BRCA/Fanconi anemia pathway implicates chemoresistance to gemcitabine in biliary tract cancer.
BRCA/Fanconi anemia pathway implicates chemoresistance to gemcitabine in biliary tract cancer.
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DOI：
10.1111/cas.12652
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发表时间：
2015-05
期刊：
影响因子：
5.7
通讯作者：
Mori M
中科院分区：
文献类型：
--
作者：
Nakashima S;Kobayashi S;Nagano H;Tomokuni A;Tomimaru Y;Asaoka T;Hama N;Wada H;Kawamoto K;Marubashi S;Eguchi H;Doki Y;Mori M
BRCA/Fanconi贫血（FA）通路在DNA双链断裂的修复中起关键作用。我们专注于这一途径，以澄清胆道癌（BTC）的耐药机制。我们还研究了可能参与化疗耐药性的CD 24 +/44+群体的变化，因为该群体可能包括癌症干细胞。我们使用三种BTC细胞系建立吉西他滨（GEM）耐药（GR）细胞，并评估BRCA/FA通路组分的表达、化疗耐药性以及BRCA/FA通路抑制对CD 24 +/44+群体的影响。对108例BTC手术切除标本进行FANCD 2和CD 24表达检测。GR细胞高表达BRCA/FA组分。BRCA/FA通路被GEM和顺铂（CDDP）暴露上调。使用siRNA和RAD 51抑制剂的抑制使GR细胞对GEM或CDDP敏感。在用GEM或CDDP和高表达BRCA/FA基因处理的GR和亲本BTC细胞中，CD 24 +/44+群体增加。FANCD 2与CD 24表达相关。GEM下BRCA/FA通路的抑制减少了MzChA 1-GR细胞中的CD 24 +/44+群体。因此，BRCA/FA途径的高表达是对GEM和/或CDDP的化学抗性的一种机制，并且与BTC中的CD 24 +/44+群体相关。
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 CD24+/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 CD24+/44+ population. FANCD2 and CD24 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 siRNA and RAD51 inhibitor sensitized GR cells to GEM or CDDP. The CD24+/44+ population was increased in GR and parent BTC cells treated with GEM or CDDP and highly expressed BRCA/FA genes. FANCD2 was related to CD24 expression in resected BTC specimens. Inhibition of the BRCA/FA pathway under GEM reduced the CD24+/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 CD24+/44+ population in BTC.
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