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

Yi Wen Chang, Min Wei Chen, Ching Feng Chiu, Chih Chen Hong, Ching Chia Cheng, Michael Hsiao, Chi An Chen, Lin Hung Wei, Jen Liang Su

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)687-695
Number of pages9
JournalAnnals of Surgical Oncology
Volume21
Issue number4
DOIs
Publication statusPublished - Jan 1 2014
Externally publishedYes

Fingerprint

NF-kappa B
Uterine Cervical Neoplasms
Neoplasm Metastasis
Arsenic
Neoplasms
SCID Mice
Protein C
arsenic trioxide
Luciferases
Cell Movement
Tail
Real-Time Polymerase Chain Reaction
Veins
Signal Transduction
Carcinogenesis
Down-Regulation
Immunohistochemistry
Apoptosis
Cell Line

ASJC Scopus subject areas

  • Surgery
  • Oncology

Cite this

Arsenic Trioxide Inhibits CXCR4-Mediated Metastasis by Interfering miR-520h/PP2A/NF-κB Signaling in Cervical Cancer. / Chang, Yi Wen; Chen, Min Wei; Chiu, Ching Feng; Hong, Chih Chen; Cheng, Ching Chia; Hsiao, Michael; Chen, Chi An; Wei, Lin Hung; Su, Jen Liang.

In: Annals of Surgical Oncology, Vol. 21, No. 4, 01.01.2014, p. 687-695.

Research output: Contribution to journalArticle

Chang, Yi Wen ; Chen, Min Wei ; Chiu, Ching Feng ; Hong, Chih Chen ; Cheng, Ching Chia ; Hsiao, Michael ; Chen, Chi An ; Wei, Lin Hung ; Su, Jen Liang. / Arsenic Trioxide Inhibits CXCR4-Mediated Metastasis by Interfering miR-520h/PP2A/NF-κB Signaling in Cervical Cancer. In: Annals of Surgical Oncology. 2014 ; Vol. 21, No. 4. pp. 687-695.
@article{fbb8a37394984180bc3208e85ef46cc0,
title = "Arsenic Trioxide Inhibits CXCR4-Mediated Metastasis by Interfering miR-520h/PP2A/NF-κB Signaling in Cervical Cancer",
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.",
author = "Chang, {Yi Wen} and Chen, {Min Wei} and Chiu, {Ching Feng} and Hong, {Chih Chen} and Cheng, {Ching Chia} and Michael Hsiao and Chen, {Chi An} and Wei, {Lin Hung} and Su, {Jen Liang}",
year = "2014",
month = "1",
day = "1",
doi = "10.1245/s10434-014-3812-5",
language = "English",
volume = "21",
pages = "687--695",
journal = "Annals of Surgical Oncology",
issn = "1068-9265",
publisher = "Springer New York",
number = "4",

}

TY - JOUR

T1 - Arsenic Trioxide Inhibits CXCR4-Mediated Metastasis by Interfering miR-520h/PP2A/NF-κB Signaling in Cervical Cancer

AU - Chang, Yi Wen

AU - Chen, Min Wei

AU - Chiu, Ching Feng

AU - Hong, Chih Chen

AU - Cheng, Ching Chia

AU - Hsiao, Michael

AU - Chen, Chi An

AU - Wei, Lin Hung

AU - Su, Jen Liang

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84939884194&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84939884194&partnerID=8YFLogxK

U2 - 10.1245/s10434-014-3812-5

DO - 10.1245/s10434-014-3812-5

M3 - Article

VL - 21

SP - 687

EP - 695

JO - Annals of Surgical Oncology

JF - Annals of Surgical Oncology

SN - 1068-9265

IS - 4

ER -