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Suppression of Dicer Increases Sensitivity to Gefitinib in Human Lung Cancer Cells

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

Abstract

Background

Accumulating evidence is revealing an important role of microRNA (miRNA) in tumor progression and chemotherapeutic resistance. Dicer is a cytoplasmic endoribonuclease type III crucial for production of mature miRNAs. The aberrant expression of Dicer has also been reportedly associated with clinical aggressiveness, prognosis, and patient survival in various cancer types. However, the molecular mechanisms of Dicer in acquired gefitinib resistance are still not clear.

Methods

In this study, we analyzed the protein level of Dicer between gefitinib-sensitive (PC9) and gefitinib-resistant (PC9/GR) non-small-cell lung cancer (NSCLC) cell lines by Western blot analysis. Silence and overexpression of the Dicer were performed to investigate the effects on gefitinib sensitivity, as assessed by (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay and sub-G1 assay of flow cytometry. To further explore the mechanism of chemoresistance, we examined whether Dicer knockdown led to modulating specific miRNAs and its miRNA target genes.

Results

Dicer expression was significantly increased in PC9/GR compared with PC9 cells. Knockdown of Dicer restores gefitinib sensitivity in resistant cells, and overexpression of Dicer enhances resistance to gefitinib in sensitive cells. Silencing of Dicer induces sensitivity to gefitinib in NSCLC cells through the downregulation of miR-30b/c and miR-221/222 to increase the protein level of caspase-3, resulting in an increase in gefitinib-induced apoptosis.

Conclusions

Dicer contributes to the resistance to gefitinib in lung cancer. These results indicate that Dicer may be a target for diagnosis and therapy of patients with resistance to gefitinib.

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Acknowledgment

This work was supported by grants from the National Science Council, Taiwan (NSC 102-2314-B-039-200, NSC 102-2314-B-038-028-MY3, and NSC 101-2320-B-400-016-MY3); from National Health Research Institutes, Taiwan (CA-102-PP-41 and CA-103-PP-35); from China Medical University Hospital (DMR-101-014); and from China Medical University (CMU99-TC-22 and CMU100-S-22).

Disclosure

No potential conflicts of interest were disclosed.

Author information

Authors and Affiliations

  1. National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan

    Jui-Chieh Chen PhD, Ching-Feng Chiu PhD, Yi-Wen Chang PhD, Chi-Feng Tseng MS & Jen-Liang Su PhD

  2. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Yen-Hao Su MD & Hsin-An Chen MD, PhD

  3. Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan

    Yen-Hao Su MD & Hsin-An Chen MD, PhD

  4. Graduate Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan

    Yi-Wen Chang PhD

  5. Genomics Research Center, Academia Sinica, Taipei, Taiwan

    Yi-Wen Chang PhD

  6. Divisions of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan

    Yang-Hao Yu MD, PhD

  7. Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan

    Yang-Hao Yu MD, PhD

  8. Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan

    Jen-Liang Su PhD

  9. Department of Biotechnology, Asia University, Taichung, Taiwan

    Jen-Liang Su PhD

  10. Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan

    Jen-Liang Su PhD

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  1. Jui-Chieh Chen PhD
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Corresponding author

Correspondence to Jen-Liang Su PhD.

Additional information

Jui-Chieh Chen and Yen-Hao Su contributed equally to this work.

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10434_2014_3673_MOESM3_ESM.tif

Oncomine analysis of Dicer expression related to sensitivity to gefitinib in lung cancer cell lines. Statistics from individual studies were also obtained from the Oncomine cancer database (http://www.oncomine.com/). The fold change and P-values are shown within box plot. (TIFF 1761 kb)

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Chen, JC., Su, YH., Chiu, CF. et al. Suppression of Dicer Increases Sensitivity to Gefitinib in Human Lung Cancer Cells. Ann Surg Oncol 21 (Suppl 4), 555–563 (2014). https://doi.org/10.1245/s10434-014-3673-y

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  • DOI: https://doi.org/10.1245/s10434-014-3673-y

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