Co-targeting prostate cancer epithelium and bone stroma by human osteonectin- promoter-mediated suicide gene therapy effectively inhibits androgen-independent prostate cancer growth

Shian Ying Sung, Junn Liang Chang, Kuan Chou Chen, Shauh Der Yeh, Yun Ru Liu, Yen Hao Su, Chia Yen Hsueh, Leland W K Chung, Chia Ling Hsieh

研究成果: 雜誌貢獻文章

5 引文 (Scopus)

摘要

Stromal-epithelial interaction has been shown to promote local tumor growth and distant metastasis. We sought to create a promising gene therapy approach that co-targets cancer and its supporting stromal cells for combating castration-resistant prostate tumors. Herein, we demonstrated that human osteonectin is overexpressed in the prostate cancer epithelium and tumor stroma in comparison with their normal counterpart. We designed a novel human osteonectin promoter (hON-522E) containing positive transcriptional regulatory elements identified in both the promoter and exon 1 region of the human osteonectin gene. In vitro reporter assays revealed that the hON-522E promoter is highly active in androgen receptor negative and metastatic prostate cancer and bone stromal cells compared to androgen receptor-positive prostate cancer cells. Moreover, in vivo prostate-tumor-promoting activity of the hON-522E promoter was confirmed by intravenous administration of an adenoviral vector containing the hON-522E promoter-driven luciferase gene (Ad-522E-Luc) into mice bearing orthotopic human prostate tumor xenografts. In addition, an adenoviral vector with the hON-522E-promoter-driven herpes simplex virus thymidine kinase gene (Ad-522E-TK) was highly effective against the growth of androgen-independent human prostate cancer PC3M and bone stromal cell line in vitro and in pre-established PC3M tumors in vivo upon addition of the prodrug ganciclovir. Because of the heterogeneity of human prostate tumors, hON-522E promoter-mediated gene therapy has the potential for the treatment of hormone refractory and bone metastatic prostate cancers.
原文英語
文章編號e0153350
期刊PLoS One
11
發行號4
DOIs
出版狀態已發佈 - 四月 1 2016

指紋

suicide genes
Osteonectin
Gene therapy
Bone Neoplasms
gene therapy
prostatic neoplasms
androgens
Genetic Therapy
Suicide
Androgens
Tumors
Prostatic Neoplasms
Bone
epithelium
Epithelium
promoter regions
bones
Growth
Prostate
Neoplasms

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

引用此文

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title = "Co-targeting prostate cancer epithelium and bone stroma by human osteonectin- promoter-mediated suicide gene therapy effectively inhibits androgen-independent prostate cancer growth",
abstract = "Stromal-epithelial interaction has been shown to promote local tumor growth and distant metastasis. We sought to create a promising gene therapy approach that co-targets cancer and its supporting stromal cells for combating castration-resistant prostate tumors. Herein, we demonstrated that human osteonectin is overexpressed in the prostate cancer epithelium and tumor stroma in comparison with their normal counterpart. We designed a novel human osteonectin promoter (hON-522E) containing positive transcriptional regulatory elements identified in both the promoter and exon 1 region of the human osteonectin gene. In vitro reporter assays revealed that the hON-522E promoter is highly active in androgen receptor negative and metastatic prostate cancer and bone stromal cells compared to androgen receptor-positive prostate cancer cells. Moreover, in vivo prostate-tumor-promoting activity of the hON-522E promoter was confirmed by intravenous administration of an adenoviral vector containing the hON-522E promoter-driven luciferase gene (Ad-522E-Luc) into mice bearing orthotopic human prostate tumor xenografts. In addition, an adenoviral vector with the hON-522E-promoter-driven herpes simplex virus thymidine kinase gene (Ad-522E-TK) was highly effective against the growth of androgen-independent human prostate cancer PC3M and bone stromal cell line in vitro and in pre-established PC3M tumors in vivo upon addition of the prodrug ganciclovir. Because of the heterogeneity of human prostate tumors, hON-522E promoter-mediated gene therapy has the potential for the treatment of hormone refractory and bone metastatic prostate cancers.",
author = "Sung, {Shian Ying} and Chang, {Junn Liang} and Chen, {Kuan Chou} and Yeh, {Shauh Der} and Liu, {Yun Ru} and Su, {Yen Hao} and Hsueh, {Chia Yen} and Chung, {Leland W K} and Hsieh, {Chia Ling}",
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AU - Sung, Shian Ying

AU - Chang, Junn Liang

AU - Chen, Kuan Chou

AU - Yeh, Shauh Der

AU - Liu, Yun Ru

AU - Su, Yen Hao

AU - Hsueh, Chia Yen

AU - Chung, Leland W K

AU - Hsieh, Chia Ling

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