Potent antitumor activity of Oct4 and hypoxia dual-regulated oncolytic adenovirus against bladder cancer

C. S. Lu, J. L. Hsieh, C. Y. Lin, H. W. Tsai, B. H. Su, G. S. Shieh, Y. C. Su, C. H. Lee, M. Y. Chang, C. L. Wu, A. L. Shiau

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Most solid tumors undergo hypoxia, leading to rapid cell division, metastasis and expansion of a cell population with hallmarks of cancer stem cells (CSCs). Tumor-selective replication of oncolytic adenoviruses may be hindered by oxygen deprivation in tumors. It is desirable to develop a potent oncolytic adenovirus, retaining its antitumor activity even in a hypoxic environment. We have previously generated an Oct4-dependent oncolytic adenovirus, namely Ad9OC, driven by nine copies of the Oct4 response element (ORE) for specifically killing Oct4-overexpressing bladder tumors. Here, we developed a novel Oct4 and hypoxia dual-regulated oncolytic adenovirus, designated AdLCY, driven by both hypoxia response element (HRE) and ORE. We showed that hypoxia-inducible factor (HIF)-2 and Oct4 were frequently overexpressed in hypoxic bladder cancer cells, and HIF-2 was involved in HRE-dependent and Oct4 transactivation. AdLCY exhibited higher cytolytic activities than Ad9OC against hypoxic bladder cancer cells, while sparing normal cells. AdLCY exerted potent antitumor effects in mice bearing human bladder tumor xenografts and syngeneic bladder tumors. It could target hypoxic CD44- and CD133-positive bladder tumor cells. Therefore, AdLCY may have therapeutic potential for targeting hypoxic bladder tumors and CSCs. As Oct4 is expressed in various cancers, AdLCY may be further explored as a broad-spectrum anticancer agent.

Original languageEnglish
Pages (from-to)305-315
Number of pages11
JournalGene Therapy
Volume22
Issue number4
DOIs
Publication statusPublished - Jan 1 2015
Externally publishedYes

Fingerprint

Urinary Bladder Neoplasms
Adenoviridae
Response Elements
Neoplastic Stem Cells
Cell Hypoxia
Neoplasms
Hypoxia
Heterografts
Cell Division
Antineoplastic Agents
Transcriptional Activation
Oxygen
Neoplasm Metastasis
Population

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Lu, C. S., Hsieh, J. L., Lin, C. Y., Tsai, H. W., Su, B. H., Shieh, G. S., ... Shiau, A. L. (2015). Potent antitumor activity of Oct4 and hypoxia dual-regulated oncolytic adenovirus against bladder cancer. Gene Therapy, 22(4), 305-315. https://doi.org/10.1038/gt.2014.122

Potent antitumor activity of Oct4 and hypoxia dual-regulated oncolytic adenovirus against bladder cancer. / Lu, C. S.; Hsieh, J. L.; Lin, C. Y.; Tsai, H. W.; Su, B. H.; Shieh, G. S.; Su, Y. C.; Lee, C. H.; Chang, M. Y.; Wu, C. L.; Shiau, A. L.

In: Gene Therapy, Vol. 22, No. 4, 01.01.2015, p. 305-315.

Research output: Contribution to journalArticle

Lu, CS, Hsieh, JL, Lin, CY, Tsai, HW, Su, BH, Shieh, GS, Su, YC, Lee, CH, Chang, MY, Wu, CL & Shiau, AL 2015, 'Potent antitumor activity of Oct4 and hypoxia dual-regulated oncolytic adenovirus against bladder cancer', Gene Therapy, vol. 22, no. 4, pp. 305-315. https://doi.org/10.1038/gt.2014.122
Lu, C. S. ; Hsieh, J. L. ; Lin, C. Y. ; Tsai, H. W. ; Su, B. H. ; Shieh, G. S. ; Su, Y. C. ; Lee, C. H. ; Chang, M. Y. ; Wu, C. L. ; Shiau, A. L. / Potent antitumor activity of Oct4 and hypoxia dual-regulated oncolytic adenovirus against bladder cancer. In: Gene Therapy. 2015 ; Vol. 22, No. 4. pp. 305-315.
@article{b1fd2a7edf7c4777b9de4f8d2e3a4579,
title = "Potent antitumor activity of Oct4 and hypoxia dual-regulated oncolytic adenovirus against bladder cancer",
abstract = "Most solid tumors undergo hypoxia, leading to rapid cell division, metastasis and expansion of a cell population with hallmarks of cancer stem cells (CSCs). Tumor-selective replication of oncolytic adenoviruses may be hindered by oxygen deprivation in tumors. It is desirable to develop a potent oncolytic adenovirus, retaining its antitumor activity even in a hypoxic environment. We have previously generated an Oct4-dependent oncolytic adenovirus, namely Ad9OC, driven by nine copies of the Oct4 response element (ORE) for specifically killing Oct4-overexpressing bladder tumors. Here, we developed a novel Oct4 and hypoxia dual-regulated oncolytic adenovirus, designated AdLCY, driven by both hypoxia response element (HRE) and ORE. We showed that hypoxia-inducible factor (HIF)-2 and Oct4 were frequently overexpressed in hypoxic bladder cancer cells, and HIF-2 was involved in HRE-dependent and Oct4 transactivation. AdLCY exhibited higher cytolytic activities than Ad9OC against hypoxic bladder cancer cells, while sparing normal cells. AdLCY exerted potent antitumor effects in mice bearing human bladder tumor xenografts and syngeneic bladder tumors. It could target hypoxic CD44- and CD133-positive bladder tumor cells. Therefore, AdLCY may have therapeutic potential for targeting hypoxic bladder tumors and CSCs. As Oct4 is expressed in various cancers, AdLCY may be further explored as a broad-spectrum anticancer agent.",
author = "Lu, {C. S.} and Hsieh, {J. L.} and Lin, {C. Y.} and Tsai, {H. W.} and Su, {B. H.} and Shieh, {G. S.} and Su, {Y. C.} and Lee, {C. H.} and Chang, {M. Y.} and Wu, {C. L.} and Shiau, {A. L.}",
year = "2015",
month = "1",
day = "1",
doi = "10.1038/gt.2014.122",
language = "English",
volume = "22",
pages = "305--315",
journal = "Gene Therapy",
issn = "0969-7128",
publisher = "Nature Publishing Group",
number = "4",

