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The sensitivity of gastric cancer to trastuzumab is regulated by the miR‐223/FBXW7 pathway

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 maj...

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Published in:International journal of cancer 2015-04, Vol.136 (7), p.1537-1545
Main Authors: Eto, Kojiro, Iwatsuki, Masaaki, Watanabe, Masayuki, Ishimoto, Takatsugu, Ida, Satoshi, Imamura, Yu, Iwagami, Shiro, Baba, Yoshifumi, Sakamoto, Yasuo, Miyamoto, Yuji, Yoshida, Naoya, Baba, Hideo
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container_issue 7
container_start_page 1537
container_title International journal of cancer
container_volume 136
creator Eto, Kojiro
Iwatsuki, Masaaki
Watanabe, Masayuki
Ishimoto, Takatsugu
Ida, Satoshi
Imamura, Yu
Iwagami, Shiro
Baba, Yoshifumi
Sakamoto, Yasuo
Miyamoto, Yuji
Yoshida, Naoya
Baba, Hideo
description 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. What's new? The monoclonal antibody trastuzumab is effective against HER2‐positive gastric cancers (GCs). However, as with breast cancer, many GCs develop resistance to this drug. In this study, the authors found that a microRNA called “miR‐233” interacts with a gene called “FBXW7” to regulate the sensitivity of HER2‐positive GC cells to trastuzumab, by altering apoptosis. These results suggest that the miR‐223/FBXW7 pathway may be a valuable therapeutic target to decrease resistance of GC to trastuzumab.
doi_str_mv 10.1002/ijc.29168
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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. What's new? The monoclonal antibody trastuzumab is effective against HER2‐positive gastric cancers (GCs). However, as with breast cancer, many GCs develop resistance to this drug. In this study, the authors found that a microRNA called “miR‐233” interacts with a gene called “FBXW7” to regulate the sensitivity of HER2‐positive GC cells to trastuzumab, by altering apoptosis. 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Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>International journal of cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Eto, Kojiro</au><au>Iwatsuki, Masaaki</au><au>Watanabe, Masayuki</au><au>Ishimoto, Takatsugu</au><au>Ida, Satoshi</au><au>Imamura, Yu</au><au>Iwagami, Shiro</au><au>Baba, Yoshifumi</au><au>Sakamoto, Yasuo</au><au>Miyamoto, Yuji</au><au>Yoshida, Naoya</au><au>Baba, Hideo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The sensitivity of gastric cancer to trastuzumab is regulated by the miR‐223/FBXW7 pathway</atitle><jtitle>International journal of cancer</jtitle><addtitle>Int J Cancer</addtitle><date>2015-04-01</date><risdate>2015</risdate><volume>136</volume><issue>7</issue><spage>1537</spage><epage>1545</epage><pages>1537-1545</pages><issn>0020-7136</issn><eissn>1097-0215</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><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. What's new? The monoclonal antibody trastuzumab is effective against HER2‐positive gastric cancers (GCs). However, as with breast cancer, many GCs develop resistance to this drug. In this study, the authors found that a microRNA called “miR‐233” interacts with a gene called “FBXW7” to regulate the sensitivity of HER2‐positive GC cells to trastuzumab, by altering apoptosis. These results suggest that the miR‐223/FBXW7 pathway may be a valuable therapeutic target to decrease resistance of GC to trastuzumab.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>25159729</pmid><doi>10.1002/ijc.29168</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record>
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subjects Antibodies, Monoclonal, Humanized - therapeutic use
Antineoplastic Agents - therapeutic use
Apoptosis
Apoptosis - drug effects
Apoptosis - genetics
Cancer
Cell Cycle Proteins - genetics
Cell Line, Tumor
Chemotherapy
Clinical medicine
Drug resistance
Drug Resistance, Neoplasm - genetics
F-Box Proteins - genetics
F-Box-WD Repeat-Containing Protein 7
Gastric cancer
Gene Expression
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Humans
Medical research
MicroRNAs - genetics
Monoclonal antibodies
RNA Interference
Stomach Neoplasms - drug therapy
Stomach Neoplasms - genetics
Trastuzumab
Ubiquitin-Protein Ligases - genetics
title The sensitivity of gastric cancer to trastuzumab is regulated by the miR‐223/FBXW7 pathway
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