Open AccessALKBH 2, a novel A lk B homologue, contributes to human bladder cancer progression by regulating MUC 1 expression
Author(s) -
Fujii Tomomi,
Shimada Keiji,
Anai Satoshi,
Fujimoto Kiyohide,
Konishi Noboru
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.12089
Subject(s) - gene knockdown , cancer research , urothelium , urothelial cell , biology , vimentin , bladder cancer , tumor progression , transfection , cancer , gene silencing , epithelial–mesenchymal transition , cell growth , small interfering rna , cancer cell , cell culture , immunohistochemistry , metastasis , immunology , endocrinology , gene , urinary system , biochemistry , genetics
The ALKBH family of proteins are highly expressed in various types of human cancer where they are involved in tumor growth and progression. However, multiple isoforms of ALKBH exist and the effect of individual isoforms on the development of urinary bladder cancer is unknown, particularly the molecular mechanisms involved in the progression from a noninvasive to invasive phenotype. We examined the role and function of ALKBH 2 in human bladder cancer development in vitro and provide the first report that suppression of ALKBH 2 in a human urothelial carcinoma cell line, KU 7, reduces the expression of the transmembrane mucin protein, MUC 1, and induces G 1 cell cycle arrest. Moreover, reduction of ALKBH 2 suppressed epithelial to mesenchymal transition ( EMT ) via increasing E‐cadherin and decreasing vimentin expression. Transfection of MUC 1 si RNA inhibited cell proliferation and EMT to the same extent as ALKBH 2 gene silencing in vitro . ALKBH 2 knockdown significantly suppressed MUC 1 expression and tumor volume of bladder cancers in vivo as assessed in an orthotopic mouse model using ALKBH 2 sh RNA transfected KU 7 cells. Immunohistochemical examination showed high expression levels of ALKBH 2 in human urothelial carcinoma samples, especially in high‐grade, superficially and deeply invasive carcinomas (pT(1) and >pT(2)), and in carcinoma in situ but not in normal urothelium. This study demonstrates that ALKBH 2 is an upstream molecule of the oncoprotein, MUC 1, and regulates cell cycle and EMT , resulting in progression of urothelial carcinomas.