A Novel m6A-Related LncRNA Signature for Predicting Prognosis, Chemotherapy and Immunotherapy Response in Patients with Lung Adenocarcinoma

1. Introduction

In 2021, lung cancer accounted for one-quarter of all of the cancer-related deaths on a global scale [1], and nearly 40% of all of the lung cancer cases fall into non-small cell lung cancer (NSCLC) [2]. Despite significant advances in cancer therapy, such as radiation therapy, chemotherapy, surgical resection and immunotherapy, which have made considerable progress in prolonging the survival of patients, the long-term prognosis for these patients remains unsatisfactory [3]. Therefore, it is essential to discover novel biomarkers and comprehensive insights into the mechanism for predicting an efficacious therapy for lung adenocarcinoma (LUAD). m6A, the methylation modification at the sixth position of the nitrogen atom of adenosine, is the most abundant modification of RNA. The m6A modification regulates the transcription, stability, splicing, degradation, localization, transport and translation of RNA [4,5]. The m6A modification is reversible and mediated by three types of regulators, including methyltransferases (writers), demethylases (erasers) and methylation recognition enzymes (readers). Therefore, m6A modification and regulators play vital roles in the carcinogenesis and the development of cancers, while novel mechanisms of the m6A modification remain largely unknown.

As crucial regulators in epigenetics, accumulating evidence has revealed that the long non-coding RNAs (lncRNAs) affect numerous biological processes with diverse mechanisms, including cell proliferation, metastatic progression [6], apoptosis [7] and the stemness and modulation of metabolism [8], especially in cancers. Moreover, the intracellular functions of the lncRNAs are mediated by the m6A regulators, indicating a complex and multiple interaction between the molecules. The lncRNA PRADX peroxiredoxin 1 (PRADX) promotes the nuclear factor-κB (NF-κB) activity via the UBX domain protein 1 (UBXN1) suppression, inducing the tumorigenesis of glioblastoma and colon adenocarcinoma by interacting with the enhancer of zeste homolog 2 (EZH2) [9]. Thus, the further identification of the m6A-related lncRNAs and an exploration of their functions in malignancies are imperative.

Immune checkpoint blockade (ICB) therapies, such as monoclonal antibodies against programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4), have achieved unprecedented efficacy in a wide range of malignancies through boosting the immune system to fight cancer. Notably, it has been shown that pembrolizumab is related to remarkably prolonged overall survival and a progression-free survival (PFS) duration in patients with advanced NSCLC patients, as well as...