Pyroptosis-Related Signature Predicts the Progression of Ulcerative Colitis and Colitis-Associated Colorectal Cancer as well as the Anti-TNF Therapeutic Response
Yumei Ning
Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China znhospital.cn
Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
Search for more papers by this authorKun Lin
Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China znhospital.cn
Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
Search for more papers by this authorJun Fang
Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China znhospital.cn
Renmin Hospital of Huangmei County, Huanggang, China
Search for more papers by this authorXiaojia Chen
Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China znhospital.cn
Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
Search for more papers by this authorXinyi Hu
Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China znhospital.cn
Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
Search for more papers by this authorLan Liu
Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China znhospital.cn
Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
Search for more papers by this authorCorresponding Author
Qiu Zhao
Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China znhospital.cn
Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
Search for more papers by this authorCorresponding Author
Haizhou Wang
Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China znhospital.cn
Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
Search for more papers by this authorCorresponding Author
Fan Wang
Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China znhospital.cn
Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
Search for more papers by this authorYumei Ning
Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China znhospital.cn
Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
Search for more papers by this authorKun Lin
Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China znhospital.cn
Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
Search for more papers by this authorJun Fang
Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China znhospital.cn
Renmin Hospital of Huangmei County, Huanggang, China
Search for more papers by this authorXiaojia Chen
Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China znhospital.cn
Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
Search for more papers by this authorXinyi Hu
Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China znhospital.cn
Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
Search for more papers by this authorLan Liu
Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China znhospital.cn
Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
Search for more papers by this authorCorresponding Author
Qiu Zhao
Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China znhospital.cn
Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
Search for more papers by this authorCorresponding Author
Haizhou Wang
Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China znhospital.cn
Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
Search for more papers by this authorCorresponding Author
Fan Wang
Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China znhospital.cn
Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
Search for more papers by this authorAbstract
Ulcerative colitis (UC) is a complex intestinal inflammation with an increasing risk of colitis-associated colorectal cancer (CAC). However, the pathogenesis is still unclear between active UC and inactive UC. Recently, it has been reported that pyroptosis-related genes (PRGs) are closely associated with inflammatory disease activity. Nevertheless, the specific roles of PRGs in the progression and treatment of UC and CAC remain unclear. In this study, we identified 30 differentially expressed PRGs based on the immune landscape of active and inactive UC samples. Meanwhile, weighted gene coexpression network analysis was applied to explore important genes associated with active UC. By intersecting with the differentially expressed PRGs, CASP5, GBP1, GZMB, IL1B, and IRF1 were selected as key PRGs to construct a pyroptosis-related signature (PR-signature). Then, logistic regression analysis was performed to validate the PR-signature and establish a pyroptosis-related score (PR-Score). We demonstrated that PR-Score had a powerful ability to distinguish active UC from inactive UC in multiple datasets. Besides, PR-Score was positively correlated with immune cell infiltration and inflammatory microenvironment in UC. Lower PR-Score was associated with a better response to anti-TNF therapy for patients with UC. Additionally, high-PR-Score was found to suppress CAC and improve the survival outcomes of patients with colorectal cancer. Finally, the levels of the PR-signature genes were validated both in vitro and in vivo. These findings can improve our understanding of PRGs in UC and provide new markers for predicting the occurrence of active UC or CAC and the treatment of UC.
Conflicts of Interest
No potential conflicts of interest were disclosed.
Open Research
Data Availability
Publicly available datasets were analyzed in this study. These data can be found here: https://portal.gdc.cancer.gov/ and https://www.ncbi.nlm.nih.gov/geo/. All processed data and R codes used in this study can be obtained from the corresponding authors on reasonable request.
Supporting Information
| Filename | Description |
|---|---|
| jimr7040113-sup-0001-f1.zipapplication/x-compressed, 16.1 MB | Supplementary Materials Figure S1: the principal component analysis of before and after batch correction of all samples in the training set. Figure S2: determination of soft-thresholding power in the coexpression network. Figure S3: the correlation of the PR-Score and PR-clusters. Figure S4: representative IHC images showing the expressions of 5 PR-signature genes in normal, DSS-induced colitis, and AOM/DSS-induced CAC tissues of mice. Table S1: detailed information of all datasets and included samples. Table S2: summary of 75 recognized pyroptosis-related genes. Table S3: the primer sequences of CASP5, GBP1, GZMB, IL1B, and IRF1. Table S4: differential expression analysis of pyroptosis-related genes in the training set (active UC vs. inactive UC). Table S5: differential expression analysis of pyroptosis-related genes in GSE75214 (active UC vs. inactive UC). Table S6: standard weight of each gene in WGCNA. Table S7: logistic regression analysis for the key PRGs. Table S8: correlation of clinicopathologic characteristics and PR-Score in GSE111889. Table S9: correlation of clinicopathologic characteristics and PR-Score in GSE94648. Table S10: correlation of clinicopathologic characteristics and PR-Score in TCGA. Table S11: correlation of clinicopathologic characteristics and PR-Score in GSE39582. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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