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RPN2 Gene Confers Osteosarcoma Cell Malignant Phenotypes and Determines Clinical Prognosis.

Fujiwara T, Takahashi RU, Kosaka N, Nezu Y, Kawai A, Ozaki T, Ochiya T - Mol Ther Nucleic Acids (2014)

Bottom Line: Drug resistance and metastasis are lethal characteristics of tumors.We previously demonstrated that silencing of ribophorin II (RPN2), which is part of the N-oligosaccharyl transferase complex, efficiently induced apoptosis and reduced resistance to docetaxel in human breast cancer cells.The results indicated that RPN2 silencing reduced cell proliferation, sphere formation, cell invasion, and sensitized drug response in vitro.

View Article: PubMed Central - PubMed

Affiliation: 1] Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan [2] Division of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan [3] Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.

ABSTRACT
Drug resistance and metastasis are lethal characteristics of tumors. We previously demonstrated that silencing of ribophorin II (RPN2), which is part of the N-oligosaccharyl transferase complex, efficiently induced apoptosis and reduced resistance to docetaxel in human breast cancer cells. Here, we report the clinical and functional correlations of RPN2 expression in osteosarcoma. Immunohistochemical evaluation of 35 osteosarcoma patient biopsies revealed that RPN2 was moderately to highly expressed in all specimens, and higher RPN2 mRNA expression was significantly correlated with poor prognosis. To investigate whether lethal phenotypes of osteosarcoma could be reduced by regulating the expression of RPN2, we conducted a study of RNAi-induced RPN2 knockdown in highly metastatic human osteosarcoma cells. The results indicated that RPN2 silencing reduced cell proliferation, sphere formation, cell invasion, and sensitized drug response in vitro. Mice bearing RPN2-silenced highly metastatic osteosarcoma xenografts showed reduced tumor growth and lung metastasis, and survived longer than mice bearing control tumor xenografts. Taken together, our data suggest that RPN2 silencing contributes to regulation of lethal osteosarcoma phenotypes and could be a novel target for RNAi-based therapeutics against osteosarcoma.

No MeSH data available.


Related in: MedlinePlus

Induction of RPN2 and MDR1 expression by doxorubicin treatment. (a) RPN2 expression levels induced by doxorubicin treatment in 143B cells. The data shown are from 48 hours after doxorubicin treatment. Data are presented as mean ± SD (n = 3 per group). **P <0.01; Student's t-test. (b) MDR1 expression levels induced by doxorubicin treatment in 143B cells. The data shown are from 48 hours after doxorubicin treatment. Data are presented as mean ± SD (n = 3 per group). **P < 0.01, ***P < 0.001; Student's t-test.
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fig3: Induction of RPN2 and MDR1 expression by doxorubicin treatment. (a) RPN2 expression levels induced by doxorubicin treatment in 143B cells. The data shown are from 48 hours after doxorubicin treatment. Data are presented as mean ± SD (n = 3 per group). **P <0.01; Student's t-test. (b) MDR1 expression levels induced by doxorubicin treatment in 143B cells. The data shown are from 48 hours after doxorubicin treatment. Data are presented as mean ± SD (n = 3 per group). **P < 0.01, ***P < 0.001; Student's t-test.

Mentions: Our previous investigation had shown that expression of RPN2 mRNA in docetaxel-sensitive breast cancer cells was markedly and dose-dependently induced by docetaxel. To confirm the effect of RPN2 mRNA expression in osteosarcoma cells by treatment with currently used drugs, we performed qRT-PCR for 143B cells after doxorubicin treatment. We found that expression of mRNA for both RPN2 and multidrug resistance gene 1 (MDR1) in 143B cells was markedly and dose-dependently induced by doxorubicin after 48 hours of treatment (Figure 3a,b). These data indicated that the cells surviving after doxorubicin treatment expressed a high amount the MDR1 and RPN2 gene products, suggesting that the development of drug resistance might correlate with induction of their expression in osteosarcoma cells.


