Open AccessHigh expression of KIBRA in low atypical protein kinase C‐expressing gastric cancer correlates with lymphatic invasion and poor prognosis
Author(s) -
Yoshihama Yohei,
Izumisawa Yusuke,
Akimoto Kazunori,
Satoh Yoshinori,
Mizushima Taichi,
Satoh Kei,
Chida Kazuhiro,
Takagawa Ryo,
Akiyama Hirotoshi,
Ichikawa Yasushi,
Kunisaki Chikara,
Inayama Yoshiaki,
Endo Itaru,
Nagashima Yoji,
Ohno Shigeo
Publication year - 2013
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/cas.12066
Subject(s) - cancer , cancer research , biology , regulator , lymphatic system , exact test , immunohistochemistry , kinase , apoptosis , medicine , immunology , gene , microbiology and biotechnology , genetics
Overexpression of atypical protein kinase Cλ/ι ( aPKC λ/ι), a regulator of cell polarity, is frequently associated with the poor prognoses of several cancers, including gastric cancer. Recent studies revealed a molecular link between aPKC and KIBRA , an upstream regulator of tumor suppressor H ippo pathway that regulates cell proliferation and apoptosis. Further, KIBRA directly inhibits the kinase activity of aPKC to regulate epithelial cell polarity. These observations suggest that the KIBRA ‐ aPKC connection plays a role in cancer progression; however, clinical significance of the correlation between these factors remains unclear. Here we examined the correlation between KIBRA / aPKC λ/ι expression, as detected by immunohistochemistry, and clinicopathological outcomes in 164 gastric cancer patients using F isher's exact test and K aplan– M eier log‐rank test. We found an intimate correlation between the expression level of KIBRA and aPKC λ/ι ( P = 0.012). Furthermore, high expression of KIBRA is correlated with lymphatic ( P = 0.046) and venous invasion ( P = 0.039). The expression level of KIBRA by itself did not correlate with the prognosis; however, high expression of KIBRA in low aPKC λ/ι‐expressing gastric cancer correlated with disease‐specific ( P = 0.037) and relapse‐free survival ( P = 0.041) by K aplan– M eier with log‐rank test and higher lymphatic invasion cases by F isher's exact test ( P = 0.042). Furthermore, overexpression of the aPKC ‐binding region of KIBRA disrupted tight junctions in epithelial cells. These results suggest that high expression of KIBRA in low aPKC ‐expressing cells causes massive loss of aPKC activity, leading to loss of polarity and invasiveness of gastric cancer cells.