Open AccessBRCA /Fanconi anemia pathway implicates chemoresistance to gemcitabine in biliary tract cancer
Author(s) -
Nakashima Shinsuke,
Kobayashi Shogo,
Nagano Hiroaki,
Tomokuni Akira,
Tomimaru Yoshito,
Asaoka Tadafumi,
Hama Naoki,
Wada Hiroshi,
Kawamoto Koichi,
Marubashi Shigeru,
Eguchi Hidetoshi,
Doki Yuichiro,
Mori Masaki
Publication year - 2015
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.12652
Subject(s) - gemcitabine , biliary tract cancer , fanconi anemia , medicine , cancer research , cancer , biliary tract , oncology , biology , genetics , gene , dna repair
The BRCA /Fanconi anemia ( FA ) pathway plays a key role in the repair of DNA double strand breaks. We focused on this pathway to clarify chemoresistance mechanisms in biliary tract cancer ( BTC ). We also investigated changes in the CD 24 + /44 + population that may be involved in chemoresistance, as this population likely includes cancer stem cells. We used three BTC cell lines to establish gemcitabine ( GEM )‐resistant ( GR ) cells and evaluated the expression of BRCA / FA pathway components, chemoresistance, and the effect of BRCA / FA pathway inhibition on the CD 24 + /44 + population. FANCD 2 and CD 24 expression were evaluated in 108 resected BTC specimens. GR cells highly expressed the BRCA / FA components. The BRCA / FA pathway was upregulated by GEM and cisplatin ( CDDP ) exposure. Inhibition using si RNA and RAD 51 inhibitor sensitized GR cells to GEM or CDDP . The CD 24 + /44 + population was increased in GR and parent BTC cells treated with GEM or CDDP and highly expressed BRCA / FA genes. FANCD 2 was related to CD 24 expression in resected BTC specimens. Inhibition of the BRCA / FA pathway under GEM reduced the CD 24 + /44 + population in MzChA1‐ GR cells. Thus, high expression of the BRCA / FA pathway is one mechanism of chemoresistance against GEM and/or CDDP and is related to the CD 24 + /44 + population in BTC .