Abstract 67: Functional analysis of lncRNA DUXAP10 in anaplastic thyroid cancer

Abstract

Abstract Anaplastic Thyroid Cancer (ATC) is one of the most aggressive forms of thyroid cancer, with only a 4% survival rate with metastatic disease. Further, ATC is highly refractory and resistant to traditional therapeutics, resulting in poor patient outcomes. Therefore, the elucidation of molecular mechanisms that contribute to ATC’s metastatic propensity, and the identification of molecular biomarkers for the early diagnosis, prognosis, and therapeutic intervention are critical unmet needs. This is reinforced by the many challenges that accompany the use of small molecular inhibitors and targeted therapy to treat ATC. Recently, long non-coding RNAs (lncRNA) have been identified as having major regulatory roles in the fine-tuning of gene expression and cellular behavior of cancer cells, highlighting the importance of identifying non-coding profiles that potentially impact ATC behavior. Using the publicly available datasets (Gene Expression Omnibus; GSE33630, GSE85457), we have investigated gene expression profiles of ATC vs. normal thyroid tissue. Bioinformatic analyses with the GEO2R program identified the lncRNA, Double Homeobox A Pseudogene 10 (DUXAP10), to be highly upregulated in ATC patient-derived tissue samples when compared to normal thyroid tissue. DUXAP10 is structurally a pseudogene-derived lncRNA that has been identified to be upregulated in hepatocellular, bladder, esophageal, and gastric cancer, as well as papillary thyroid cancer. We found that the expression of DUXAP10 is also upregulated in the ATC cell line, T238, in comparison to Nthy-ori-3-1, an immortalized normal thyroid cell line. T238 is homozygous for the BRAF V600E mutation, which serves as a driver mutation. However, breakthrough alterations can limit the effectiveness of anti-BRAF therapeutics and highlight the utility of combination therapies. To understand the consequences of DUXAP10 overexpression in ATC, we used CRISPRi technology to determine the phenotypic and genotypic effects of DUXAP10 downregulation. CRISPRi knockdown of DUXAP10 significantly reduces the migratory capabilities of T238 by 87%. This provides evidence that elevated DUXAP10 expression may increase the probability and negative consequences of metastases. Thus, targeting DUXAP10 expression may have beneficial clinical consequences. The role of DUXAP10 on thyroid cell proliferation and invasion are currently in progress. Thus, we have identified DUXAP10 as a potential biomarker for ATC diagnosis and prognosis, as well as a potential therapeutic target. Further analysis remains to be determined if DUXAP10 can be targeted for standalone or combination therapy, as well as the elucidation of the full range of interactions that DUXAP10 has in ATC. Citation Format: Nicole DeSouza, Michelle Carnazza, Danielle Quaranto, Tara Jarboe, Kaci Kopec, Sarnath Singh, Augustine Moscatello, Jan Geliebter, Raj K. Tiwari. Functional analysis of lncRNA DUXAP10 in anaplastic thyroid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 67.