Open AccessRedifferentiation and ZO‐1 reexpression in liver‐metastasized colorectal cancer: Possible association with epidermal growth factor receptor‐induced tyrosine phosphorylation of ZO‐1
Author(s) -
Kaihara Tsukasa,
Kawamata Hitoshi,
Imura Johji,
Fujii Shigehiko,
Kitajima Kazuaki,
Omotehara Fumie,
Maeda Naomi,
Nakamura Tetsuya,
Fujimori Takahiro
Publication year - 2003
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2003.tb01414.x
Subject(s) - metastasis , colorectal cancer , grading (engineering) , epidermal growth factor receptor , epidermal growth factor , phosphorylation , cancer research , primary tumor , pathology , medicine , biology , cancer , receptor , microbiology and biotechnology , ecology
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 me‐tastases. 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 ty‐rosine‐phosphorylated only in the primary CRC, but was dephos‐phorylated 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. (Cancer Sci 2003; 94: 166–172)