Abstract 2804: Long non-coding RNA LINC01614 regulates ferroptosis-mediated carcinogenic phenotypes in papillary thyroid cancer

Abstract Papillary thyroid cancer (PTC) is the most common endocrine malignancy and is increasing annually in incidence by about 3%. PTC has a significantly higher prevalence in females of childbearing age and aggressiveness increases among males. Despite a high survival rate, disease recurrence and metastasis remain prominent issues-even decades after diagnosis. Therefore, the identification of prognostic biomarkers and actionable therapeutic targets remains a critical need. A newer class of epigenetic and regulatory molecules, known as long non-coding RNAs (lncRNAs), have demonstrated differential expression patterns in a variety of cancer types. lncRNAs modulate gene expression and drive carcinogenic behavior- making them attractive biomarkers and/or therapeutic targets for investigation. Bioinformatic analysis of our PTC vs. normal thyroid genomic repository identified the lncRNA LINC01614 transcript as significantly 12-fold upregulated in PTC. Thus, we are studying LINC01614 as a potential PTC biomarker. LINC01614 was found to be upregulated in thyroid cancer cell lines. Two PTC cell lines, TPC1 (∼5 fold upregulated; RET/PTC rearrangement; female) and K1 (∼2 fold upregulated; BRAFV600E; male), were selected for in vitro study. For phenotypic evaluation, CRISPRi technique was employed to achieve transcriptional repression of LINC01614 in TPC1and K1. LINC01614 knockdown in TPC1 and K1 resulted in decreased migration (∼20%), clonogenicity (∼50% and ∼34%, respectively), and proliferation (∼55% and ∼45%, respectively). RNA sequencing analysis of CRISPRi knockdown cell lines vs. CRISPRi controls demonstrated reduced expression of key ferroptosis-related genes- SLC7A11 and SLC3A2. Both genes encode for the xCT system (cystine/glutamate reverse transporter) that regulates the uptake of cystine - a key precursor for glutathione (GSH) synthesis. GSH is a critical antioxidant defense against lipid peroxidation, further preventing ferroptosis. Total cell iron levels were quantified and found to be significantly higher in our LINC01614 knockdowns, signifying increased ferroptosis induction. Studies are currently underway to identify the impact of LINC01614 on lipid peroxidation levels, reactive oxygen species production, as well as identification of ferroptosis-related protein expression in our PTC in vitro model. Elucidation of LINC01614’s carcinogenic mechanism of action through ferroptosis regulation is a promising and novel avenue of exploration for PTC prognosis and therapy. Citation Format: Danielle Quaranto, Michelle Carnazza, Nicole R. DeSouza, Sina Dadafarin, Augustine Moscatello, Humayun K. Islam, Codrin Iacob, Raj K. Tiwari, Jan Geliebter. Long non-coding RNA LINC01614 regulates ferroptosis-mediated carcinogenic phenotypes in papillary thyroid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2804.