Despite great efforts made in recent years, the incidence of Lung squamous cell carcinoma (LUSC), a histological subtype of non-small cell lung carcinoma (NSCLCs) (Travis, 2002; Travis et al., 2015; Youlden, Cramb, & Baade, 2008), remains increasing and is a leading cause of cancer death worldwide (Stinchcombe, 2014). A poor 5-year overall survival (OS) rate of LUSC by current treatments further prompts that novel and efficient clinical managements are urgent to be established (Garon et al., 2019; Miller et al., 2012). Therefore, it is strongly required that definite diagnostic biomarkers, new therapeutic targets, and favorable prognostic signatures for patients with LUSC be found.
Iron not only is a vital microelement in normal cell physiological growth and development, but also plays a vital role in tumor cell of LUSCs (Babu & Muckenthaler, 2016; Feger et al., 2001; G. X. Wang et al., 2017). Previous studies have shown that ferroptosis, as a unique iron-dependent form of regulated cell death characterized by overwhelming lipid peroxidation due to accumulation of reactive oxygen species (ROS) (Doll et al., 2017; Yang et al., 2014; J. Zheng & Conrad, 2020), which differs from others such as apoptosis, necrosis and autophagy in respects of morphology, genetics and biochemistry (Dixon et al., 2012), is involved in the pathological process of lung cancer cell proliferation, migration and prognosis (Han et al., 2021; C. Y. Wu et al., 2021). Meanwhile, the adjustable sensitivity of lung cancer cells to ferroptosis by pharmacological strategies can affect the outcomes of lung carcinoma (Alvarez et al., 2017; Freire Boullosa et al., 2021). Overexpression of ΔNp63α protects LUSC from oxidative damage-induced ferroptosis to implement cancer cell with high viability (G. X. Wang et al., 2017). Thus, exploring regulations of ferroptosis is significant for the development of novel anti-LUSCs drugs and the improvement OS of patient with LUSC (J. Guo et al., 2018).
Long non-coding RNAs (lncRNAs) are transcripts composed by nucleotides ranging in length from 200bp to 10kbp (D. Wang et al., 2020). Although limited in protein-encode function, lncRNAs have been found to perform various functions in a wide variety of important biological and pathological processes, such as chronic inflammatory response, cell migration and invasion (Bai et al., 2020; Qian et al., 2018). Notably, previous studies have shown lncRNAs play as the essential regulators in ferroptosis and iron metabolism in lung cancers. For instance, LINC0036 exerts anti-ferroptosis effect in lung carcinoma by acting as an endogenous sponge of microRNA 6852 to regulate the expression of cystathionine-β-synthase (CBS), a surrogate marker of ferroptosis (M. Wang et al., 2019). Metallothionein 1D pseudogene (MT1DP) sensitizes NSCLCs toward ferroptosis via elevating lipid reactive oxygen species (ROS) (Gai et al., 2020). Silencing nuclear enriched transcript 1 (NEAT1) aggravates erastin-induced ferroptosis through decreasing levels of ACSL4, SLC7A11, and GPX4 in NSCLCs (H. Wu & Liu, 2021). Those have indicated ferroptosis-related lncRNAs (FerLncRNAs) are closely related to pathological outcome of NSCLCs, but whether to regulate LUSC and the specific mechanism maintains unclear. Therefore, identifying FerLncRNAs in LUSC is a key link in creating a prognostic signature based on FerLncRNAs, which may be contribute to a theoretical basis for novel strategies to treat patients with LUSC.
Immune checkpoint molecules, the receptors expressed on immune cell, inhibit immune response by triggering immune cells into a state of “exhaustion” (Wykes & Lewin, 2018; Zhou et al., 2017). Tumor cells activate immune checkpoint pathways to escape from host immune surveillance and create a microenvironment benefitting for neoplasia (McGranahan et al., 2016; Zhou et al., 2019). Administration of immune checkpoint inhibitors (ICIs) as an immunotherapy has been applied in clinical treatments partly to cancer patients (Grasselly et al., 2018; D. Liu, 2019). There have been studies finding lncRNAs are closely correlated with tumor immunity, but the role of FerLncRNAs in LUSC tumor immunity remains largely unexplored.
In this study, a prognosis signature of FerLncRNAs was constructed to evaluate actual scientific relevance and applicability to LUSC and identified the roles in tumor immunity, which contributes to clarifying the relationship between FerLncRNAs and LUSC, providing potential diagnostic biomarker and therapeutic targets to LUSC in clinic.