title: Role of X-Linked Inhibitor of Apoptosis as a Prognostic Marker and Therapeutic Target in Papillary Thyroid Carcinoma.
abstract: BACKGROUND
  Papillary thyroid cancer (PTC) is the second most common cancer in females in Saudi Arabia. However, the pathogenesis of PTC is still not fully elucidated.
  
  
  OBJECTIVE
  To identify potential genes that play important role in progression of PTC, we studied the role of X-linked inhibitor of apoptosis protein (XIAP) as a potential prognostic marker and therapeutic target in a large cohort of PTC samples and cell lines.
  
  
  METHODS
  A DNA microarray chip was used to screen for gene copy number. XIAP expression was assessed by immunohistochemistry in a tissue microarray format on a cohort of 1022 clinical samples. In vitro and in vivo studies were performed using Embelin and/or LY294002 on PTC cell lines.
  
  
  RESULTS
  XIAP was found to be amplified in 14 of 29 and overexpressed in 48.8% of PTC cases. XIAP overexpression was significantly associated with old age, extrathyroidal extension, tumor size, nodal involvement, tall-cell variant, advanced stage disease, and significantly poor disease-free survival (P = .0341). XIAP was also significantly associated with phosphorylated AKT (P < .0001), Bcl-Xl (P < .0001), and Ki67 (P = .0006) proteins. Embelin treatment caused growth inhibition and apoptosis in PTC cell lines and induced tumor regression in PTC xenograft in nude mice. Finally, the combination of suboptimal doses of Embelin and LY294002 induced a synergistic apoptotic response in PTC cells.
  
  
  CONCLUSIONS
  XIAP dysregulation in PTC confers an aggressive phenotype with poor outcome. In vitro and in vivo studies using an XIAP inhibitor suggest that this subgroup of PTC with overexpression of XIAP can be therapeutically targeted, either alone or in combination, to induce efficient apoptosis in these cancers.
authors.affiliation: Human Cancer Genomic Research Unit (A.R.H., R.B., M.A., Z.J., S.B., A.K.S., S.U., K.S.A.-K.) and Departments of Endocrinology (S.A.-S.) and Pathology (F.A.-D.), King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; and Alfaisal University (K.S.A.-K.), 11533 Riyadh, Saudi Arabia.
authors.forename: Azhar R
authors.initials: AR
authors.lastname: Hussain
authors.affiliation: Human Cancer Genomic Research Unit (A.R.H., R.B., M.A., Z.J., S.B., A.K.S., S.U., K.S.A.-K.) and Departments of Endocrinology (S.A.-S.) and Pathology (F.A.-D.), King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; and Alfaisal University (K.S.A.-K.), 11533 Riyadh, Saudi Arabia.
authors.forename: Rong
authors.initials: R
authors.lastname: Bu
authors.affiliation: Human Cancer Genomic Research Unit (A.R.H., R.B., M.A., Z.J., S.B., A.K.S., S.U., K.S.A.-K.) and Departments of Endocrinology (S.A.-S.) and Pathology (F.A.-D.), King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; and Alfaisal University (K.S.A.-K.), 11533 Riyadh, Saudi Arabia.
authors.forename: Maqbool
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: Human Cancer Genomic Research Unit (A.R.H., R.B., M.A., Z.J., S.B., A.K.S., S.U., K.S.A.-K.) and Departments of Endocrinology (S.A.-S.) and Pathology (F.A.-D.), King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; and Alfaisal University (K.S.A.-K.), 11533 Riyadh, Saudi Arabia.
authors.forename: Zeenath
authors.initials: Z
authors.lastname: Jehan
authors.affiliation: Human Cancer Genomic Research Unit (A.R.H., R.B., M.A., Z.J., S.B., A.K.S., S.U., K.S.A.-K.) and Departments of Endocrinology (S.A.-S.) and Pathology (F.A.-D.), King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; and Alfaisal University (K.S.A.-K.), 11533 Riyadh, Saudi Arabia.
authors.forename: Shaham
authors.initials: S
authors.lastname: Beg
authors.affiliation: Human Cancer Genomic Research Unit (A.R.H., R.B., M.A., Z.J., S.B., A.K.S., S.U., K.S.A.-K.) and Departments of Endocrinology (S.A.-S.) and Pathology (F.A.-D.), King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; and Alfaisal University (K.S.A.-K.), 11533 Riyadh, Saudi Arabia.
authors.forename: Saif
authors.initials: S
authors.lastname: Al-Sobhi
authors.affiliation: Human Cancer Genomic Research Unit (A.R.H., R.B., M.A., Z.J., S.B., A.K.S., S.U., K.S.A.-K.) and Departments of Endocrinology (S.A.-S.) and Pathology (F.A.-D.), King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; and Alfaisal University (K.S.A.-K.), 11533 Riyadh, Saudi Arabia.
authors.forename: Fouad
authors.initials: F
authors.lastname: Al-Dayel
authors.affiliation: Human Cancer Genomic Research Unit (A.R.H., R.B., M.A., Z.J., S.B., A.K.S., S.U., K.S.A.-K.) and Departments of Endocrinology (S.A.-S.) and Pathology (F.A.-D.), King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; and Alfaisal University (K.S.A.-K.), 11533 Riyadh, Saudi Arabia.
authors.forename: Abdul K
authors.initials: AK
authors.lastname: Siraj
authors.affiliation: Human Cancer Genomic Research Unit (A.R.H., R.B., M.A., Z.J., S.B., A.K.S., S.U., K.S.A.-K.) and Departments of Endocrinology (S.A.-S.) and Pathology (F.A.-D.), King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; and Alfaisal University (K.S.A.-K.), 11533 Riyadh, Saudi Arabia.
authors.forename: Shahab
authors.initials: S
authors.lastname: Uddin
authors.affiliation: Human Cancer Genomic Research Unit (A.R.H., R.B., M.A., Z.J., S.B., A.K.S., S.U., K.S.A.-K.) and Departments of Endocrinology (S.A.-S.) and Pathology (F.A.-D.), King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; and Alfaisal University (K.S.A.-K.), 11533 Riyadh, Saudi Arabia.
authors.forename: Khawla S
authors.initials: KS
authors.lastname: Al-Kuraya
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000235:genetics; D016227:Benzoquinones / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000502:physiology; D002277:Carcinoma / Q000175:diagnosis* / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002291:Carcinoma, Papillary; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods*; D011379:Prognosis; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors* / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D014408:Biomarkers, Tumor; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C010945:embelin