Pyroptosis-related genes regulate proliferation and invasion of pancreatic cancer and serve as the prognostic signature for modeling patient survival
Abstract Objective Pancreatic ductal adenocarcinoma (PDAC) has high mortality and poor prognosis. Pyroptosis can influence the prognosis of patients by regulating the proliferation, invasion, and metastasis of cancer cells. However, the role of pyroptosis-related genes (PRGs) in PDAC remains unclear...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer
2022-05-01
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| Series: | Discover Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1007/s12672-022-00495-0 |
| _version_ | 1818213446670352384 |
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| author | Wenjing Song Zhicheng Liu Kunlei Wang Kai Tan Anbang Zhao Xinyin Li Yufeng Yuan Zhiyong Yang |
| author_facet | Wenjing Song Zhicheng Liu Kunlei Wang Kai Tan Anbang Zhao Xinyin Li Yufeng Yuan Zhiyong Yang |
| author_sort | Wenjing Song |
| collection | DOAJ |
| description | Abstract Objective Pancreatic ductal adenocarcinoma (PDAC) has high mortality and poor prognosis. Pyroptosis can influence the prognosis of patients by regulating the proliferation, invasion, and metastasis of cancer cells. However, the role of pyroptosis-related genes (PRGs) in PDAC remains unclear. Methods In this study, based on the Cancer Genome Atlas (TCGA) cohort of PDAC samples, univariate Cox analysis and LASSO regression analysis were used to screen the prognostic PRGs and establish the gene signature. To further evaluate the functional significance of CASP4 and NLRP1 in PDAC, we also conducted an in vitro study to explore the mechanism of CASP4 and NLRP1 regulating the occurrence and development of PDAC. Finally, we investigated the relationship between CASP4 and NLRP1 expression levels and drug sensitivity in pancreatic cancer cells. Results A risk prediction model based on CASP4 and NLRP1 was established, which can distinguish high-risk patients from low-risk patients (P < 0.001). Both internal validation and external GEO data sets validation demonstrate good predictive capability of the model (AUC = 0.732, AUC = 0.802, AUC = 0.632, P < 0.05). In vitro, CCK8 and Transwell assay suggested that CASP4 may accelerate the progression of PDAC by promoting proliferation and migration of pancreatic cancer cells, while NLRP1 has been found to have tumor suppressive effect. It should be noted that knockdown of CASP4 reduced the level of coke death, the expression levels of acetyl-CoA carboxylase, FASN, SREBP-1 and SREBP-2 were decreased, and the number of lipid droplets was also significantly reduced. Moreover, the enrichment of signaling pathways showed that NLRP1 was significantly correlated with MAPK and RAS/ERK signaling pathways, and knocking down NLRP1 could indeed up-regulate p-ERK expression. Finally, high expression of CASP4 and low expression of NLRP1 increased the sensitivity of pancreatic cancer cells to ERK inhibitors. Conclusions In especial, CASP4 can promote tumor progression by promoting the synthesis and accumulation of fatty acids, while NLRP1 acts on RAS/ERK signaling pathway. Both of genes play an important role in the diagnosis and treatment of PDAC, which may also affect the inhibitors of MAPK/ERK efficiency. |
| first_indexed | 2024-12-12T06:04:25Z |
| format | Article |
| id | doaj.art-be717e43bc4045c08f93a28d730cc428 |
| institution | Directory Open Access Journal |
| issn | 2730-6011 |
| language | English |
| last_indexed | 2024-12-12T06:04:25Z |
| publishDate | 2022-05-01 |
| publisher | Springer |
| record_format | Article |
| series | Discover Oncology |
