Identification and Validation of a Prognostic Signature for Thyroid Cancer Based on Ferroptosis-Related Genes

Abstract

Background: Thyroid cancer is the most common endocrine malignancy. Most PTC patients have a good prognosis; however, there are 5–20% of PTC patients with extra-thyroidal invasion, vascular invasion, or distant metastasis who have relatively poor prognoses. The aim of this study is to find new and feasible molecular pathological markers and therapeutic targets for early identification and appropriate management. Methods: The GEO and TCGA databases were used to gather gene expression data and clinical outcomes. Based on gene expression and clinical parameters, we developed a ferroptosis-related gene-based prognostic model and a nomogram. CCK-8, wound-healing, and transwell assays were conducted to explore the proliferation, migration, and invasion abilities of thyroid cancer cells. Results: We found 75 genes associated with ferroptosis that were differentially expressed between normal thyroid tissue and thyroid cancer tissues. The prognostic values of the 75 ferroptosis-related gene expressions were evaluated using the TCGA-THCA dataset, and five (AKR1C3, BID, FBXW7, GPX4, and MAP3K5) of them were of significance. Following that, we chose AKR1C3 as the subject for further investigation. By combining gene expression and clinical parameters, we developed a ferroptosis-related gene-based prognostic model with an area under the curve (AUC) of 0.816, and the nomogram also achieved good predictive efficacy for the three-year survival rate of thyroid cancer patients. Knocking down AKR1C3 enhances thyroid cancer cell proliferation, invasion, and migration abilities. Conclusions: A ferroptosis-related gene-based prognostic model was constructed that provided unique insights into THCA prognosis prediction. In addition, AKR1C3 was found to be a progression promoter in thyroid cancer cell lines.

AKR1C3 silencing inhibits autophagy‐dependent glycolysis in thyroid cancer cells by inactivating ERK signaling

“…A previous study has reported that AKR1C3 expression is significantly elevated in thyroid cancer tissues, and high expression of AKR1C3 tends to have poor prognosis (Wang et al, 2022). However, the exact role of AKR1C3 in the malignant phenotypes of thyroid cancer remains to be elucidated.…”

“…A growing number of studies have shown that overexpressed AKR1C3 occurs in multiple types of human cancer and is involved in the development of human cancer and chemotherapy resistance, such as hepatocellular carcinoma, prostate cancer, breast cancer and esophageal cancer (Doig et al, 2016;Li, 2018a;Pan et al, 2022;Xu et al, 2017). More intriguingly, AKR1C3 exhibits elevated expression in thyroid cancer tissues, and high AKR1C3 expression tends to have a poor prognosis (Wang et al, 2022). Consistent with the aforementioned studies, the present work supported that AKR1C3 was upregulated in thyroid As an indispensable molecular process for maintaining cellular homeostasis, autophagy is a protective mechanism for cells to respond to dangerous stimuli by degrading damaged macromolecular proteins or organelles (Deretic, 2021).…”

“…Aldo‐keto reductase family 1 member C3 (AKR1C3), a member of the aldo‐keto reductase protein superfamily, has been demonstrated to be closely related to tumorigenesis (Penning, 2017). According to the Gene Expression Omnibus dataset and the literature, AKR1C3 is differentially expressed in thyroid cancer tissues, and the higher the expression, the worse the prognosis (Wang et al, 2022). It is worth noting that interference with AKR1C3 can inhibit extracellular signal‐regulated kinase (ERK) phosphorylation, which leads to the elevation of autophagy level and reduction of glycolytic ability in thyroid cancer cells (Jing et al, 2022; Wang et al, 2018, 2019b).…”

Construction and validation of an oxidative-stress-related risk model for predicting the prognosis of osteosarcoma

“…MAP3K5 is a serine/threonine kinase that mediates the MAP kinase signal transduction pathway [ 44 ] in different cancer types, such as pancreatic cancer [ 45 ], prostate cancer [ 46 ], and thyroid cancer [ 47 ]. It is also a ferroptosis-related gene associated with increased ROS accumulation [ 48 ].…”

A novel ferroptosis‑related gene signature for overall survival prediction and immune infiltration in patients with breast cancer

“…A previous study developed a 13-gene prognostic model ( 49 ), wherein AUCs were recorded to be 0.819, 0.815 and 0.891 for 1-, 3- and 5-year survival rates of patients with acute myeloid leukemia. In another study, five FRGs were used to construct a prognostic model with an AUC of 0.816, and the nomogram exhibited good performance in the prediction of 3-year survival rate of patients with thyroid cancer ( 50 ). However, the effect of FRGs in prognostic prediction for patients with breast cancer has not been fully evaluated.…”