Cloning of WWOX gene and its growth-inhibiting effects on ovarian cancer cells

Xiong, Zhoufang; Hu, Sha; Wang, Zehua

doi:10.1007/s11596-010-0358-z

Cited by 17 publications

(20 citation statements)

References 6 publications

(7 reference statements)

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“…These results are similar to our previously reported gene expression analysis conducted on breast cancer (11) and glioblastoma multiforme patients (9). Investigations on apoptosis of an A2780 ovarian cancer cell line transfected with the WWOX gene demonstrated a decreased ability for anchorage-independent growth with a simultaneous increase of apoptosis (31). An important regulator of the cell cycle is cyclin D1.…”

Section: Discussionsupporting

confidence: 90%

The WWOX tumor suppressor gene in endometrial adenocarcinoma

Płuciennik

Kośla

Wójcik‐Krowiranda

et al. 2013

International Journal of Molecular Medicine

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Abstract. Endometrial cancer is a lethal malignancy, the causes of which remain to be determined. The aim of the present study, carried out on tumor samples from 79 patients, was to evaluate the role of the WWOX tumor suppressor gene in endometrial adenocarcinoma. The expression levels of WWOX and its protein content were assessed in normal endometrium and cancer samples. Quantitative PCR was used to assess the correlation between the expression levels of WWOX and the genes involved in the proliferation (MKI67), apoptosis (BAX, BCL2), signal transduction (EGFR), cell cycle (CCNE1, CCND1), cell adhesion (CDH1) and transcription regulation (TP73, NCOR1). The relationship between loss of hetero zygosity (LOH) and WWOX mRNA levels was also investigated using high resolution melting. Results of the present study demonstrated a positive correlation of WWOX expression with BCL2 and CCND1 and a negative correlation with BAX, CDH1, NCOR1 and BCL2/BAX ratio. The results also showed that loss of heterozygosity at two analyzed loci of the WWOX gene is frequent in patients with endometrial cancer and that WWOX expression levels are lower in tumor samples than in normal tissue. In conclusion, WWOX may be involved in endometrial cancer.

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Section: Discussionsupporting

confidence: 90%

The WWOX tumor suppressor gene in endometrial adenocarcinoma

Płuciennik

Kośla

Wójcik‐Krowiranda

et al. 2013

International Journal of Molecular Medicine

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“…Soft agar growth assay showed the restoration of WWOX gene expression in breast cancer cell lines MDA-MB-453, T47D (31), BT-474, MDA-MB-231 (68, 69) and HCC1937 (69) significantly reduced their ability to anchor independent growth. Similar observations were reported for other WWOX -transduced cell lines from other cancers: pancreatic–AsPc1 and Panc1 (15, 16), prostate–DU145 (66), lung–A549, H460 and H1299 (65), and ovarian–A2780 (70). …”

Section: Biological and Clinical Implications Of Wwox In Breast Cancersupporting

confidence: 86%

WWOX Tumor Suppressor Gene in Breast Cancer, a Historical Perspective and Future Directions

Pospiech

Płuciennik

2018

Front. Oncol.

