Overexpression of leptin receptor predicts an unfavorable outcome in Middle Eastern ovarian cancer.
BACKGROUND
Recent epidemiological studies have suggested that obesity is associated with ovarian cancer. Obesity hormone leptin and its receptor (Ob-R) contribute to tumor development by enhancing cell growth and survival. This study was design to investigate the prevalence of leptin and Ob-R in Middle Eastern epithelial ovarian cancer (EOC) and to analyze the role of leptin and the mechanisms under its action in EOC tissue sample and cell lines.


METHODS
The expression of leptin and Ob-R was examined by immunohistochemistry in a tissue microarray of 156 EOC samples. Proliferation of EOC cells in response to leptin was assessed by MTT assays, and its anti-apoptotic effects were determined by flow cytometry. Effect of leptin on PI3K/AKT signaling pathway was further determined by western blotting.


RESULTS
In clinical samples, Ob-R overexpression was seen in 59.2% EOCs and was significantly associated with poor progression free survival (p = 0.0032). Furthermore, Ob-R expression was associated with anti apoptotic proteins Bcl-XL (p = 0.0035) and XIAP (p = 0.0001). In vitro analysis using EOC cell lines showed that leptin stimulated cell proliferation and inhibits apoptosis via activation of PI3K/AKT signaling pathway. Inhibition of PI3K activity by LY294002, a specific inhibitor of PI3-kinase abrogated leptin mediated PI3K/AKT signaling. Gene silencing of Ob-R with Ob-R siRNA in EOC cells resulted in down regulation of phospho-AKT and its down stream targets.


CONCLUSIONS
Our findings have potential clinical implication for EOC development and progression.
Uddin
Shahab
S
Department of Human Cancer Genomic Research, Research Center, Department of Pathology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Bu
Rong
R
Ahmed
Maqbool
M
Abubaker
Jehad
J
Al-Dayel
Fouad
F
Bavi
Prashant
P
Al-Kuraya
Khawla S
KS
D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004848:Epithelium / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000706:statistics & numerical data; D053208:Kaplan-Meier Estimate; D020738:Leptin / Q000494:pharmacology; D008875:Middle Aged; D008877:Middle East; D051058:Oncogene Protein v-akt / Q000378:metabolism; D017063:Outcome Assessment, Health Care; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D034622:RNA Interference; D054411:Receptors, Leptin / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D046888:Tissue Array Analysis
D016895:Culture Media, Serum-Free; D020738:Leptin; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054411:Receptors, Leptin