Numerous previous studies have demonstrated that pyroptosis related genes are significantly linked to prognostic factors such as tumor types. While, the definitive relationship between pyroptosis and integral tumor-associated immune infiltrates is unknown[1, 14–16]. Pyroptosis suppresses tumor formation while provides a favorable microenvironment for tumor growth as inflammatory cell death. Inflammasomes stimulate caspase-1, which cleaves GSDMD as well as proIL-18 and proIL-1, causing membrane gaps to develop and IL-18 and IL-1 to be secreted from the cytoplasm to the surrounding environments in a canonical pyroptotic pathway. Compared to GSDMD protein levels in similar neighboring tumor tissues, GSDMD protein levels in NSCLC were considerably higher. Higher levels of GSDMD were linked to aggressive characteristics such as bigger tumor sizes and TNM stages. Furthermore, increased GSDMD expression in LUAD was associated with a bad prognosis. In vitro and in vivo, knocking down GSDMD inhibited tumor growth[19, 20]. Our research found that pyroptosis related genes differed in the immunological subtype, and tumor microenvironment across 33 cancer types, providing a new strategy to investigate the crucial function of pyroptosis related genes in pan-cancer.
Pyroptosis shares some features with apoptosis, such as DNA damage, nuclear condensation, and caspase independence, but it differs from other forms of programmed cell death due to its morphology. Inflammasomes are multimolecular complexes that contain pattern-recognition receptors (PRRs), which when activated, can cause pyroptosis by inducing inflammatory responses. The complex causes pyroptosis by activating caspase-1 in the canonical inflammasome pathway and activating caspase-11 and caspase-4, 5 in the noncanonical inflammasome pathway. The Polo-like Kinase 1 (PLK1) inhibitor BI2536 increased the sensitivity of oesophageal squamous cell carcinoma (ESCC) cells to cisplatin by inducing pyroptosis, according to a latest study. When low doses of BI2536 were combined with DDP, the apoptosis-related protein BAX and caspase-3 were activated, causing GSDME to be cleaved and increased DNA damage. In ESCC cells, GSDME expression is higher than in normal cells. In ESCC cells, high levels of GSDME transition apoptosis to pyroptosis. When compared to neighboring normal equivalents, the LncRNA RP1-85F18.6 was overexpressed in colorectal cancer. LncRNA RP1-85F18.6 inhibited pyroptosis and apoptosis in colorectal cancer cells and played a key role in their proliferation, metastasis, and normal cell cycle disruption. P63 is a member of the p53 tumor suppressor family, which is identical to p53. Two p63 gene promoters influence p63 expression, resulting in two distinct isotypes: TAp63 and Np63, which operate in carcinogenesis in completely different ways.
Presently, CASP1, CHMP3, CHMP4A, CHMP4C, CHMP7, CYCS, GZMB, IL18, IL1B, IRF1, IRF2, TP53, and TP63 were all shown to be substantially linked with overall survival of BRCA patients in our research (p < 0.001). The CHMP3 gene was shown to be considerably downregulated in a variety of human tumors, including BRCA, according to the study. Patients with BRCA who had a greater level of CHMP3 gene exhibited a better 3- and 5-year survival rate. Comprehensive research revealed that the 12 autophagy-related genes, including TP63, were linked to BRCA
patients' overall survival and were expressed significantly in BRCA and normal breast tissue at the protein level. In our study, CHMP4A was found to be strongly linked with overall survival in LUAD, KICH, BRCA, and ACC patients (p < 0.001). CYCS was reported to be a viable prognostic biomarker for predicting the overall survival of BRCA and CRC patients. Besides, chemotherapy did not benefit patients in terms of survival. The effectiveness of chemotherapy in patients with PACC should be evaluated further.