}

TY - JOUR

T1 - Potent antitumor activity of Oct4 and hypoxia dual-regulated oncolytic adenovirus against bladder cancer

AU - Lu, C. S.

AU - Hsieh, J. L.

AU - Lin, C. Y.

AU - Tsai, H. W.

AU - Su, B. H.

AU - Shieh, G. S.

AU - Su, Y. C.

AU - Lee, C. H.

AU - Chang, M. Y.

AU - Wu, C. L.

AU - Shiau, A. L.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Most solid tumors undergo hypoxia, leading to rapid cell division, metastasis and expansion of a cell population with hallmarks of cancer stem cells (CSCs). Tumor-selective replication of oncolytic adenoviruses may be hindered by oxygen deprivation in tumors. It is desirable to develop a potent oncolytic adenovirus, retaining its antitumor activity even in a hypoxic environment. We have previously generated an Oct4-dependent oncolytic adenovirus, namely Ad9OC, driven by nine copies of the Oct4 response element (ORE) for specifically killing Oct4-overexpressing bladder tumors. Here, we developed a novel Oct4 and hypoxia dual-regulated oncolytic adenovirus, designated AdLCY, driven by both hypoxia response element (HRE) and ORE. We showed that hypoxia-inducible factor (HIF)-2 and Oct4 were frequently overexpressed in hypoxic bladder cancer cells, and HIF-2 was involved in HRE-dependent and Oct4 transactivation. AdLCY exhibited higher cytolytic activities than Ad9OC against hypoxic bladder cancer cells, while sparing normal cells. AdLCY exerted potent antitumor effects in mice bearing human bladder tumor xenografts and syngeneic bladder tumors. It could target hypoxic CD44- and CD133-positive bladder tumor cells. Therefore, AdLCY may have therapeutic potential for targeting hypoxic bladder tumors and CSCs. As Oct4 is expressed in various cancers, AdLCY may be further explored as a broad-spectrum anticancer agent.

AB - Most solid tumors undergo hypoxia, leading to rapid cell division, metastasis and expansion of a cell population with hallmarks of cancer stem cells (CSCs). Tumor-selective replication of oncolytic adenoviruses may be hindered by oxygen deprivation in tumors. It is desirable to develop a potent oncolytic adenovirus, retaining its antitumor activity even in a hypoxic environment. We have previously generated an Oct4-dependent oncolytic adenovirus, namely Ad9OC, driven by nine copies of the Oct4 response element (ORE) for specifically killing Oct4-overexpressing bladder tumors. Here, we developed a novel Oct4 and hypoxia dual-regulated oncolytic adenovirus, designated AdLCY, driven by both hypoxia response element (HRE) and ORE. We showed that hypoxia-inducible factor (HIF)-2 and Oct4 were frequently overexpressed in hypoxic bladder cancer cells, and HIF-2 was involved in HRE-dependent and Oct4 transactivation. AdLCY exhibited higher cytolytic activities than Ad9OC against hypoxic bladder cancer cells, while sparing normal cells. AdLCY exerted potent antitumor effects in mice bearing human bladder tumor xenografts and syngeneic bladder tumors. It could target hypoxic CD44- and CD133-positive bladder tumor cells. Therefore, AdLCY may have therapeutic potential for targeting hypoxic bladder tumors and CSCs. As Oct4 is expressed in various cancers, AdLCY may be further explored as a broad-spectrum anticancer agent.

UR - http://www.scopus.com/inward/record.url?scp=84926419632&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84926419632&partnerID=8YFLogxK

U2 - 10.1038/gt.2014.122

DO - 10.1038/gt.2014.122

M3 - Article

VL - 22

SP - 305

EP - 315

JO - Gene Therapy

JF - Gene Therapy

SN - 0969-7128

IS - 4

ER -