| spelling | doaj.art-be717e43bc4045c08f93a28d730cc4282022-12-22T00:35:19ZengSpringerDiscover Oncology2730-60112022-05-0113112210.1007/s12672-022-00495-0Pyroptosis-related genes regulate proliferation and invasion of pancreatic cancer and serve as the prognostic signature for modeling patient survivalWenjing Song0Zhicheng Liu1Kunlei Wang2Kai Tan3Anbang Zhao4Xinyin Li5Yufeng Yuan6Zhiyong Yang7Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan UniversityDepartment of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan UniversityDepartment of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan UniversityDepartment of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan UniversityDepartment of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan UniversityDepartment of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan UniversityDepartment of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan UniversityDepartment of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan UniversityAbstract Objective Pancreatic ductal adenocarcinoma (PDAC) has high mortality and poor prognosis. Pyroptosis can influence the prognosis of patients by regulating the proliferation, invasion, and metastasis of cancer cells. However, the role of pyroptosis-related genes (PRGs) in PDAC remains unclear. Methods In this study, based on the Cancer Genome Atlas (TCGA) cohort of PDAC samples, univariate Cox analysis and LASSO regression analysis were used to screen the prognostic PRGs and establish the gene signature. To further evaluate the functional significance of CASP4 and NLRP1 in PDAC, we also conducted an in vitro study to explore the mechanism of CASP4 and NLRP1 regulating the occurrence and development of PDAC. Finally, we investigated the relationship between CASP4 and NLRP1 expression levels and drug sensitivity in pancreatic cancer cells. Results A risk prediction model based on CASP4 and NLRP1 was established, which can distinguish high-risk patients from low-risk patients (P < 0.001). Both internal validation and external GEO data sets validation demonstrate good predictive capability of the model (AUC = 0.732, AUC = 0.802, AUC = 0.632, P < 0.05). In vitro, CCK8 and Transwell assay suggested that CASP4 may accelerate the progression of PDAC by promoting proliferation and migration of pancreatic cancer cells, while NLRP1 has been found to have tumor suppressive effect. It should be noted that knockdown of CASP4 reduced the level of coke death, the expression levels of acetyl-CoA carboxylase, FASN, SREBP-1 and SREBP-2 were decreased, and the number of lipid droplets was also significantly reduced. Moreover, the enrichment of signaling pathways showed that NLRP1 was significantly correlated with MAPK and RAS/ERK signaling pathways, and knocking down NLRP1 could indeed up-regulate p-ERK expression. Finally, high expression of CASP4 and low expression of NLRP1 increased the sensitivity of pancreatic cancer cells to ERK inhibitors. Conclusions In especial, CASP4 can promote tumor progression by promoting the synthesis and accumulation of fatty acids, while NLRP1 acts on RAS/ERK signaling pathway. Both of genes play an important role in the diagnosis and treatment of PDAC, which may also affect the inhibitors of MAPK/ERK efficiency.https://doi.org/10.1007/s12672-022-00495-0PyroptosisCASP4NLRP1Pancreatic ductal adenocarcinomaGene signaturePrognosis |
| spellingShingle | Wenjing Song Zhicheng Liu Kunlei Wang Kai Tan Anbang Zhao Xinyin Li Yufeng Yuan Zhiyong Yang Pyroptosis-related genes regulate proliferation and invasion of pancreatic cancer and serve as the prognostic signature for modeling patient survival Discover Oncology Pyroptosis CASP4 NLRP1 Pancreatic ductal adenocarcinoma Gene signature Prognosis |
| title | Pyroptosis-related genes regulate proliferation and invasion of pancreatic cancer and serve as the prognostic signature for modeling patient survival |
| title_full | Pyroptosis-related genes regulate proliferation and invasion of pancreatic cancer and serve as the prognostic signature for modeling patient survival |
| title_fullStr | Pyroptosis-related genes regulate proliferation and invasion of pancreatic cancer and serve as the prognostic signature for modeling patient survival |
| title_full_unstemmed | Pyroptosis-related genes regulate proliferation and invasion of pancreatic cancer and serve as the prognostic signature for modeling patient survival |
| title_short | Pyroptosis-related genes regulate proliferation and invasion of pancreatic cancer and serve as the prognostic signature for modeling patient survival |
| title_sort | pyroptosis related genes regulate proliferation and invasion of pancreatic cancer and serve as the prognostic signature for modeling patient survival |
| topic | Pyroptosis CASP4 NLRP1 Pancreatic ductal adenocarcinoma Gene signature Prognosis |
| url | https://doi.org/10.1007/s12672-022-00495-0 |
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