title: The sensitivity of gastric cancer to trastuzumab is regulated by the miR-223/FBXW7 pathway.
abstract: A recent large-scale phase III study (the ToGA trial) demonstrated the significant efficacy of trastuzumab combined with chemotherapy in patients with HER2-positive gastric cancer. Although trastuzumab has become a key drug in cancer treatment, the resistance of breast cancer to trastuzumab is a major problem in clinical practice. However, it is unclear whether similar mechanisms of trastuzumab resistance are involved in gastric cancer (GC). The aim of the current study was to identify a novel micro-RNA (miR)/gene pathway that regulates the sensitivity of HER2-positive GC cells to trastuzumab. We focused on F-box and WD repeat domain-containing 7 (FBXW7), which is one of the major causes of drug resistance. We also identified miR-223, which can regulate FBXW7, using miR quantitative reverse transcription-PCR array analysis using by resistance cell line, which we established. Overexpression of miR-223 decreased FBXW7 expression and the sensitivity of GC cells to trastuzumab, while suppression of miR-223 restored FBXW7 expression and the sensitivity of GC cells to trastuzumab. Moreover, overexpression of miR-223 significantly suppressed trastuzumab-induced apoptosis. This study is the first report to reveal that the miR-223/FBXW7 pathway regulates the sensitivity of a HER2-positive GC cell line to trastuzumab through the modulation of apoptosis. These findings suggest that this pathway can be crucial for the mechanism of trastuzumab resistance in GC, which may lead to the development of individualized treatment in clinical practice.
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Japan, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-0811, Japan.
authors.forename: Kojiro
authors.initials: K
authors.lastname: Eto
authors.forename: Masaaki
authors.initials: M
authors.lastname: Iwatsuki
authors.forename: Masayuki
authors.initials: M
authors.lastname: Watanabe
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Ishimoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ida
authors.forename: Yu
authors.initials: Y
authors.lastname: Imamura
authors.forename: Shiro
authors.initials: S
authors.lastname: Iwagami
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Baba
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Sakamoto
authors.forename: Yuji
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Naoya
authors.initials: N
authors.lastname: Yoshida
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D044783:F-Box Proteins / Q000235:genetics*; D000073979:F-Box-WD Repeat-Containing Protein 7; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D034622:RNA Interference; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics*; D000068878:Trastuzumab; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D035683:MicroRNAs; D000068878:Trastuzumab; D044767:Ubiquitin-Protein Ligases; C513273:FBXW7 protein, human; C525067:MIR223, human