Role of PELP1/MNAR signaling in ovarian tumorigenesis.
Emerging evidence suggests that nuclear receptor (NR) coregulators have potential to act as master genes and their deregulation can promote oncogenesis. Proline-, glutamic acid-, and leucine-rich protein-1 (PELP1/MNAR) is a novel NR coregulator. Its expression is deregulated in hormone-driven cancers. However, the role of PELP1/MNAR in ovarian cancer progression remains unknown. Analysis of serial analysis of gene expression data suggested deregulation of PELP1/MNAR expression in ovarian tumors. Western analysis of PELP1/MNAR in normal and serous ovarian tumor tissues showed 3- to 4-fold higher PELP1/MNAR expression in serous tumors compared with normal ovarian tissues. To examine the significance of PELP1/MNAR in ovarian cancer progression, we have generated model cells that overexpress PELP1/MNAR and ovarian cancer cells in which PELP1/MNAR expression is down-regulated by stable expression of PELP1/MNAR-specific shRNA. Down-regulation of PELP1/MNAR in cancerous ovarian model cells (OVCAR3) resulted in reduced proliferation, affected the magnitude of c-Src and protein kinase B (AKT) signaling, and reduced tumorigenic potential of ovarian cancer cells in a nude mouse model. PELP1/MNAR overexpression in nontumorigenic immortalized surface epithelial cells (IOSE cells) promoted constitutive activation of c-Src and AKT signaling pathways and promoted anchorage-independent growth. Immunohistochemical studies using human ovarian cancer tissue arrays (n = 123) showed that PELP1/MNAR is 2- to 3-fold overexpressed in 60% of ovarian tumors, and PELP1/MNAR deregulation occurs in all different types of ovarian cancer. Collectively, these results suggest that PELP1/MNAR signaling plays a role in ovarian cancer cell proliferation and survival, and that its expression is deregulated in ovarian carcinomas.
Dimple
Chakravarty
C
Department of Obstetrics and Gynecology and Cancer Research and Therapy Center at The University of Texas Health Science Center, San Antonio, Texas, USA.
Nair
Sujit S
SS
Rajhans
Rajib
R
Pitcheswara
Perla R
PR
Liu
Jinsong
J
Balasenthil
Seetharaman
S
Le
Xiao-Feng
XF
Burow
Matthew E
ME
Auersperg
Nelly
N
Tekmal
Rajeshwar Rao
RR
Broaddus
Russell R
RR
Vadlamudi
Ratna K
RK
D018262:Adenocarcinoma, Clear Cell / Q000378:metabolism / Q000473:pathology; D002288:Adenocarcinoma, Mucinous / Q000378:metabolism / Q000473:pathology; D000818:Animals; D018269:Carcinoma, Endometrioid / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D049109:Cell Proliferation; D056970:Co-Repressor Proteins; D018284:Cystadenocarcinoma, Serous / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction; D046888:Tissue Array Analysis; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases / Q000378:metabolism
D056970:Co-Repressor Proteins; C438485:PELP1 protein, human; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D015534:Trans-Activators; D014157:Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt