Long noncoding RNA LINC02432 inhibits papillary thyroid cancer via promoting ferroptosis

Abstract

Long noncoding RNAs (lncRNAs) are essential in regulating the development and progression of different types of cancer. However, our insights into their impact and mechanisms in papillary thyroid carcinoma (PTC) are still insufficient. In this study, we investigate the effects of the ferroptosis-associated long noncoding RNA LINC02432 on PTC, which recognizes ferroptosis as a critical mechanism in cancer biology and lncRNAs as significant factors in various malignancies. To identify lncRNAs associated with ferroptosis in PTC, we conduct bioinformatics analyses and perform functional assays to evaluate the biological impact of LINC02432 on PTC cells, as well as its relationship with ferroptosis. Mechanistic studies employ methods such as western blot analysis, flow cytometry, and real-time PCR. Our analysis of transcriptome data from TCGA reveals that LINC02432 is the only lncRNA consistently identified by all 10 machine learning methods used, and its expression is significantly downregulated in PTC. Overexpression of LINC02432 in PTC cells inhibits cell proliferation and migration while promoting ferroptosis through inactivation of the NRF2 pathway. LINC02432 knockdown in PTC cells yields the opposite result. These findings highlight the potential of LINC02432 as a tumor suppressor in PTC progression, offering new insights into the mechanisms underlying the development and progression of this malignancy.

1. Introduction

Thyroid cancer (TC) is one of the most prevalent endocrine malignancies globally, with an estimated 586,000 new cases reported in the latest Global Cancer Observatory survey from 2020 [1]. TC can be categorized into several subtypes, namely, papillary thyroid cancer (PTC), follicular thyroid cancer, anaplastic thyroid cancer, and medullary thyroid cancer, with PTC being the dominant subtype, accounting for approximately 80% of cases [2]. While the majority of PTC patients have a favorable prognosis, a subset may experience disease progression, including invasive growth and distant metastasis, leading to poor clinical outcomes [3,4]. Therefore, elucidating the molecular mechanisms underlying PTC progression is crucial for understanding the etiology of this disease.

Ferroptosis, a recently characterized form of programmed cell death, is characterized by the accumulation of iron-dependent lipid peroxides, resulting in phospholipid peroxidation and subsequent cellular damage [5]. Emerging evidence indicates a significant relationship between ferroptosis and TC, with effective induction of ferroptosis shown to markedly inhibit the proliferation of TC cells and impede tumor progression [6]. Additionally, research has demonstrated that hepatic leukemia factor promotes ferroptosis resistance in triple-negative breast cancer cells through gamma-glutamyltransferase 1, ultimately facilitating malignant tumor progression [7]. Thus, targeting ferroptosis represents a promising avenue for the development of innovative therapeutic strategies for TC.

Long noncoding RNAs (lncRNAs), which are noncoding RNAs longer than 200 nucleotides, are generated from extensive transcriptional processes [8]. These lncRNAs can interact with diverse cellular biomolecules, including RNA, DNA, and proteins, thereby influencing a range of cellular functions. Dysregulation of lncRNA expression has been implicated in the pathogenesis of various human diseases, including numerous cancer types, highlighting the essential roles of lncRNAs in both cellular health and disease [9]. LncRNAs have been shown to participate in numerous physiological and pathological processes, including inflammation, the immune response, carcinogenesis, and development [10,11]. Aberrant lncRNA expression has been documented in multiple cancers, including PTC [12]. Currently, lncRNAs are recognized for their ability to regulate oncogenes and critical signaling pathways, acting either upstream to initiate these pathways or downstream to modulate their effects [13]. The regulation of tumor suppressors and oncogenes involves various mechanisms, such as the ability of lncRNAs to function as RNA decoys, modulate alternative splicing, and serve as scaffolds for protein complexes.