observations suggest that tyrosine phosphorylation of ZO-1 leads to down-regulation of the function of ZO-1 and dedifferentiation of the glands in CRCs, and these phenomena contribute to liver metastases, and redifferentiation of the glands occurs in the liver metastases.
authors.affiliation: Department of Surgical and Molecular Pathology, Dokkyo University School of Medicine, 880 Kita-kobayashi, Mibu, Shimotsuga, Tochigi 321-0293.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Kaihara
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kawamata
authors.forename: Johji
authors.initials: J
authors.lastname: Imura
authors.forename: Shigehiko
authors.initials: S
authors.lastname: Fujii
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Kitajima
authors.forename: Fumie
authors.initials: F
authors.lastname: Omotehara
authors.forename: Naomi
authors.initials: N
authors.lastname: Maeda
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nakamura
authors.forename: Takahiro
authors.initials: T
authors.lastname: Fujimori
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002454:Cell Differentiation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D066246:ErbB Receptors / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D009928:Organ Specificity; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D062826:Zonula Occludens-1 Protein
chemical_list: D008565:Membrane Proteins; D009363:Neoplasm Proteins; D010750:Phosphoproteins; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D066246:ErbB Receptors