Role of X-Linked Inhibitor of Apoptosis as a Prognostic Marker and Therapeutic Target in Papillary Thyroid Carcinoma

• Published in: The journal of clinical endocrinology and metabolism 2015-07, Vol.100 (7), p.E974-E985
• Main Authors: Hussain, Azhar R, Bu, Rong, Ahmed, Maqbool, Jehan, Zeenath, Beg, Shaham, Al-Sobhi, Saif, Al-Dayel, Fouad, Siraj, Abdul K, Uddin, Shahab, Al-Kuraya, Khawla S
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Animals; Antineoplastic Agents - therapeutic use; Apoptosis - genetics; Benzoquinones - therapeutic use; Biomarkers, Tumor - antagonists & inhibitors; Biomarkers, Tumor - physiology; Carcinoma - diagnosis; Carcinoma - drug therapy; Carcinoma - mortality; Carcinoma - pathology; Carcinoma, Papillary; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, Nude; Middle Aged; Molecular Targeted Therapy - methods; Prognosis; Thyroid Cancer, Papillary; Thyroid Neoplasms - diagnosis; Thyroid Neoplasms - drug therapy; Thyroid Neoplasms - mortality; Thyroid Neoplasms - pathology; X-Linked Inhibitor of Apoptosis Protein - antagonists & inhibitors; X-Linked Inhibitor of Apoptosis Protein - physiology; Xenograft Model Antitumor Assays
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2014-4356

Context: 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. Design: 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. Conclusion: 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.