Ectopic expression of the WWOX gene suppresses stemness of human ovarian cancer stem cells
- Authors:
- Hong Chao Yan
- Jun Xu
- Li Sha Fang
- Ying Ying Qiu
- Xiao Man Lin
- Hong Xiang Huang
- Qiu Yu Han
View Affiliations
Affiliations: Department of Obstetrics and Gynecology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu 221002, P.R. China
- Published online on: February 17, 2015 https://doi.org/10.3892/ol.2015.2971
-
Pages:
1614-1620
-
Copyright: © Yan
et al. This is an open access article distributed under the
terms of Creative
Commons Attribution License.
Metrics: Total
Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
This article is mentioned in:
Abstract
The present study aimed to investigate the effects of the WW domain‑containing oxidoreductase (WWOX) gene on the stem cell properties of human ovarian cancer stem cells. A eukaryotic expression vector containing the WWOX gene was transfected into human ovarian cancer stem cells and Western blotting was used to assess the expression of WWOX protein in the transfected cells compared with the control cells (untransfected cells and cells transfected with the empty vector). The self‑renewal abilities of these three types of stem cells was also assessed in vitro. To monitor changes in their differentiation potential, cells were cultured in medium supplemented with serum, and the expression of specific stem cell markers was determined. Drug‑sensitivity tests were used to measure the sensitivity of the stem cells to cisplatin, doxorubicin, and mitoxantrone. The cells were also transplanted into non‑obese diabetic (NOD)/severe combined immunodeficiency (SCID) mice to determine the changes in their tumorigenicity in vivo. Cells transfected with the WWOX‑expressing plasmid stably expressed WWOX protein, while no WWOX protein was detected in control cells. Compared with the two types of control cells, WWOX‑expressing stem cells manifested significantly reduced self‑renewal ability. Compared with control cells, the expression levels of stem cell markers, including CD133, CD117, ATP‑binding cassette sub‑family G member 2, Nanog, octamer‑binding transcription factor 4 and breast cancer resistance protein, were significantly lower in WWOX‑expressing cells, while the level of the differentiation marker E‑cadherin was significantly higher in WWOX‑expressing cells. Furthermore, WWOX‑expressing cells were more sensitive to treatment with cisplatin, doxorubicin and mitoxantrone. In NOD/SCID mice, the tumorigenicity of WWOX‑expressing cells was significantly lower compared with that of control cells. The results indicate that the tumor suppressor WWOX suppresses stem cell properties in cancer stem cells, including self‑renewal ability, differentiation potential, in vivo tumorigenic capability, high‑level expression of stem cell genes and multidrug resistance.
View References
1
|
Gangemi R, Paleari L, Orengo AM, et al:
Cancer stem cells: a new paradigm for understanding tumor growth
and progression and drug resistance. Curr Med Chem. 16:1688–1703.
2009. View Article : Google Scholar : PubMed/NCBI
|
2
|
Bellayr IH and Li Y: Stem Cells: It’s Good
To Have Choices. J Am Col Certif Wound Spec. 23:92–94. 2009.
|
3
|
Ghadially R: The role of stem and
circulating cells in cancer metastasis. J Surg Oncol. 103:555–557.
2011. View Article : Google Scholar : PubMed/NCBI
|
4
|
Yan HC, Yu N and Tong JY: Isolation of
cancer stem cells from ovarian cancer cell line HO9810 and
identification of their biological characteristics. Jiang Su Yi
Yao. 10:1152–1155. 2012.(In Chinese).
|
5
|
Bednarek AK, Laflin KJ, Daniel RL, et al:
WWOX, a novel WW domain-containing protein mapping to human
chromosome 16q23.3–24.1, a region frequently affected in breast
cancer. Cancer Res. 60:2140–2145. 2000.PubMed/NCBI
|
6
|
Del Mare S, Salah Z and Aqeilan RI: WWOX:
its genomics, partners, and functions. J Cell Biochem. 108:737–745.
2009. View Article : Google Scholar : PubMed/NCBI
|
7
|
Li J, Liu J, Ren Y, Yang J and Liu P:
Common Chromosomal Fragile Site Gene WWOX in Metabolic Disorders
and Tumors. Int J Biol Sci. 10:142–148. 2014. View Article : Google Scholar : PubMed/NCBI
|
8
|
Yan HC and Zhang J: Effects of sodium
valproate on the growth of human ovarian cancer cell line HO8910.
Asian Pac J Cancer Prev. 13:6429–6433. 2012. View Article : Google Scholar : PubMed/NCBI
|
9
|
Yan H and Sun J: Methylation status of
WWOX gene promoter CpG islands in epithelial ovarian cancer and its
clinical significance. Biomed Rep. 1:375–378. 2013.
|
10
|
Yan H, Yu N and Tong J: Effects of
5-Aza-2′-deoxycytidine on the methylation state and function of the
WWOX gene in the HO-8910 ovarian cancer cell line. Oncol Lett.
6:845–849. 2013.PubMed/NCBI
|
11
|
Yan HC, Lu XY, Han QY and Jin LS:
Construction and identification of WWOX gene eukaryotic expression
vector. Jiang Su Yi Yao. 3:287–288. 2008.(In Chinese).
|
12
|
Dick JE: Stem cell concepts renew cancer
research. Blood. 112:4793–4807. 2008. View Article : Google Scholar : PubMed/NCBI
|
13
|
Suzuki Y, Ishii H, Sekimoto M, Doki Y and
Mori M: Cancer stem cell. Nihon Rinsho. 69:98–102. 2011.(In
Japanese).
|
14
|
Ghaffari S: Cancer, stem cells and cancer
stem cells: old ideas, new developments. F1000 Med Rep. 3:232011.
View Article : Google Scholar : PubMed/NCBI
|
15
|
Natarajan TG, Ganesan N and Fitzgerald KT:
Cancer stem cells and markers: new model of tumorigenesis with
therapeutic implications. Cancer Biomark. 9:65–99. 2010.
|
16
|
Maitland NJ and Collins AT: Cancer stem
cells - A therapeutic target? Curr Opin Mol Ther. 12:662–673.
2010.PubMed/NCBI
|
17
|
Stevenson K, McGlynn L and Shiels PG: Stem
cells: outstanding potential and outstanding questions. Scott Med
J. 54:35–37. 2009. View Article : Google Scholar : PubMed/NCBI
|
18
|
Fukuda K, Saikawa Y, Ohashi M, et al:
Tumor initiating potential of side population cells in human
gastric cancer. Int J Oncol. 34:1201–1207. 2009.PubMed/NCBI
|
19
|
Ning ZF, Huang YJ, Lin TX, et al:
Subpopulations of stem-like cells in side population cells from the
human bladder transitional cell cancer cell line T24. J Int Med
Res. 37:621–630. 2009. View Article : Google Scholar : PubMed/NCBI
|
20
|
Hirose H, Yamamoto H, Miyoshi N, et al:
Cancer stem cells in solid tumors. Gan To Kagaku Ryoho.
37:2809–2812. 2010.(In Japanese). PubMed/NCBI
|
21
|
Roy S and Majumdar AP: Cancer Stem Cells
in Colorectal Cancer: Genetic and Epigenetic Changes. J Stem Cell
Res Ther. 7:103422012.
|
22
|
Cetin I and Topcul M: Cancer stem cells in
oncology. J BUON. 17:644–648. 2012.
|