A link between mir-100 and FRAP1/mTOR in clear cell ovarian cancer

Ankur K. Nagaraja, Chad J. Creighton, Zhifeng Yu, Huifeng Zhu, Preethi H. Gunaratne, Jeffrey G. Reid, Emuejevoke Olokpa, Hiroaki Itamochi, Naoto T. Ueno, Shannon Hawkins, Matthew L. Anderson, Martin M. Matzuk

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Abstract

MicroRNAs (miRNAs) are small noncoding RNAs that direct gene regulation through translational repression and degradation of complementary mRNA. Although miRNAs have been implicated as oncogenes and tumor suppressors in a variety of human cancers, functional roles for individual miRNAs have not been described in clear cell ovarian carcinoma, an aggressive and chemoresistant subtype of ovarian cancer.Weperformed deep sequencing to comprehensively profile miRNA expression in 10 human clear cell ovarian cancer cell lines compared with normal ovarian surface epithelial cultures and discovered 54 miRNAs that were aberrantly expressed. Because of the critical roles of the phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog 1/mammalian target of rapamycin (mTOR) pathway in clear cell ovarian cancer, we focused on mir-100, a putative tumor suppressor that was the most down-regulated miRNA in our cancer cell lines, and its up-regulated target, FRAP1/mTOR. Overexpression of mir-100 inhibited mTOR signaling and enhanced sensitivity to the rapamycin analog RAD001 (everolimus), confirming the key relationship between mir-100 and the mTOR pathway. Furthermore, overexpression of the putative tumor suppressor mir-22 repressed the EVI1 oncogene, which is known to suppress apoptosis by stimulating phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog 1 signaling. In addition to these specific effects, reversing the expression of mir-22 and the putative oncogene mir-182 had widespread effects on target and nontarget gene populations that ultimately caused a global shift in the cancer gene signature toward a more normal state. Our experiments have revealed strong candidate miRNAs and their target genes that may contribute to the pathogenesis of clear cell ovarian cancer, thereby highlighting alternative therapeutic strategies for the treatment of this deadly cancer.

Original languageEnglish (US)
Pages (from-to)447-463
Number of pages17
JournalMolecular Endocrinology
Volume24
Issue number2
DOIs
StatePublished - Feb 2010
Externally publishedYes

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Sirolimus
MicroRNAs
Ovarian Neoplasms
Oncogenes
Phosphatidylinositol 3-Kinase
Neoplasms
Thymoma
Genes
High-Throughput Nucleotide Sequencing
Cell Line
Small Untranslated RNA
Neoplasm Genes
RNA Stability
Apoptosis
Carcinoma
Population

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Nagaraja, A. K., Creighton, C. J., Yu, Z., Zhu, H., Gunaratne, P. H., Reid, J. G., ... Matzuk, M. M. (2010). A link between mir-100 and FRAP1/mTOR in clear cell ovarian cancer. Molecular Endocrinology, 24(2), 447-463. https://doi.org/10.1210/me.2009-0295

A link between mir-100 and FRAP1/mTOR in clear cell ovarian cancer. / Nagaraja, Ankur K.; Creighton, Chad J.; Yu, Zhifeng; Zhu, Huifeng; Gunaratne, Preethi H.; Reid, Jeffrey G.; Olokpa, Emuejevoke; Itamochi, Hiroaki; Ueno, Naoto T.; Hawkins, Shannon; Anderson, Matthew L.; Matzuk, Martin M.

In: Molecular Endocrinology, Vol. 24, No. 2, 02.2010, p. 447-463.

Research output: Contribution to journalArticle

Nagaraja, AK, Creighton, CJ, Yu, Z, Zhu, H, Gunaratne, PH, Reid, JG, Olokpa, E, Itamochi, H, Ueno, NT, Hawkins, S, Anderson, ML & Matzuk, MM 2010, 'A link between mir-100 and FRAP1/mTOR in clear cell ovarian cancer', Molecular Endocrinology, vol. 24, no. 2, pp. 447-463. https://doi.org/10.1210/me.2009-0295
Nagaraja AK, Creighton CJ, Yu Z, Zhu H, Gunaratne PH, Reid JG et al. A link between mir-100 and FRAP1/mTOR in clear cell ovarian cancer. Molecular Endocrinology. 2010 Feb;24(2):447-463. https://doi.org/10.1210/me.2009-0295
Nagaraja, Ankur K. ; Creighton, Chad J. ; Yu, Zhifeng ; Zhu, Huifeng ; Gunaratne, Preethi H. ; Reid, Jeffrey G. ; Olokpa, Emuejevoke ; Itamochi, Hiroaki ; Ueno, Naoto T. ; Hawkins, Shannon ; Anderson, Matthew L. ; Matzuk, Martin M. / A link between mir-100 and FRAP1/mTOR in clear cell ovarian cancer. In: Molecular Endocrinology. 2010 ; Vol. 24, No. 2. pp. 447-463.
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