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The MicroRNA-21/PTEN Pathway Regulates the Sensitivity of HER2-Positive Gastric Cancer Cells to Trastuzumab

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

The ToGA trial demonstrated the significant efficacy of trastuzumab in addition to chemotherapy in patients with HER2-positive gastric cancer (GC). Although trastuzumab has become a key drug in breast cancer treatment, resistance to trastuzumab is a major problem in clinical practice. The aim of the current study was to identify the micro-RNA (miR)/gene pathway regulating the sensitivity of HER2-positive GC cells to trastuzumab.

Methods

Correlations between the expression levels of miR-21, PTEN, and p-AKT were analyzed by real-time PCR and Western blot test in HER2-positive GC cell lines. The effects of overexpression or suppression of miR-21 on the sensitivity of GC cells to trastuzumab were also analyzed in vitro.

Results

Overexpression of miR-21 down-regulated PTEN expression, increased AKT phosphorylation, and did not affect HER2 expression. Inversely, suppression of miR-21 increased PTEN expression and down-regulated AKT phosphorylation, but still did not affect HER2 expression. Overexpression of miR-21 decreased the sensitivity of GC cells to trastuzumab, while suppression of miR-21 expression restored the resistance of GC cells to trastuzumab. Overexpression of miR-21 significantly suppressed trastuzumab-induced apoptosis.

Conclusions

To our knowledge, this study was the first reveal the miR-21/PTEN pathway regulated the sensitivity of HER2-positive GC cell lines to trastuzumab through modulation apoptosis. These findings suggest that this pathway may be crucial to the mechanism of resistance to trastuzumab in GC, which may lead to the development of individualized treatment in clinical practice.

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Acknowledgment

We thank Mr. Miyake and Ms. Yokoyama for their technical assistance. This work was supported in part by the Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research (Grant 25462027).

Disclosure

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

    Kojiro Eto MD, Masaaki Iwatsuki MD, PhD, Masayuki Watanabe MD, PhD, Satoshi Ida MD, PhD, Takatsugu Ishimoto MD, PhD, Shiro Iwagami MD, PhD, Yoshifumi Baba MD, PhD, Yasuo Sakamoto MD, PhD, Yuji Miyamoto MD, PhD, Naoya Yoshida MD, PhD & Hideo Baba MD, PhD, FACS

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  1. Kojiro Eto MD
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  2. Masaaki Iwatsuki MD, PhD
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  3. Masayuki Watanabe MD, PhD
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  4. Satoshi Ida MD, PhD
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  5. Takatsugu Ishimoto MD, PhD
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  6. Shiro Iwagami MD, PhD
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  7. Yoshifumi Baba MD, PhD
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  8. Yasuo Sakamoto MD, PhD
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  11. Hideo Baba MD, PhD, FACS
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Corresponding author

Correspondence to Hideo Baba MD, PhD, FACS.

Electronic supplementary material

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10434_2013_3325_MOESM1_ESM.tif

Figure S1. (a) miR-21 expression levels by quantitative real-time PCR (qRT-PCR) in 3 HER2 positive gastric cancer cell lines (MKN45, NUGC4 and NCI-N87). (b) Western blotting for detection of PTEN and HER2 in NUGC4, MKN45 and NCI-N87 cells. Supplementary material 1 (TIFF 48 kb)

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Eto, K., Iwatsuki, M., Watanabe, M. et al. The MicroRNA-21/PTEN Pathway Regulates the Sensitivity of HER2-Positive Gastric Cancer Cells to Trastuzumab. Ann Surg Oncol 21, 343–350 (2014). https://doi.org/10.1245/s10434-013-3325-7

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  • DOI: https://doi.org/10.1245/s10434-013-3325-7

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