MicroRNA profiles involved in trifluridine resistance
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Kenta Tsunekuni1,2,3,*, Masamitsu Konno1,4,*, Ayumu Asai1,2,4, Jun Koseki2, Takashi Kobunai3, Teiji Takechi3, Yuichiro Doki1, Masaki Mori1 and Hideshi Ishii1,2
1Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan
2Department of Medical Data Science, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan
3Translational Research Laboratory, Taiho Pharmaceutical Co, Ltd, Tokushima City, Tokushima, 771-0194, Japan
4Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan
*These authors contributed equally to this work
Masaki Mori, email: firstname.lastname@example.org
Hideshi Ishii, email: email@example.com
Keywords: colorectal cancer, trifluridine, 5-fluorouracil, let-7d-5p, drug resistance
Received: March 28, 2017 Accepted: May 09, 2017 Published: May 23, 2017
Trifluridine (FTD) is a key component of the novel oral antitumor drug trifluridine/tipiracil, which is approved for the treatment of patients with metastatic colorectal cancer refractory to standard chemotherapies. A microRNA analysis of three colorectal cell lines was conducted to investigate causes of FTD resistance. Drug resistant sublines of DLD-1, HCT-116, and RKO cells were developed by continuous administration of increasing doses of FTD for 5 months. The let-7d-5p gene, which maps to chromosome 9q22.32, was downregulated in the FTD-resistant DLD-1 sublines. DLD-1 cells became more resistant to FTD when let-7d-5p was knocked down and more sensitive when let-7d-5p was overexpressed. The FTD-resistant sublines were not cross-resistant to 5-fluorouracil (5-FU); 5-FU sensitivity was affected only slightly when let-7d-5p was overexpressed or knocked down. These data indicate that let-7d-5p increases sensitivity of FTD but not 5-FU and that let-7d-5p is a potential clinical marker of treatment sensitivity.
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