MicroRNA-34a regulates WNT/TCF7 signaling and inhibits bone metastasis in Ras-activated prostate cancer

Wei Yu Chen, Shih Yang Liu, Yung Sheng Chang, Juan Juan Yin, Hsiu Lien Yeh, Tarek H. Mouhieddine, Ola Hadadeh, Wassim Abou-Kheir, Yen Nien Liu

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Aberrant activation of Ras and WNT signaling are key events that have been shown to be up-regulated in prostate cancer that has metastasized to the bone. However, the regulatory mechanism of combinatorial Ras and WNT signaling in advanced prostate cancer is still unclear. TCF7, a WNT signaling-related gene, has been implicated as a critical factor in bone metastasis, and here we show that TCF7 is a direct target of miR-34a. In samples of prostate cancer patients, miR-34a levels are inversely correlated with TCF7 expression and a WNT dependent gene signature. Ectopic miR-34a expression inhibited bone metastasis and reduced cancer cell proliferation in a Ras-dependent xenograft model. We demonstrate that miR- 34a can directly interfere with the gene expression of the anti-proliferative BIRC5, by targeting BIRC5 3'UTR. Importantly, BIRC5 overexpression was sufficient to reconstitute anti-apoptotic signaling in cells expressing high levels of miR-34a. In prostate cancer patients, we found that BIRC5 levels were positively correlated with a Ras signaling signature expression. Our data show that the bone metastasis and anti-apoptotic effects found in Ras signaling-activated prostate cancer cells require miR-34a deficiency, which in turn aids in cell survival by activating the WNT and antiapoptotic signaling pathways thereby inducing TCF7 and BIRC5 expressions.

Original languageEnglish
Pages (from-to)441-457
Number of pages17
JournalOncotarget
Volume6
Issue number1
Publication statusPublished - 2015

Fingerprint

MicroRNAs
Prostatic Neoplasms
Neoplasm Metastasis
Bone and Bones
3' Untranslated Regions
Heterografts
Genes
Cell Survival
Cell Proliferation
Gene Expression
Neoplasms

Keywords

  • BIRC5
  • Bone metastasis
  • miR-34a
  • Prostate cancer
  • TCF7

ASJC Scopus subject areas

  • Oncology

Cite this

Chen, W. Y., Liu, S. Y., Chang, Y. S., Yin, J. J., Yeh, H. L., Mouhieddine, T. H., ... Liu, Y. N. (2015). MicroRNA-34a regulates WNT/TCF7 signaling and inhibits bone metastasis in Ras-activated prostate cancer. Oncotarget, 6(1), 441-457.

MicroRNA-34a regulates WNT/TCF7 signaling and inhibits bone metastasis in Ras-activated prostate cancer. / Chen, Wei Yu; Liu, Shih Yang; Chang, Yung Sheng; Yin, Juan Juan; Yeh, Hsiu Lien; Mouhieddine, Tarek H.; Hadadeh, Ola; Abou-Kheir, Wassim; Liu, Yen Nien.

In: Oncotarget, Vol. 6, No. 1, 2015, p. 441-457.

Research output: Contribution to journalArticle

Chen, WY, Liu, SY, Chang, YS, Yin, JJ, Yeh, HL, Mouhieddine, TH, Hadadeh, O, Abou-Kheir, W & Liu, YN 2015, 'MicroRNA-34a regulates WNT/TCF7 signaling and inhibits bone metastasis in Ras-activated prostate cancer', Oncotarget, vol. 6, no. 1, pp. 441-457.
Chen WY, Liu SY, Chang YS, Yin JJ, Yeh HL, Mouhieddine TH et al. MicroRNA-34a regulates WNT/TCF7 signaling and inhibits bone metastasis in Ras-activated prostate cancer. Oncotarget. 2015;6(1):441-457.
Chen, Wei Yu ; Liu, Shih Yang ; Chang, Yung Sheng ; Yin, Juan Juan ; Yeh, Hsiu Lien ; Mouhieddine, Tarek H. ; Hadadeh, Ola ; Abou-Kheir, Wassim ; Liu, Yen Nien. / MicroRNA-34a regulates WNT/TCF7 signaling and inhibits bone metastasis in Ras-activated prostate cancer. In: Oncotarget. 2015 ; Vol. 6, No. 1. pp. 441-457.
@article{a758a7cf5de2450c9eeafc75b39c54a7,
title = "MicroRNA-34a regulates WNT/TCF7 signaling and inhibits bone metastasis in Ras-activated prostate cancer",
abstract = "Aberrant activation of Ras and WNT signaling are key events that have been shown to be up-regulated in prostate cancer that has metastasized to the bone. However, the regulatory mechanism of combinatorial Ras and WNT signaling in advanced prostate cancer is still unclear. TCF7, a WNT signaling-related gene, has been implicated as a critical factor in bone metastasis, and here we show that TCF7 is a direct target of miR-34a. In samples of prostate cancer patients, miR-34a levels are inversely correlated with TCF7 expression and a WNT dependent gene signature. Ectopic miR-34a expression inhibited bone metastasis and reduced cancer cell proliferation in a Ras-dependent xenograft model. We demonstrate that miR- 34a can directly interfere with the gene expression of the anti-proliferative BIRC5, by targeting BIRC5 3'UTR. Importantly, BIRC5 overexpression was sufficient to reconstitute anti-apoptotic signaling in cells expressing high levels of miR-34a. In prostate cancer patients, we found that BIRC5 levels were positively correlated with a Ras signaling signature expression. Our data show that the bone metastasis and anti-apoptotic effects found in Ras signaling-activated prostate cancer cells require miR-34a deficiency, which in turn aids in cell survival by activating the WNT and antiapoptotic signaling pathways thereby inducing TCF7 and BIRC5 expressions.",
keywords = "BIRC5, Bone metastasis, miR-34a, Prostate cancer, TCF7",
author = "Chen, {Wei Yu} and Liu, {Shih Yang} and Chang, {Yung Sheng} and Yin, {Juan Juan} and Yeh, {Hsiu Lien} and Mouhieddine, {Tarek H.} and Ola Hadadeh and Wassim Abou-Kheir and Liu, {Yen Nien}",
year = "2015",
language = "English",
volume = "6",
pages = "441--457",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals LLC",
number = "1",

