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Tumor Suppressor WWOX inhibits osteosarcoma metastasis by modulating RUNX2 function.

Del Mare S, Aqeilan RI - Sci Rep (2015)

Bottom Line: We recently demonstrated that WW domain-containing oxidoreductase (WWOX) is frequently inactivated in human OS and that WWOX restoration in WWOX-negative OS cells suppresses tumorigenicity.Mechanistically, WWOX function is associated with reduced levels of RUNX2 metastatic target genes implicated in adhesion and motility.Our results suggest that WWOX plays a critical role in determining the aggressive phenotype of OS, and its expression could be an attractive therapeutic target to combat this devastating adolescent disease.

View Article: PubMed Central - PubMed

Affiliation: The Lautenberg Center for Immunology and Cancer Research, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Israel 91220.

ABSTRACT
Osteosarcoma (OS) is among the most frequently occurring primary bone tumors, primarily affecting adolescents and young adults. This malignant osteoid forming tumor is characterized by its metastatic potential, mainly to lungs. We recently demonstrated that WW domain-containing oxidoreductase (WWOX) is frequently inactivated in human OS and that WWOX restoration in WWOX-negative OS cells suppresses tumorigenicity. Of note, WWOX levels are reduced in paired OS samples of post-treatment metastastectomies as compared to pre-treatment biopsies suggesting that decreased WWOX levels are associated with a more aggressive phenotype at the metastatic site. Nevertheless, little is known about WWOX function in OS metastasis. Here, we investigated the role of tumor suppressor WWOX in suppressing pulmonary OS metastasis both in vitro and in vivo. We demonstrated that ectopic expression of WWOX in OS cells, HOS and LM-7, inhibits OS invasion and cell migration in vitro. Furthermore, WWOX expression reduced tumor burden in vivo and inhibited metastases' seeding and colonization. Mechanistically, WWOX function is associated with reduced levels of RUNX2 metastatic target genes implicated in adhesion and motility. Our results suggest that WWOX plays a critical role in determining the aggressive phenotype of OS, and its expression could be an attractive therapeutic target to combat this devastating adolescent disease.

No MeSH data available.


Related in: MedlinePlus

High levels of WWOX in OS cells are associated with decreased expression of RUNX2 target genes.(A,B) HOS and LM7 control and WWOX-restored cells were subjected to real-time PCR for genes known to be involved in OS metastasis. (C,D) RUNX2 target genes are significantly downregulated upon WWOX restoration in both HOS and LM7 cell lines. Relative fold induction is shown. Results are expressed as mean ± SEM. *p < 0.05 as compared with HOS/LM7-EV cells.
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f4: High levels of WWOX in OS cells are associated with decreased expression of RUNX2 target genes.(A,B) HOS and LM7 control and WWOX-restored cells were subjected to real-time PCR for genes known to be involved in OS metastasis. (C,D) RUNX2 target genes are significantly downregulated upon WWOX restoration in both HOS and LM7 cell lines. Relative fold induction is shown. Results are expressed as mean ± SEM. *p < 0.05 as compared with HOS/LM7-EV cells.

Mentions: Our results so far indicate that WWOX restrains OS metastasis. To shed light on the mechanism by which WWOX could exert its anti-metastatic activity, we perform real-time PCR analysis on known metastatic genes implicated in OS progression. To this end, total RNA was isolated from manipulated HOS and LM-7 cells. Our results indicate that the expression of ezrin, integrins alpha 4 and 5, MMP13 and VEGF were reduced upon WWOX expression in HOS and LM7 cells (Fig. 4A,B).


Tumor Suppressor WWOX inhibits osteosarcoma metastasis by modulating RUNX2 function.

Del Mare S, Aqeilan RI - Sci Rep (2015)

High levels of WWOX in OS cells are associated with decreased expression of RUNX2 target genes.(A,B) HOS and LM7 control and WWOX-restored cells were subjected to real-time PCR for genes known to be involved in OS metastasis. (C,D) RUNX2 target genes are significantly downregulated upon WWOX restoration in both HOS and LM7 cell lines. Relative fold induction is shown. Results are expressed as mean ± SEM. *p < 0.05 as compared with HOS/LM7-EV cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4542681&req=5

f4: High levels of WWOX in OS cells are associated with decreased expression of RUNX2 target genes.(A,B) HOS and LM7 control and WWOX-restored cells were subjected to real-time PCR for genes known to be involved in OS metastasis. (C,D) RUNX2 target genes are significantly downregulated upon WWOX restoration in both HOS and LM7 cell lines. Relative fold induction is shown. Results are expressed as mean ± SEM. *p < 0.05 as compared with HOS/LM7-EV cells.
Mentions: Our results so far indicate that WWOX restrains OS metastasis. To shed light on the mechanism by which WWOX could exert its anti-metastatic activity, we perform real-time PCR analysis on known metastatic genes implicated in OS progression. To this end, total RNA was isolated from manipulated HOS and LM-7 cells. Our results indicate that the expression of ezrin, integrins alpha 4 and 5, MMP13 and VEGF were reduced upon WWOX expression in HOS and LM7 cells (Fig. 4A,B).

Bottom Line: We recently demonstrated that WW domain-containing oxidoreductase (WWOX) is frequently inactivated in human OS and that WWOX restoration in WWOX-negative OS cells suppresses tumorigenicity.Mechanistically, WWOX function is associated with reduced levels of RUNX2 metastatic target genes implicated in adhesion and motility.Our results suggest that WWOX plays a critical role in determining the aggressive phenotype of OS, and its expression could be an attractive therapeutic target to combat this devastating adolescent disease.

View Article: PubMed Central - PubMed

Affiliation: The Lautenberg Center for Immunology and Cancer Research, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Israel 91220.

ABSTRACT
Osteosarcoma (OS) is among the most frequently occurring primary bone tumors, primarily affecting adolescents and young adults. This malignant osteoid forming tumor is characterized by its metastatic potential, mainly to lungs. We recently demonstrated that WW domain-containing oxidoreductase (WWOX) is frequently inactivated in human OS and that WWOX restoration in WWOX-negative OS cells suppresses tumorigenicity. Of note, WWOX levels are reduced in paired OS samples of post-treatment metastastectomies as compared to pre-treatment biopsies suggesting that decreased WWOX levels are associated with a more aggressive phenotype at the metastatic site. Nevertheless, little is known about WWOX function in OS metastasis. Here, we investigated the role of tumor suppressor WWOX in suppressing pulmonary OS metastasis both in vitro and in vivo. We demonstrated that ectopic expression of WWOX in OS cells, HOS and LM-7, inhibits OS invasion and cell migration in vitro. Furthermore, WWOX expression reduced tumor burden in vivo and inhibited metastases' seeding and colonization. Mechanistically, WWOX function is associated with reduced levels of RUNX2 metastatic target genes implicated in adhesion and motility. Our results suggest that WWOX plays a critical role in determining the aggressive phenotype of OS, and its expression could be an attractive therapeutic target to combat this devastating adolescent disease.

No MeSH data available.


Related in: MedlinePlus