Human ovarian cancer stroma contains luteinized theca cells harboring tumor suppressor gene GT198 mutations

Min Peng, Hao Zhang, Lahcen Jaafar, John I. Risinger, Shuang Huang, Nahid F Mivechi, Lan Ko

Research output: Contribution to journalArticle

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Abstract

Ovarian cancer is a highly lethal gynecological cancer, and its causes remain to be understood. Using a recently identified tumor suppressor gene, GT198 (PSMC3IP), as a unique marker, we searched for the identity of GT198 mutant cells in ovarian cancer. GT198 has germ line mutations in familial and early onset breast and ovarian cancers and recurrent somatic mutations in sporadic fallopian tube cancers. GT198 protein has been shown as a steroid hormone receptor coregulator and also as a crucial factor in DNA repair. In this study, using GT198 as a marker for microdissection, we find that ovarian tumor stromal cells harboring GT198 mutations are present in various types of ovarian cancer including high and low grade serous, endometrioid, mucinous, clear cell, and granulosa cell carcinomas and in precursor lesions such as inclusion cysts. The mutant stromal cells consist of a luteinized theca cell lineage at various differentiation stages including CD133+, CD44+, and CD34+ cells, although the vast majority of them are differentiated overexpressing steroidogenic enzyme CYP17, a theca cellspecific marker. In addition, wild type GT198 suppresses whereas mutant GT198 protein stimulates CYP17 expression. The chromatin-bound GT198 on the human CYP17 promoter is decreased by overexpressing mutant GT198 protein, implicating the loss of wild type suppression in mutant cells. Together, our results suggest that GT198 mutant luteinized theca cells overexpressing CYP17 arecommonin ovarian cancer stroma. Because first hit cancer gene mutations would specifically mark cancer-inducing cells, the identification of mutant luteinized theca cells may add crucial evidence in understanding the cause of human ovarian cancer.

Original languageEnglish (US)
Pages (from-to)33387-33397
Number of pages11
JournalJournal of Biological Chemistry
Volume288
Issue number46
DOIs
StatePublished - Nov 15 2013

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Thecoma
Steroid 17-alpha-Hydroxylase
Tumor Suppressor Genes
Ovarian Neoplasms
Tumors
Genes
Theca Cells
Mutation
Microdissection
Steroid hormones
Mutant Proteins
Stromal Cells
Proteins
Fallopian Tube Neoplasms
Chromatin
Neoplasms
Repair
Germ-Line Mutation
Granulosa Cells
Steroid Receptors

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Human ovarian cancer stroma contains luteinized theca cells harboring tumor suppressor gene GT198 mutations. / Peng, Min; Zhang, Hao; Jaafar, Lahcen; Risinger, John I.; Huang, Shuang; Mivechi, Nahid F; Ko, Lan.

In: Journal of Biological Chemistry, Vol. 288, No. 46, 15.11.2013, p. 33387-33397.

Research output: Contribution to journalArticle

Peng, Min ; Zhang, Hao ; Jaafar, Lahcen ; Risinger, John I. ; Huang, Shuang ; Mivechi, Nahid F ; Ko, Lan. / Human ovarian cancer stroma contains luteinized theca cells harboring tumor suppressor gene GT198 mutations. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 46. pp. 33387-33397.
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