Introduction
Lung cancer (LC), the most common cancer worldwide, is a significant cause of cancer death [
1]. Non-small cell lung cancer (NSCLC) accounts for the majority of LC, and lung adenocarcinoma (LUAD) accounts for more than half of NSCLC [
2]. Despite the excellent surgical outcome and prognosis of early-stage LUAD, the overall prognosis of LUAD is still poor. Comprehensive therapy, represented by chemotherapy such as platinum drugs and immune checkpoint blockade therapy such as PD-1 and PD-L1 inhibitors, has shown promising benefits in advanced LUAD [
3,
4]. Unfortunately, due to the widespread tumor heterogeneity, a large number of patients are resistant to the medication, leading to cancer death [
5,
6]. Therefore, it is necessary to discover novel subtypes of LUAD to predict the overall survival and provide more appropriate therapy options for the patients.
Pyroptosis is a type of programmed cell death that can promote inflammation. It is characterized by two major features, cell swelling and rupture, and the release of a range of inflammatory factors [
7,
8]. Pyroptosis is strongly associated with various cancer, such as gastric cancer, esophageal cancer, and lung cancer [
9‐
13].
Activation of pyroptosis has been found to have an impressive inhibitory effect on lung cancer. Cucurbitacin B can inhibit NSCLC through activation of TLR4/NLRP3/GSDMD-dependent pyroptosis [
14]. Polyphyllin VI exerts anti-tumor effects by regulating the ROS/NF-κB/NLRP3/GSDMD signaling axis [
15].
In our study, we constructed a model based on different PRGs signatures to predict the overall survival rate using the gene expression datasets from the TCGA and GEO databases. Our findings can guide individualized treatment and prognosis prediction of LUAD patients.
Discussion
Pyroptosis is a unique form of cell death executed by the GSDM protein family, involving multiple immune and inflammatory responses [
8]. The classical pyroptosis is associated with NLRP3 inflammasome complex, which comprises NLRP3, ACS and caspase-1 [
18]. Pyroptosis plays a dual role in cancer progression and therapeutic mechanisms [
19]. Pyroptosis-derived cytokines can induce the transformation of normal cells into tumor cells. However, pyroptosis can also promote tumor cell death. Pyroptosis signature has been used to predict prognosis in a variety of malignancies, but the role in lung adenocarcinoma is unclear, and the aim of our study was to elucidate this role.
The current tumor-node-metastasis (TNM) staging system is important in assessing the prognosis of patients with malignancies [
20]. Our results also revealed differences in the prognosis of patients with different T stages, N stages, and total stages (Fig.
5). However, it is difficult to make accurate survival predictions and treatment decisions for LUAD patients based on TNM stages. Therefore, we developed a risk scoring system (Risk Score) associated with DEGs of different PRGs subtypes in LUAD patients. In this study, assessing the expression levels of 13 PRGs-related genes in combination with traditional TNM classification can better guide survival predictions and treatment decisions for patients with LUAD (Fig.
5).
In this study, we established a prognosis prediction model for LUAD patients based on the pyroptosis-related genes (PRGs), and confirmed the validity and applicability of the model. 13 PRGs-related genes (IL-1A, P2RX1, GSTM2, ESYT3, ZNF682, KCNF1, STK32A, HHIPL2, GDF10, NDC80, GSTA1, BCL2L10 and CCR2) were found for the prognostic signature. For further understanding of the model, we searched the information on key genes.
Interleukin-1 (IL-1) is a symbol of systemic inflammation and cancer in humans. IL-1A is a member of the IL-1 family, which is widely involved in the genesis, progression, and metastasis of tumors. The expression level of IL-1A was found to be significantly increased in a variety of cancers, including non-small cell lung cancer, colon cancer, and squamous cell carcinoma [
21]. Similarly, IL-1A can also promote macrophage aggregation to stimulate angiogenesis, leading to the progression and metastasis of tumor [
22,
23]. Glutathione S-transferase Mu 2 (GSTM2) and Glutathione S-transferase A1 (GSTA1) are enzymes belonging to the GST family that are significant in carcinogen detoxification. GSTM2 plays an important role in the development and metastasis of lung cancer. The results of previous studies showed that GSTM2 mRNA levels were significantly lower in the tumor tissues of NSCLC patients compared to the paired adjacent normal tissues [
24]. The high expression of GSTM2 is also correlated with the favorable survival of patients with lung cancer [
25]. Our finding reveals that the expression level of GSTM2 is higher in patients of cluster 1 (C1), which have better clinical outcomes. GSTA1 is closely associated with metastasis in lung cancer. Overexpression of GSTA1 can mediate lung cancer cells metastasis by promoting epithelial–mesenchymal transition (EMT) [
26]. The expression level of GSTA1 is also an important predictive factor associated with postoperative recurrence in NSCLC patients [
27]. The expression level of GSTA1 is higher in patients of cluster 2 (C2), which have worse clinical outcomes. Serine/threonine kinase 32A (STK32A) has been confirmed by epidemiological investigations as a susceptibility gene for lung cancer [
28]. Overexpression of STK32A enhances migration and proliferation of lung cancer cells while inhibiting apoptosis, which is essential for lung cancer progression [
29]. However, miR-130a-5p can inhibit the expression of STK32A by regulating RUNX2 to suppress the above process. C–C motif chemokine receptor 2 (CCR2) encoded protein is a chemokine that specifically mediates monocyte chemotaxis. It is involved in monocyte infiltration in inflammatory diseases and as well as in the inflammatory response against tumors. The inflammatory microenvironment is a key factor contributing to lung cancer progression. Tumor-associated macrophages (TAMs) are important components of the inflammatory microenvironment [
30]. Evidence reveals that M2-polarized TAMs play an important role in the progression and metastasis of lung cancer [
31]. It has been found that estrogen receptor α (Erα) can activate the CCL2/CCR2 axis to promote macrophage infiltration, M2 polarization, and MMP9 production, which can then increase NSCLC cell invasion [
32]. Significant correlations were found among the higher expression of CCR2 and the worse pathological stage and the shorter OS of LUAD patients [
33]. Therefore, interventions of CCR2 expression and M2 polarization TAMs may be potential options for the treatment of lung cancer.
Our research categorizes the LUAD patients based on differential expression levels of PRGs, discovers the DEGs between different subtypes, and establishes a nomogram to identify the relationship between pyroptosis and patients’ prognosis. The significance of pyroptosis-mediated immunophenotype in the occurrence, development, and prognosis of LUAD was also systematically revealed. The prediction model we have developed can be a powerful tool for predicting the prognosis of different subtypes of LUAD. However, this study remains some limitations. First, we only used the datasets from the TCGA and GEO databases for the analysis, more data from different regions are needed for validation. Furthermore, due to the limited information contained in the databases, the predictive model cannot be well used to guide the clinical treatment of patients with different subtypes of LUAD. Finally, further in vivo and in vitro experiments are needed to validate the results.
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