title: High expression of KIBRA in low atypical protein kinase C-expressing gastric cancer correlates with lymphatic invasion and poor prognosis.
abstract: Overexpression of atypical protein kinase Cλ/ι (aPKCλ/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 Hippo 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/aPKCλ/ι expression, as detected by immunohistochemistry, and clinicopathological outcomes in 164 gastric cancer patients using Fisher's exact test and Kaplan-Meier log-rank test. We found an intimate correlation between the expression level of KIBRA and aPKCλ/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 aPKCλ/ι-expressing gastric cancer correlated with disease-specific (P = 0.037) and relapse-free survival (P = 0.041) by Kaplan-Meier with log-rank test and higher lymphatic invasion cases by Fisher'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.
authors.affiliation: Department of Molecular Biology, Graduate School of Medical Science, Yokohama City University, Yokohama, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Yoshihama
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Izumisawa
authors.forename: Kazunori
authors.initials: K
authors.lastname: Akimoto
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Satoh
authors.forename: Taichi
authors.initials: T
authors.lastname: Mizushima
authors.forename: Kei
authors.initials: K
authors.lastname: Satoh
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Chida
authors.forename: Ryo
authors.initials: R
authors.lastname: Takagawa
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Akiyama
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ichikawa
authors.forename: Chikara
authors.initials: C
authors.lastname: Kunisaki
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Inayama
authors.forename: Itaru
authors.initials: I
authors.lastname: Endo
authors.forename: Yoji
authors.initials: Y
authors.lastname: Nagashima
authors.forename: Shigeo
authors.initials: S
authors.lastname: Ohno
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002450:Cell Communication / Q000235:genetics; D016764:Cell Polarity / Q000187:drug effects; D002478:Cells, Cultured; D018572:Disease-Free Survival; D004285:Dogs; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D011493:Protein Kinase C / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D013274:Stomach Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D019108:Tight Junctions / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; C513637:WWC1 protein, human; C115015:PKC-3 protein; D011493:Protein Kinase C