RPN2 Gene Confers Osteosarcoma Cell Malignant Phenotypes and Determines Clinical Prognosis.

Fujiwara T, Takahashi RU, Kosaka N, Nezu Y, Kawai A, Ozaki T, Ochiya T - Mol Ther Nucleic Acids (2014)

Induction of RPN2 and MDR1 expression by doxorubicin treatment. (a) RPN2 expression levels induced by doxorubicin treatment in 143B cells. The data shown are from 48 hours after doxorubicin treatment. Data are presented as mean ± SD (n = 3 per group). **P <0.01; Student's t-test. (b) MDR1 expression levels induced by doxorubicin treatment in 143B cells. The data shown are from 48 hours after doxorubicin treatment. Data are presented as mean ± SD (n = 3 per group). **P < 0.01, ***P < 0.001; Student's t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4222647&req=5

fig3: Induction of RPN2 and MDR1 expression by doxorubicin treatment. (a) RPN2 expression levels induced by doxorubicin treatment in 143B cells. The data shown are from 48 hours after doxorubicin treatment. Data are presented as mean ± SD (n = 3 per group). **P <0.01; Student's t-test. (b) MDR1 expression levels induced by doxorubicin treatment in 143B cells. The data shown are from 48 hours after doxorubicin treatment. Data are presented as mean ± SD (n = 3 per group). **P < 0.01, ***P < 0.001; Student's t-test.
Mentions: Our previous investigation had shown that expression of RPN2 mRNA in docetaxel-sensitive breast cancer cells was markedly and dose-dependently induced by docetaxel. To confirm the effect of RPN2 mRNA expression in osteosarcoma cells by treatment with currently used drugs, we performed qRT-PCR for 143B cells after doxorubicin treatment. We found that expression of mRNA for both RPN2 and multidrug resistance gene 1 (MDR1) in 143B cells was markedly and dose-dependently induced by doxorubicin after 48 hours of treatment (Figure 3a,b). These data indicated that the cells surviving after doxorubicin treatment expressed a high amount the MDR1 and RPN2 gene products, suggesting that the development of drug resistance might correlate with induction of their expression in osteosarcoma cells.

Bottom Line: Drug resistance and metastasis are lethal characteristics of tumors.We previously demonstrated that silencing of ribophorin II (RPN2), which is part of the N-oligosaccharyl transferase complex, efficiently induced apoptosis and reduced resistance to docetaxel in human breast cancer cells.The results indicated that RPN2 silencing reduced cell proliferation, sphere formation, cell invasion, and sensitized drug response in vitro.

View Article: PubMed Central - PubMed

Affiliation: 1] Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan [2] Division of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan [3] Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.

ABSTRACT
Drug resistance and metastasis are lethal characteristics of tumors. We previously demonstrated that silencing of ribophorin II (RPN2), which is part of the N-oligosaccharyl transferase complex, efficiently induced apoptosis and reduced resistance to docetaxel in human breast cancer cells. Here, we report the clinical and functional correlations of RPN2 expression in osteosarcoma. Immunohistochemical evaluation of 35 osteosarcoma patient biopsies revealed that RPN2 was moderately to highly expressed in all specimens, and higher RPN2 mRNA expression was significantly correlated with poor prognosis. To investigate whether lethal phenotypes of osteosarcoma could be reduced by regulating the expression of RPN2, we conducted a study of RNAi-induced RPN2 knockdown in highly metastatic human osteosarcoma cells. The results indicated that RPN2 silencing reduced cell proliferation, sphere formation, cell invasion, and sensitized drug response in vitro. Mice bearing RPN2-silenced highly metastatic osteosarcoma xenografts showed reduced tumor growth and lung metastasis, and survived longer than mice bearing control tumor xenografts. Taken together, our data suggest that RPN2 silencing contributes to regulation of lethal osteosarcoma phenotypes and could be a novel target for RNAi-based therapeutics against osteosarcoma.

No MeSH data available.


Related in: MedlinePlus