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Carcinogenesis Advance Access published online on June 11, 2009
Carcinogenesis, doi:10.1093/carcin/bgp145
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Leptin Receptor Expression in Middle Eastern Colorectal Cancer and it's Potential Clinical Implication

Shahab Uddin{diamondsuit}, Prashant Bavi{diamondsuit}, Azhar R. Hussain, Ghazi Alsbeih{wedge}, Nasser Al-Sanea$, Alaa AbdulJabbar$, Luai H. Ashari$, Samar Alhomoud$, Fouad Al-Dayel@, Maqbool Ahmed and Khawla S. Al-Kuraya#

Cancer Centre For Children's Cancer and Research
{wedge} Department of Radiation Biology at Research Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
$ Department of Colorectal Surgery, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
@ Department of Pathology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

# Correspondence: Khawla S. Al-Kuraya, MD, FCAP, Department of Cancer Genomic Research, King Fahad National Center for Children's Cancer & Research, King Faisal Specialist Hospital and Research Cancer, MBC#98-16, P.O. Box 3354, Riyadh 11211, Saudi Arabia, Tel; (966)-1-205-5167; Fax (966)-1-205-5170, Email: Kkuraya{at}kfshrc.edu.sa

We investigated the role of leptin receptor(Ob-R) and its relationship with PI3K/AKT activation in colorectal carcinomas(CRC) tissues followed by in vitro studies using a panel of CRC cell lines. Obesity serves an important risk factor of several cancers including CRC which ranks as the second most common cancer in Saudi Arabia. High levels of adipokine leptin and its Ob-R are seen in obesity and also in various carcinomas including CRC. We investigated the proliferative and antiapoptotic effect of leptin on human CRC cell lines Caco-2, HT-29 and SW-840 and the role of PI3K/AKT signaling pathway in mediating these actions. Then the expression of Ob-R and its relationship with clinicopathological features was analyzed in 448 CRC, 229 normal colon mucosa and 24 colorectal adenomas using tissue microarray technology. Treatment with leptin resulted in increased proliferation of CRC cell lines and involved activation of PI3K/AKT signaling pathway. Pretreatment with Ob-R siRNA or PI3K inhibitor inhibited these responses. Ob-R was significantly over expressed in primary CRC relative to adenomas and normal colonic mucosa. In primary CRC, Ob-R significantly correlated with leptin expression, early stage and well differentiated tumors. Intriguingly, patient with Ob-R positive tumors showed significantly better overall survival(p = 0.0098). Leptin plays a critical role in CRC carcinogenesis through PI3K/AKT pathway via Ob-R. Ob-R is a prognostic marker associated with better survival.

Key Words: Leptin receptor • PI3K-AKTpathway • colorectal cancer • obesity • tissue microarray

{diamondsuit} Joint First Author

Received March 11, 2009; revised May 30, 2009; accepted June 6, 2009.


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