title: Leptin receptor expression in Middle Eastern colorectal cancer and its potential clinical implication.
abstract: 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.
authors.affiliation: Human Cancer Genomic Research, Research Centre, Saudi Arabia.
authors.forename: Shahab
authors.initials: S
authors.lastname: Uddin
authors.forename: Prashant P
authors.initials: PP
authors.lastname: Bavi
authors.forename: Azhar R
authors.initials: AR
authors.lastname: Hussain
authors.forename: Ghazi
authors.initials: G
authors.lastname: Alsbeih
authors.forename: Nasser
authors.initials: N
authors.lastname: Al-Sanea
authors.forename: Alaa
authors.initials: A
authors.lastname: Abduljabbar
authors.forename: Luai H
authors.initials: LH
authors.lastname: Ashari
authors.forename: Samar
authors.initials: S
authors.lastname: Alhomoud
authors.forename: Fouad
authors.initials: F
authors.lastname: Al-Dayel
authors.forename: Maqbool
authors.initials: M
authors.lastname: Ahmed
authors.forename: Khawla S
authors.initials: KS
authors.lastname: Al-Kuraya
mesh_terms: D000236:Adenoma / Q000209:etiology / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D020738:Leptin / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D009367:Neoplasm Staging; D009765:Obesity / Q000150:complications / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D054411:Receptors, Leptin / Q000096:biosynthesis*; D012529:Saudi Arabia; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; D020738:Leptin; D054411:Receptors, Leptin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt