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Arsenic Trioxide Inhibits CXCR4-Mediated Metastasis by Interfering miR-520h/PP2A/NF-κB Signaling in Cervical Cancer

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

Abstract

Background

Arsenic apparently affects numerous intracellular signal transduction pathways and causes many alterations leading to apoptosis and differentiation in malignant cells. We and others have demonstrated that arsenic inhibits the metastatic capacity of cancer cells. Here we present additional mechanistic studies to elucidate the potential of arsenic as a promising therapeutic inhibitor of metastasis.

Methods

The effects of arsenic trioxide (ATO) on human cervical cancer cell lines migration and invasion were observed by transwell assays. In experimental metastasis assays, cancer cells were injected into tail veins of severe combined immunodeficient mice for modeling metastasis. The mechanisms involved in ATO regulation of CXCR4 were analyzed by immunoblot, real-time polymerase chain reaction, and luciferase reporter assays. Immunohistochemistry was utilized to identify PP2A/C and CXCR4 protein expressions in human cervical cancer tissues.

Results

ATO inhibited CXCR4-mediated cervical cancer cell invasion in vitro and distant metastasis in vivo. We determined that ATO modulates the pivotal nuclear factor-kappa B (NF-κB)/CXCR4 signaling pathway that contributes to cancer metastasis. Substantiating our findings, we demonstrated that ATO activates PP2A/C activity by downregulating miR-520h, which results in IKK inactivation, IκB-dephosphorylation, NF-κB inactivation, and, subsequently, a reduction in CXCR4 expression. Furthermore, PP2A/C was reduced during cervical carcinogenesis, and the loss of PP2A/C expression was closely associated with the nodal status of cervical cancer patients.

Conclusions

Our results indicate a functional link between ATO-mediated PP2A/C regulation, CXCR4 expression, and tumor-suppressing ability. This information will be critical in realizing the potential for synergy between ATO and other anti-cancer agents, thus providing enhanced benefit in cancer therapy.

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Acknowledgment

This work was supported by grants from the Department of Health, Executive Yuan, Taiwan (CCMP94-RD-020) and the National Taiwan University Medical College and China Medical University (97F008-109) to Lin-Hung Wei; National Science Council grant NSC 96-2320-B-004-MY2, a Taiwan Merit Scholarship TMS-094-2-B-023 from the National Science Council of Taiwan, National Health Research Institutes grant from Taiwan (NHRI-EX97-9712BC), grants from the Department of Health, Executive Yuan, Taiwan (DOH97-TD-G-111-024), and the National Science Council, Taiwan (NSC 102-2314-B-039-200, NSC 102-2314-B-038-028-MY3, NSC 101-2320-B-400-016-MY3); grants from the Ministry of Health and Welfare, Taiwan (DOH 102-TD-C-111-004), the National Health Research Institutes, Taiwan (CA-102-PP-41, CA-103-PP-35), the China Medical University Hospital (DMR-101-014), and the China Medical University (CMU99-TC-22, CMU100-S-22).

Disclosure

No potential conflicts of interest were disclosed.

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Authors and Affiliations

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

    Yi-Wen Chang PhD

  2. Genomics Research Center, Academia Sinica, Nankang, Taipei, Taiwan

    Yi-Wen Chang PhD & Michael Hsiao PhD

  3. National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan

    Yi-Wen Chang PhD, Ching-Feng Chiu PhD, Chih-Chen Hong PhD, Ching-Chia Cheng MS & Jen-Liang Su PhD

  4. Department of Obstetrics & Gynecology, National Taiwan University Hospital, Taipei, Taiwan

    Min-Wei Chen PhD, Chi-An Chen MD & Lin-Hung Wei MD, PhD

  5. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan

    Lin-Hung Wei MD, PhD

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

    Jen-Liang Su PhD

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

    Jen-Liang Su PhD

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

    Jen-Liang Su PhD

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  1. Yi-Wen Chang PhD
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  2. Min-Wei Chen PhD
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  8. Lin-Hung Wei MD, PhD
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Corresponding authors

Correspondence to Michael Hsiao PhD, Lin-Hung Wei MD, PhD or Jen-Liang Su PhD.

Additional information

Yi-Wen Chang and Min-Wei Chen have contributed equally to this work.

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Chang, YW., Chen, MW., Chiu, CF. et al. Arsenic Trioxide Inhibits CXCR4-Mediated Metastasis by Interfering miR-520h/PP2A/NF-κB Signaling in Cervical Cancer. Ann Surg Oncol 21 (Suppl 4), 687–695 (2014). https://doi.org/10.1245/s10434-014-3812-5

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  • DOI: https://doi.org/10.1245/s10434-014-3812-5

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