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The WWOX tumor suppressor gene is located at 16q23. 1–23.2, which covers the region of FRA16D—a common fragile sites. Deletions within the WWOX coding sequence are observed in up to 80% of breast cancer cases, which makes it one of the most common genetic alterations in this tumor type. The WWOX gene is known to play a role in breast cancer: increased expression of WWOX inhibits cell proliferation in suspension, reduces tumor growth rates in xenographic transplants, but also enhances cell migration through the basal membrane and contributes to morphological changes in 3D matrix-based cell cultures. The WWOX protein may act in several ways, as it has three functional domains—two WW domains, responsible for protein-protein interactions and an SDR domain (short dehydrogenase/reductase domain) which catalyzes conversions of low molecular weight ligands, most likely steroids. In epithelial cells, WWOX modulates gene transcription through interaction with p73, AP-2γ, and ERBB4 proteins. In steroid hormone-regulated tissues like mammary gland epithelium, the WWOX SDR domain acts as a steroid dehydrogenase. The relationship between WWOX and hormone receptors was shown in an animal model, where WWOX(C3H)+/–mice exhibited loss of both ER and PR receptors. Moreover, in breast cancer specimens, a positive correlation was observed between WWOX expression and ER status. On the other hand, decreased WWOX expression was associated with worse prognosis, namely higher relapse and mortality rates in BC patients. Recently, it was shown that genomic instability might be driven by the loss of WWOX expression. It was reported that WWOX plays role in DNA damage response (DDR) and DNA repair by regulating ATM activation through physical interaction. A genome caretaker function has also been proposed for WWOX, as it was found that WWOX sufficiency decreases homology directed repair (HDR) and supports non-homologous end-joining (NHEJ) repair as the dominant DSB repair pathway by Brca1-Wwox interaction. In breast cancer cells, WWOX was also found to modulate the expression of glycolysis pathway genes, through hypoxia-inducible transcription factor 1α (HIF1α) regulation. The paper presents the current state of knowledge regarding the WWOX tumor suppressor gene in breast cancer, as well as future research perspectives.

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“…Gourley et al (26) revealed that WWOX expression abolishes ovarian cancer tumorigenicity in vivo, and Fabbri et al (10) also found an increase of WWOX in lung cancer cells exhibits marked suppression of tumorigenicity. Recent publications demonstrated that ectopic expression of WWOX leads to cell apoptosis in tumors such as lung cancer, glioblastoma multiforme, hepatoma, ovarian and prostate cancer as well (17,19,24,27,28). Consistent with these findings, we also observed a restoration of Wwox in its absent leukemic cells led to a marked inhibition of cell growth and colony formation, and apoptosis effects were exhibited by the microscopic changes of nucleus in phase Ⅱb of apoptosis accompanied by DNA ladders appearing in pGC-FU-WWOX-infected cells.…”

Section: Discussionmentioning

confidence: 99%

The role of the WWOX gene in leukemia and its mechanisms of action

et al. 2013

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Abstract. The WW domain-containing oxidoreductase (WWOX) gene which encompasses the common human fragile site FRA16D has been proposed as a putative tumor suppressor gene, and loss of WWOX expression has been found in several types of solid cancer. As the role of WWOX in human leukemia has not yet been fully elucidated, the present study examined the expression of WWOX in patients with different types of leukemia as well as in leukemia-derived cell lines. Based on the data, WWOX mRNA (WWOX) and protein (Wwox) were significantly reduced or absent in the leukemia patients as well as in the cell lines. In addition, a recombinant expression vector, pGC-FU-WWOX, was constructed and transfected WWOX cDNA into Jurkat cells (acute T-lymphoblastic leukemia) and K562 cells (chronic myeloid leukemia in erythroid crisis) which all lack endogenous Wwox. In vitro experiments indicated that restoration of Wwox in Jurkat and K562 cells significantly suppressed proliferation and colony formation. Of note, apoptosis was also induced by Wwox restoration. Furthermore, we traced the mechanisms underlying this process and found that Wwox restoration could trigger the mitochondrial pathway in leukemia. Our data provide evidence that WWOX exerts a role as a tumor suppressor gene in leukemia, possibly by inhibiting proliferation and promoting apoptosis via the mitochondrial pathway.

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Cloning of WWOX gene and its growth-inhibiting effects on ovarian cancer cells

Cited by 17 publications

References 6 publications

The WWOX tumor suppressor gene in endometrial adenocarcinoma

The WWOX tumor suppressor gene in endometrial adenocarcinoma

WWOX Tumor Suppressor Gene in Breast Cancer, a Historical Perspective and Future Directions

The role of the WWOX gene in leukemia and its mechanisms of action

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