Abstract
Adrenocortical carcinoma (ACC) has high recurrence rates and poor prognosis with limited response to conventional cancer therapy. Recent contributions of high-throughput transcriptomic profiling identified microRNA-497 (miR-497) as significantly underexpressed, while lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) as overexpressed in ACC. miR-497 is located in the chromosomal region 17p13.1, in which there is a high frequency of loss of heterozygosity in ACC. We aim to investigate the interaction of miR-497 and MALAT1 in ACC and its functional roles in the process of tumourigenesis. In this study, we demonstrated miR-497 post-transcriptionally repressed MALAT1 while MALAT1 also competes for miR-497 binding to its molecular target, EIF4E (eukaryotic translation initiation factor 4E). We showed that overexpression of miR-497 and silencing of MALAT1 suppressed cellular proliferation and induced cell cycle arrest through downregulation of EIF4E expression. Furthermore, MALAT1 directly binds to SFPQ (splicing factor proline and glutamine rich) protein, indicating its multifaceted roles in ACC pathophysiology. This is the first study to identify the feedback axis of miR-497-MALAT1/EIF4E in ACC tumourigenesis, providing novel insights into the molecular functions of noncoding RNAs in ACC.
Highlights
Adrenocortical carcinoma (ACC) is an ultra-rare and aggressive cancer with an incidence of 0.7–2.0 cases per million populations (Kerkhofs et al 2013)
We report for the first time the reciprocal interplay of miRNA and lncRNA in ACC and its critical roles during the tumourigenic process
This study demonstrates miR-497 functions as a tumour suppressor through post-transcriptional repression of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) while MALAT1 competes for miR-497 binding to its molecular targets
Summary
Adrenocortical carcinoma (ACC) is an ultra-rare and aggressive cancer with an incidence of 0.7–2.0 cases per million populations (Kerkhofs et al 2013). Its 5-year survival rate is lower than 35% (Lughezzani et al 2010). Surgical removal of the tumour is the first-line treatment and the best chance for long-term control of malignancy (Erdogan et al 2013). Approximately 50% of patients have recurrence 6–24 months after surgical resection (Libe 2015). For patients with advanced or metastatic disease, mitotane remains the only approved adrenolytic drug that is given in parallel with cytotoxic chemotherapy, but due to its limited response rates and long-term side effects, mitotane is not an effective treatment for most patients with ACC (Schteingart et al 2012).
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