Interestingly, BAK1, BAX, CASP1, CASP3, CASP4, CASP5, CHMP2A, CHMP2B, CHMP3, CHMP4A, CHMP4B, CHMP4C, CHMP7, CYCS, ELANE, GSDMD, GZMB, HMGB1, IL18, IL1A, IL1B, IRF1, IRF2, TP53, TP63 were all identified to exhibit different levels of expression in immunological subtype. The pyroptosis related genes have been linked to the tumor microenvironment in a variety of cancers. Our research looked at the association between the expression of pyroptosis related genes and the tumor stem cell score in 33 cancer types. With the diverse expression of pyroptosis related genes, we discovered that while there was a higher content of immune and stromal cells, the content of tumor cells was low. The expression of TP53 in LUAD was favorably linked with the LUAD stem cell score, according to our findings (based on RNA expression). The higher the level of TP53 expression, the more tumor LUAD stem cell features and the higher the tumor LUAD differentiation. Cancer stem cells (CSCs) are self-renewing and developing cells that play a vital role in the development and therapeutic resistance of cancers, including LIHC, according to a recent study. Angiogenesis, negative control of DNA-binding transcription factor activity, apoptosis, and autophagy are all pathways enriched in CSC-related genes, according to functional analysis. The LIHC stem cell score was positively linked with the expression of CASP3, CASP5, CHMP6, CHMP7, HMGB1, and IL1B. (based on RNA expression). The more features of tumor LIHC stem cells and the lower the tumor LIHC differentiation, the higher the expression level of CASP3, CASP5, CHMP6, CHMP7, HMGB1 and IL1B.
The nascent relevance of necroptosis and pyroptosis of non-small-cell lung cancer was recently shown in a study that examined pyroptosis related genes expression patterns within immuno-transmitters and the role of neurotransmitters in immune evasion, tumor progression and the survival. Higher BAK1, CASP3, CHMP4C, and CYCS expression was related with a worse prognosis in LUAD patients (Figs. 1O, 4B), indicating that these genes perform as oncogenes that drive LUAD carcinogenesis. ELANE expression was found to be strongly linked with poorer PRAD patient survival (Figs. 1M, 4D), demonstrating that ELANE plays a critical role in PRAD carcinogenesis. Lower TP53 expression was related with a worse outcome in COAD and ACC patients (Figs. 1E, 4I), revealing that TP53 functions as a tumor suppressor gene in COAD and ACC carcinogenesis.
Several pyroptosis related genes exhibited a significantly positive association with the drug in our investigation, for example, ELANE was significantly positively correlated with the drug sensitivity of Hydroxyurea and Carboplatin. The drug sensitivity of Floxuridine, Bleomycin, Gemcitabine, and Triethylenemelamine was significantly positively related to the expression of IL18 and CHMP4A, while the drug sensitivity of Floxuridine, Bleomycin, Gemcitabine, and Triethylenemelamine was significantly negatively related to the expression of CHMP6. CellMiner is a database of genomic and pharmacologic tools for identifying drug patterns and transcripts in the NCI-60 cell line. CellMiner is a database of genomic and pharmacologic tools for identifying drug patterns and transcripts in the NCI-60 cell line. The CellMiner database allows users to quickly access and compare gene expression levels for 360 microRNAs, 22,379 genes, and 20,503 chemicals containing 102 FDA-approved medicines. Our research initially looked at the association between pyroptosis related genes and anticancer drug sensitivity, which offered a bright insight into tumor therapy treatment and avoiding tumor resistance. Selumetinib has shown efficacy in several cancers, including non-small cell lung cancer (NSCLC), melanoma, and locally advanced cervical cancer, both preclinically and therapeutically as a single agent or in combination with conventional chemotherapy and other targeted treatments. For patients with stage III NSCLC, phase II studies found that the combination of ciplatin and vinorelbine provides a novel treatment with clinically substantial anticancer efficacy and a dose-depending safety profile[27, 28]. The combination of pericardial drainage and bleomycin instillation was proven to be a safe and effective therapy for malignant pericardial effusion associated with NSCLC.
In summary, our research found that pyroptosis related genes play an essential role in the immune microenvironment of 33 TCGA cancer types; in addition, it revealed a critical link between pyroptosis related genes and anticancer drug sensitivity, shedding new light on mechanistic and therapeutic targets in the immune microenvironment of 33 cancer types and NSCLC.