Relationship of Focally Amplified Long Noncoding on Chromosome 1 (FAL1) lncRNA with E2F Transcription Factors in Thyroid Cancer

Abstract

Recent functional genomic studies revealed that the oncogenic activity of focally amplified lncRNA on chromosome 1 (FAL1, ENSG00000228126) contributes to tumor growth by p21 repression in human cancers. However, the expression of FAL1 was not investigated in papillary thyroid cancer (PTC). We aimed to determine if FAL1 was up-regulated in PTC compared to paired contralateral normal thyroid tissues, and to investigate the potential targets of this lncRNA and its clinicopathological significance in PTC. We analyzed FAL1 and p21 expression levels in 100 PTC samples and matched normal thyroid tissue by qRT-PCR. Using lncRNA microarray data from the Gene Expression Omnibus (accession no. GSE61763), we explored potential targets of FAL1 by Gene Set Enrichment Analysis, followed by verification by qRT-PCR in our PTC samples. A cross-sectional observational study was conducted to investigate the relationship between patients' clinicopathological features and FAL1 expression. FAL1 expression was significantly higher in PTC than in paired normal thyroid tissues (paired t test, P < 0.001). p21 mRNA expression was also increased, not decreased, in PTC, and had no correlation with FAL1 expression (r = 0.0897, P = 0.4002). Gene Set Enrichment Analysis, using publicly available microarray data, indicated that a gene set related to the cell cycle, including E2F transcription factors 1 and 2, and cyclin D1, was coordinately enriched among samples with high FAL1 expression. A volcano plot showed that E2F1, E2F2, and VEGFA mRNAs were increased in the high FAL1 samples. In clinicopathological analyses, multifocality was more frequently observed in PTC patients with high FAL1 (P = 0.018). Multivariate analysis showed that high FAL1 expression increased the risk of multifocality (after adjustment for clinical variables, OR = 4.019, CI = 1.041-11.020, P = 0.043). FAL1 may have a role in cell-cycle progression and may be associated with aggressive tumor behavior in PTC.