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MicroRNA-21 is a candidate driver gene for 17q23-25 amplification in ovarian clear cell carcinoma.

Hirata Y, Murai N, Yanaihara N, Saito M, Saito M, Urashima M, Murakami Y, Matsufuji S, Okamoto A - BMC Cancer (2014)

Bottom Line: The patients with 17q23-25 amplification had significantly shorter progression-free and overall survival than those without 17q23-25 amplification (log-rank test: p = 0.0496; p = 0.0469, respectively).A significant correlation was observed between miR-21 overexpression and endometriosis.Aberrant expression of miR-21 by chromosomal amplification might play an important role in CCC carcinogenesis through the regulation of the PTEN tumor suppressor gene.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan. yanazou@jikei.ac.jp.

ABSTRACT

Background: Epithelial ovarian cancer (EOC) is the most common cause of gynecological malignancy-related mortality. Ovarian clear cell carcinoma (CCC) has unique clinical characteristics and behaviors that differ from other histological types of EOC, including a frequent association with endometriosis and a highly chemoresistant nature, resulting in poor prognosis. However, factors underlying its malignant behavior are still poorly understood. Aberrant expression of microRNAs has been shown to be involved in oncogenesis, and microRNA-21 (miR-21) is frequently overexpressed in many types of cancers. The aim of this study was to investigate the role of miR-21 in 17q23-25 amplification associated with CCC oncogenesis.

Methods: We identified 17q23-25 copy number aberrations among 28 primary CCC tumors by using a comparative genomic hybridization method. Next, we measured expression levels of the candidate target genes, miR-21 and PPM1D, for 17q23-25 amplification by real-time RT-PCR analysis and compared those data with copy number status and clinicopathological features. In addition, immunohistochemical analysis of PTEN (a potential target of miR-21) was performed using the same primary CCC cases. We investigated the biological significance of miR-21 overexpression in CCC using a loss-of-function antisense approach.

Results: 17q23-25 amplification with both miR-21 overexpression and PTEN protein loss was detected in 4/28 CCC cases (14.2%). The patients with 17q23-25 amplification had significantly shorter progression-free and overall survival than those without 17q23-25 amplification (log-rank test: p = 0.0496; p = 0.0469, respectively). A significant correlation was observed between miR-21 overexpression and endometriosis. Both PTEN mRNA and PTEN protein expression were increased by miR-21 knockdown in CCC cells. We also confirmed that miR-21 directly bound to the 3'-untranslated region of PTEN mRNA using a dual-luciferase reporter assay.

Conclusions: MiR-21 is a possible driver gene other than PPM1D for 17q23-25 amplification in CCC. Aberrant expression of miR-21 by chromosomal amplification might play an important role in CCC carcinogenesis through the regulation of the PTEN tumor suppressor gene.

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Related in: MedlinePlus

Chromosome 17q23-25 amplification,miR-21expression, and PTEN protein expression in CCC. CGH array was performed to evaluate chromosomal alterations in 28 primary CCC tumors. Nine out of 28 patients (32%) showed chromosomal amplification in the 17q23-25 region that contains miR-21. Seven of 9 tumors (77.7%) with 17q23-25 amplification showed miR-21 overexpression. 17q23-25 amplification with both miR-21 overexpression and PTEN protein loss was detected in 4/28 cases (14.2%).
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Fig4: Chromosome 17q23-25 amplification,miR-21expression, and PTEN protein expression in CCC. CGH array was performed to evaluate chromosomal alterations in 28 primary CCC tumors. Nine out of 28 patients (32%) showed chromosomal amplification in the 17q23-25 region that contains miR-21. Seven of 9 tumors (77.7%) with 17q23-25 amplification showed miR-21 overexpression. 17q23-25 amplification with both miR-21 overexpression and PTEN protein loss was detected in 4/28 cases (14.2%).

Mentions: This study is the first to indicate miR-21 as the gene of interest in 17q23-25 amplification associated with CCC (FigureĀ 4). Aberrant expression of miR-21 by chromosomal amplification might play an important role in CCC carcinogenesis through regulating the PTEN tumor suppressor gene. Moreover, the modulation by miR-21 overexpression of genes other than PTEN should not be overlooked in determining the oncogenic mechanism of CCC.Figure 4


MicroRNA-21 is a candidate driver gene for 17q23-25 amplification in ovarian clear cell carcinoma.

