Abstract
Simple SummaryMerging evidence has indicated that dedifferentiation is the main concern associated with radioactive iodine (RAI) refractoriness in patients with papillary thyroid cancer (PTC), and the underlying mechanisms of PTC dedifferentiation remain unclear. This study systematically delineated the expression pattern, tumor immune microenvironment, drug sensitivity, and prognostic value of differentiation-related lncRNAs. It also demonstrated that DPH6-DT could be considered as a novel signature to indicate differentiation and promote TC progression via activating the PI3K-AKT signaling pathway.Dedifferentiation is the main concern associated with radioactive iodine (RAI) refractoriness in patients with papillary thyroid cancer (PTC), and the underlying mechanisms of PTC dedifferentiation remain unclear. The present work aimed to identify a useful signature to indicate dedifferentiation and further explore its role in prognosis and susceptibility to chemotherapy drugs. A total of five prognostic-related DR-lncRNAs were selected to establish a prognostic-predicting model, and corresponding risk scores were closely associated with the infiltration of immune cells and immune checkpoint blockade. Moreover, we built an integrated nomogram based on DR-lncRNAs and age that showed a strong ability to predict the 3- and 5-year overall survival. Interestingly, drug sensitivity analysis revealed that the low-risk group was more sensitive to Bendamustine and TAS-6417 than the high-risk group. In addition, knockdown of DR-lncRNAs (DPH6-DT) strongly promoted cell proliferation, invasion, and migration via PI3K-AKT signal pathway in vitro. Furthermore, DPH6-DT downregulation also increased the expression of vimentin and N-cadherin during epithelial-mesenchymal transition. This study firstly confirms that DR-lncRNAs play a vital role in the prognosis and immune cells infiltration in patients with PTC, as well as a predictor of the drugs’ chemosensitivity. Based on our results, DR-lncRNAs can serve as a promising prognostic biomarkers and treatment targets.
Highlights
To identify the functions and interaction of DR-Long noncoding RNAs (lncRNA) regulators in papillary thyroid cancer (PTC), we analyzed the 58 normal tissues and 492 PTC tissues from the The Cancer Genome Atlas (TCGA) dataset and showed that most of the expressions of differentiation-related regulators were significantly lower in PTC, including PAX8, SLC5A5, SLC5A8, SLC26A4, FOXE1, TG, TSHR, THRA, THRB, DIO1-2, GLIS3, and TPO
The PPI network showed that TSHR was a hub gene which could interact with the other 15 genes (Figure S1A)
To study the relationship between differentiation-related regulators and lncRNA, Pearson correlation analysis was used to screen out DR-lncRNAs based on the criterion of Pearson’s coefficient |R| > 0.5 and p < 0.001
Summary
The incidence of thyroid cancer (TC) has been increasing in recent years and papillary. The vast majority of patients with PTC have a favorable prognosis via reasonable treatments, including thyroidectomy, thyroid-stimulating hormone (TSH) suppressive therapy, and radioactive iodine (RAI) therapy, approximately. 10–20% of PTCs suffer from disease recurrence and progress to distant metastasis during follow-up [2]. Among these patients, dedifferentiation is the main reason that leads to PTC transform into poorly differentiated or anaplastic TC (ATC) with poor clinical outcome. The treatment options for these patients are limited, and the molecular mechanisms of PTC dedifferentiation remain unclear
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