}

TY - JOUR

T1 - MicroRNA-34a regulates WNT/TCF7 signaling and inhibits bone metastasis in Ras-activated prostate cancer

AU - Chen, Wei Yu

AU - Liu, Shih Yang

AU - Chang, Yung Sheng

AU - Yin, Juan Juan

AU - Yeh, Hsiu Lien

AU - Mouhieddine, Tarek H.

AU - Hadadeh, Ola

AU - Abou-Kheir, Wassim

AU - Liu, Yen Nien

PY - 2015

Y1 - 2015

N2 - Aberrant activation of Ras and WNT signaling are key events that have been shown to be up-regulated in prostate cancer that has metastasized to the bone. However, the regulatory mechanism of combinatorial Ras and WNT signaling in advanced prostate cancer is still unclear. TCF7, a WNT signaling-related gene, has been implicated as a critical factor in bone metastasis, and here we show that TCF7 is a direct target of miR-34a. In samples of prostate cancer patients, miR-34a levels are inversely correlated with TCF7 expression and a WNT dependent gene signature. Ectopic miR-34a expression inhibited bone metastasis and reduced cancer cell proliferation in a Ras-dependent xenograft model. We demonstrate that miR- 34a can directly interfere with the gene expression of the anti-proliferative BIRC5, by targeting BIRC5 3'UTR. Importantly, BIRC5 overexpression was sufficient to reconstitute anti-apoptotic signaling in cells expressing high levels of miR-34a. In prostate cancer patients, we found that BIRC5 levels were positively correlated with a Ras signaling signature expression. Our data show that the bone metastasis and anti-apoptotic effects found in Ras signaling-activated prostate cancer cells require miR-34a deficiency, which in turn aids in cell survival by activating the WNT and antiapoptotic signaling pathways thereby inducing TCF7 and BIRC5 expressions.

AB - Aberrant activation of Ras and WNT signaling are key events that have been shown to be up-regulated in prostate cancer that has metastasized to the bone. However, the regulatory mechanism of combinatorial Ras and WNT signaling in advanced prostate cancer is still unclear. TCF7, a WNT signaling-related gene, has been implicated as a critical factor in bone metastasis, and here we show that TCF7 is a direct target of miR-34a. In samples of prostate cancer patients, miR-34a levels are inversely correlated with TCF7 expression and a WNT dependent gene signature. Ectopic miR-34a expression inhibited bone metastasis and reduced cancer cell proliferation in a Ras-dependent xenograft model. We demonstrate that miR- 34a can directly interfere with the gene expression of the anti-proliferative BIRC5, by targeting BIRC5 3'UTR. Importantly, BIRC5 overexpression was sufficient to reconstitute anti-apoptotic signaling in cells expressing high levels of miR-34a. In prostate cancer patients, we found that BIRC5 levels were positively correlated with a Ras signaling signature expression. Our data show that the bone metastasis and anti-apoptotic effects found in Ras signaling-activated prostate cancer cells require miR-34a deficiency, which in turn aids in cell survival by activating the WNT and antiapoptotic signaling pathways thereby inducing TCF7 and BIRC5 expressions.

KW - BIRC5

KW - Bone metastasis

KW - miR-34a

KW - Prostate cancer

KW - TCF7

UR - http://www.scopus.com/inward/record.url?scp=84921370750&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84921370750&partnerID=8YFLogxK

M3 - Article

C2 - 25436980

AN - SCOPUS:84921370750

VL - 6

SP - 441

EP - 457

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 1

ER -