BRCA/Fanconi anemia pathway implicates chemoresistance to gemcitabine in biliary tract cancer.

Abstract

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.

• Authors: Shinsuke Nakashima, Shogo Kobayashi, Hiroaki Nagano, Akira Tomokuni, Yoshito Tomimaru, Tadafumi Asaoka, Naoki Hama, Hiroshi Wada, Koichi Kawamoto, Shigeru Marubashi, Hidetoshi Eguchi, Yuichiro Doki, Masaki Mori
• Journal: Cancer science (Cancer Sci) Vol. 106 Issue 5 Pg. 584-91 (May 2015) ISSN: 1349-7006 [Electronic] England
• PMID: 25736055 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Chemical References

• AC133 Antigen
• Antigens, CD
• Antimetabolites, Antineoplastic
• BRCA2 Protein
• BRCA2 protein, human
• CD24 Antigen
• CD24 protein, human
• CD44 protein, human
• FANCD2 protein, human
• Fanconi Anemia Complementation Group D2 Protein
• Glycoproteins
• Hyaluronan Receptors
• Peptides
• RNA, Small Interfering
• Deoxycytidine
• RAD51 protein, human
• Rad51 Recombinase
• Cisplatin
• Gemcitabine

Topics

• AC133 Antigen
• Aged
• Antigens, CD (metabolism)
• Antimetabolites, Antineoplastic (pharmacology)
• BRCA2 Protein (genetics, metabolism)
• Biliary Tract Neoplasms (drug therapy, genetics, metabolism)
• CD24 Antigen (metabolism)
• Cell Line, Tumor
• Cisplatin (pharmacology)
• Deoxycytidine (analogs & derivatives, pharmacology)
• Drug Resistance, Neoplasm (drug effects)
• Fanconi Anemia Complementation Group D2 Protein (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Glycoproteins (metabolism)
• Humans
• Hyaluronan Receptors (metabolism)
• Male
• Metabolic Networks and Pathways (drug effects)
• Middle Aged
• Peptides (metabolism)
• RNA, Small Interfering
• Rad51 Recombinase (genetics, metabolism)
• Gemcitabine