OR29-2 A PROGNOSTIC ROLE OF MIR-9 AND MIR-30C MICRORNAS IN ADULT METASTATIC ADRENOCORTICAL CANCER THROUGH LIN28 POST-TRANSCRIPTIONAL REPRESSION

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR29-Adrenal Tumors & Pheochromocytoma
Translational
Monday, June 17, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 11:30 AM
Room 134 (Moscone Center)
Andre Murad Faria*1, Beatriz Marinho Mariani1, Tamaya Castro Ribeiro1, Ibere Cauduro Soares2, Gabriela R V Sousa1, Danilo Bacic1, Antonio Marcondes Lerario1, Daniel Soares Freire1, Alda Wakamatsu3, Rodrigo A Ressio3, Venancio A F Alves3, Maria Claudia N Zerbini3, Berenice Bilharinho Mendonca1, Maria Candida Barisson Villares Fragoso1, Ana Claudia Latronico1 and Madson Q Almeida1
1Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, 2Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, 3Faculdade de Medicina da Universidade de São Paulo
Introduction: LIN28, an evolutionarily conserved RNA-binding protein, has emerged as an important modulator of cell reprogramming and pluripotency of embryonic stem cells. LIN28 can bind to the terminal loops of the precursor of the let-7 family of microRNAs (miRNA), thereby blocking the processing of let-7 into its mature form. Aberrant LIN28 expression has been demonstrated in different human cancers. However, the mechanisms of transcriptional and post-transcriptional regulation of LIN28 are still poorly known. Recently, 4 miRNAs were identified as directly repressing LIN28 (let-7, mir-125, mir-9, and mir-30). In this study, we investigated the expression of LIN28A and its miRNA regulators in adrenocortical cancer (ACC). Patients and Methods: LIN28 staining was evaluated in 28 adult ACC (14 non-metastatic and 14 metastatic). Expression of LIN28A and of its miRNAs regulators (let-7a, let-7b, let-7c, let-7d, let-7e, let-7f, let-7g, mir-98, mir-9, mir-30b, mir-30c, mir-125a-3p, mir-125a-5p, mir-125b) was assessed in 31 adult ACC (16 non-metastatic and 15 metastatic) and in a pool of normal adrenal cortex by real time PCR. LIN28A copy number variation was studied by multiplex ligation-dependent probe amplification in 22 cases. Results: LIN28 protein expression was significantly lower in metastatic ACC (H score median 0, range from 0 to 1.0) when compared to non-metastatic ACC (1.0, from 0 to 2.31; p=0.001). In addition, LIN28A gene deletion was not detected in the tumors. A weak LIN28 staining was also associated with a reduced recurrence-free survival in ACC patients (p=0.01). LIN28A expression at mRNA level did not correlate with overall and recurrence-free survival (p=0.79 and p=0.27, respectively), suggesting a post-transcriptional defect. Interestingly, mir-9  and mir-30c expression clustered together in ACC (r=0.5, p=0.02). mir-9 expression was higher in metastatic (fold change 2076, from 36.2 to 15.975) than in non-metastatic ACC (134.8, from 2.4 to 9307; p=0.02). mir-9 overexpression was significantly associated with reduced overall and recurrence-free survival (p=0.03 and 0.01, respectively). Moreover, mir-30c overexpression was correlated with a reduced overall survival (p=0.04). The other miRNAs did not present any prognostic role in ACC. Conclusion: Our findings demonstrate for the first time a prognostic role of mir-9 and mir-30c in adult ACC, and suggest that their overexpression leads to a LIN28 post-transcriptional repression in metastatic ACC.

Nothing to Disclose: AMF, BMM, TCR, ICS, GRVS, DB, AML, DSF, AW, RAR, VAFA, MCNZ, BBM, MCBVF, ACL, MQA

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: FAPESP (2011/09092-0)