Hirata Y, Murai N, Yanaihara N, Saito M, Saito M, Urashima M, Murakami Y, Matsufuji S, Okamoto A - BMC Cancer (2014)

Chromosome 17q23-25 amplification,miR-21expression, and PTEN protein expression in CCC. CGH array was performed to evaluate chromosomal alterations in 28 primary CCC tumors. Nine out of 28 patients (32%) showed chromosomal amplification in the 17q23-25 region that contains miR-21. Seven of 9 tumors (77.7%) with 17q23-25 amplification showed miR-21 overexpression. 17q23-25 amplification with both miR-21 overexpression and PTEN protein loss was detected in 4/28 cases (14.2%).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4289307&req=5

Fig4: Chromosome 17q23-25 amplification,miR-21expression, and PTEN protein expression in CCC. CGH array was performed to evaluate chromosomal alterations in 28 primary CCC tumors. Nine out of 28 patients (32%) showed chromosomal amplification in the 17q23-25 region that contains miR-21. Seven of 9 tumors (77.7%) with 17q23-25 amplification showed miR-21 overexpression. 17q23-25 amplification with both miR-21 overexpression and PTEN protein loss was detected in 4/28 cases (14.2%).
Mentions: This study is the first to indicate miR-21 as the gene of interest in 17q23-25 amplification associated with CCC (FigureĀ 4). Aberrant expression of miR-21 by chromosomal amplification might play an important role in CCC carcinogenesis through regulating the PTEN tumor suppressor gene. Moreover, the modulation by miR-21 overexpression of genes other than PTEN should not be overlooked in determining the oncogenic mechanism of CCC.Figure 4

Bottom Line: The patients with 17q23-25 amplification had significantly shorter progression-free and overall survival than those without 17q23-25 amplification (log-rank test: p = 0.0496; p = 0.0469, respectively).A significant correlation was observed between miR-21 overexpression and endometriosis.Aberrant expression of miR-21 by chromosomal amplification might play an important role in CCC carcinogenesis through the regulation of the PTEN tumor suppressor gene.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan. yanazou@jikei.ac.jp.

ABSTRACT

Background: Epithelial ovarian cancer (EOC) is the most common cause of gynecological malignancy-related mortality. Ovarian clear cell carcinoma (CCC) has unique clinical characteristics and behaviors that differ from other histological types of EOC, including a frequent association with endometriosis and a highly chemoresistant nature, resulting in poor prognosis. However, factors underlying its malignant behavior are still poorly understood. Aberrant expression of microRNAs has been shown to be involved in oncogenesis, and microRNA-21 (miR-21) is frequently overexpressed in many types of cancers. The aim of this study was to investigate the role of miR-21 in 17q23-25 amplification associated with CCC oncogenesis.

Methods: We identified 17q23-25 copy number aberrations among 28 primary CCC tumors by using a comparative genomic hybridization method. Next, we measured expression levels of the candidate target genes, miR-21 and PPM1D, for 17q23-25 amplification by real-time RT-PCR analysis and compared those data with copy number status and clinicopathological features. In addition, immunohistochemical analysis of PTEN (a potential target of miR-21) was performed using the same primary CCC cases. We investigated the biological significance of miR-21 overexpression in CCC using a loss-of-function antisense approach.

Results: 17q23-25 amplification with both miR-21 overexpression and PTEN protein loss was detected in 4/28 CCC cases (14.2%). The patients with 17q23-25 amplification had significantly shorter progression-free and overall survival than those without 17q23-25 amplification (log-rank test: p = 0.0496; p = 0.0469, respectively). A significant correlation was observed between miR-21 overexpression and endometriosis. Both PTEN mRNA and PTEN protein expression were increased by miR-21 knockdown in CCC cells. We also confirmed that miR-21 directly bound to the 3'-untranslated region of PTEN mRNA using a dual-luciferase reporter assay.

Conclusions: MiR-21 is a possible driver gene other than PPM1D for 17q23-25 amplification in CCC. Aberrant expression of miR-21 by chromosomal amplification might play an important role in CCC carcinogenesis through the regulation of the PTEN tumor suppressor gene.

Show MeSH
Related in: MedlinePlus