Carcinogenesis Advance Access originally published online on June 11, 2009
Carcinogenesis 2009 30(11):1832-1840; doi:10.1093/carcin/bgp145
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Leptin receptor expression in Middle Eastern colorectal cancer and its potential clinical implication
Human Cancer Genomic Research, Research Centre
1 Department of Radiation Biology at Research Centre
2 Department of Colorectal Surgery
3 Department of Pathology, King Faisal Specialist Hospital and Research Centre, MBC 98-16, PO Box 3354, Riyadh 11211, Saudi Arabia
* To whom correspondence should be addressed. 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 phosphatidylinositol 3-kinase (PI3K)/AKT activation in colorectal carcinomas (CRCs) tissues followed by in vitro studies using a panel of CRC cell lines. Obesity serves an important risk factor of several cancers including CRC that ranks as the second most common cancer in Saudi Arabia. High levels of adipokine leptin (Ob) and its Ob-R are seen in obesity and also in various carcinomas including CRC. We investigated the proliferative and antiapoptotic effect of Ob 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 Ob resulted in increased proliferation of CRC cell lines and involved activation of PI3K/AKT-signaling pathway. Pretreatment with Ob-R small interfering RNA or PI3K inhibitor inhibited these responses. Ob-R was significantly overexpressed in primary CRC relative to adenomas and normal colonic mucosa. In primary CRC, Ob-R significantly correlated with Ob expression, early stage and well-differentiated tumors. Intriguingly, patient with Ob-R positive tumors showed significantly better overall survival (P = 0.0098). Ob plays a critical role in CRC carcinogenesis through PI3K/AKT pathway via Ob-R. Ob-R is a prognostic marker associated with better survival.
Abbreviations: AJCC, American Joint Committee on Cancer; BCL-XL, basal cell lymphoma-extra large; CRC, colorectal carcinoma; p-FoxO1, forkhead box O1; IHC, immunohistochemistry; Ob, leptin; Ob-R, obesity or leptin receptor; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; PTEN, phosphatase and tensin homolog; PI3K, phosphatidylinositol 3-kinase; siRNA, small interfering RNA; XIAP, X-linked inhibitor of apoptosis protein
These are joint first authors. Received March 11, 2009; revised May 30, 2009; accepted June 6, 2009.