Lung cancer is one of zhe malignant tumor that shows the highest global morbidity and mortality(1), and its mortality rate is rising annually. Non-small cell lung cancer (NSCLC) is the most frequent pathological type representing 85% of all lung cancers, with over 4000 new diagnosed cases every year and a 5-year survival rate of approximately 15%(2). Due to the typical concealed characteristic of genesis and development of lung tumors, many NSCLC patients receive their cancer diagnoses at the middle and late stages and miss the opportunity for surgery(3). Statistics from the National Lung Cancer Center in 2016 illustrate that lung cancer is currently the principal cause of morbidity and mortality among malignancies in China. Nevertheless, recent commercialization and clinical expansion of targeted therapies certainly contribute to improving the 5-year survival rate of patients, and targeted therapy has been also adopted as one of the major therapeutic strategies for NSCLC(4). However, some NSCLC patients with contraindications against targeted therapy may develop primary drug resistance or the therapeutic efficacy may be attenuated owing to the presence of coexisting mutations. Although the third-generation EGFR-TKI drugs have shown advantages in the treatment of patients with EGFR-sensitive mutations on the strength of clinical data, primary drug resistance still exists. Furthermore, only patients with EGFR mutation or EGFR T790M mutation benefit from the therapeutics, yet only about 36–48% of advanced NSCLC patients in China are EGFR mutation-positive. As a consequence, not all patients can undergo targeted therapy(5). Additionally, the drug resistance of targeted therapies is currently high, which forces us to urgently find more new targets, so that more lung cancer patients will benefit from targeted therapies.
Non-coding RNAs (ncRNAs) are non-protein-coding RNAs that can modulate gene expression and protein function. ncRNAs are implicated in all tumors being investigated and can affect all major characteristics related to cancers(6). Additionally, they are also engaged in complicated biological processes, encompassing the development and function of immune cells, immune diseases, etc. Therefore, therapies targeting these naturally occurring ncRNAs against various diseases are a highly promising approach for the treatment of tumors(7).
Long non-coding RNAs (lncRNAs) are a recently identified class of ncRNAs. Human genome encode statistics reveal that the human genome contains more than 16,000 lncRNAs. Although the functions of most lncRNAs have not been substantiated, accumulating evidence suggests the critical cellular functions of lncRNAs(8). A number of lncRNAs control downstream gene expression via affecting their transcription, thereby altering the other aspects of biology, such as DNA replication and DNA damage repair responses. Some of which function in diverse gene modulatory mechanisms. Some lncRNAs possess are structural and/or regulatory functions and can participate in mRNA splicing, turnover, and translation processes as well as signaling pathways(9). Hence, several cellular functions strongly linked to physiology can be affected by lncRNAs, and alterations in their expression are engaged in the initiation and development of many diseases. The specific expression patterns of these functional lncRNAs exhibit their potential serving as biomarkers for multiple diseases such as human cancers and as attractive therapeutic targets(10).
Given the resistance of most tumors to apoptosis, inducing cell death mechanisms such as necroptosis are strikingly recognized as a promising therapeutic modality against tumors. Necroptosis is a new programmed form of necrotic cells different from apoptosis, and anti-tumor immunity enhancement mediated by CD8+ leukocytes upon RIPK1 and RIPK3 activation in the tumor microenvironment (TME) comprises its main mechanism. Meanwhile, necroptosis can accelerate the apoptosis and necrosis of malignant tumor cells by producing immunosuppressive TME through CXCL1 and Mincle, which suggests necroptosis to be a potential immunotherapeutic target against malignant tumors(11–14).
Studies have illustrated that lncRNAs motivate tumor inflammatory response and contribute to immune escape of malignant tumors. The necroptosis-relevant lncRNAs have not been extensively identified, and their functionality in lung cancer has yet to be ascertained. Identification and characteristics of necroptosis-associated lncRNAs can allow us to deeply understand the significance of necroptosis and its related lncRNAs in immunotherapy. Given that the lncRNAs have been highly recognized as novel humoral biomarkers for tumors, we attempted to classify patients according to necroptosis-relevant lncRNAs and determine the relevance of necroptosis-associated lncRNAs and prognosis of NSCLC, to seek more effective therapeutic targets.