Abstract
Background: Hepatocellular carcinoma (HCC) is a common abdominal cancer. The existing therapeutic approaches often fail to achieve satisfactory results. Pyroptosis, an inflammatory form of programmed cell death, provides new ideas for anticancer treatment. However, the roles of pyroptosis-related (PR) genes (PRGs) in HCC remain elusive. Methods: Differentially expressed genes (DEGs) (n = 22) were screened out using TCGA and GTEx databases. A novel PR risk signature was constructed through Lasso regression analysis. Its prognostic value was evaluated through a series of survival analyses and was tested in ICGC and GSE14520 cohorts. CIBERSORT, ssGSEA, and ESTIMATE methods were employed to determine the effects of the PR risk score on the tumor immune microenvironment (TIM). The TIDE scoring system, IMvigor210 cohort, GSE109211 dataset, and GSDC database were applied to explore the associations of the PR risk score with therapeutic effects. The biofunctions of WNK1 in hepatocellular cancer (HC) cells were confirmed through qPCR, colony formation, and Transwell assays. Results: Overall, 22 of 45 PRGs (48.9%) were abnormally expressed in HCC samples. Then, a PR risk signature consisting of eight PRGs was constructed. A high PR risk score led to an unfavorable prognosis. The PR risk score was identified as an independent prognostic factor of HCC and could increase the decision-making benefit of the traditional TNM model. In addition, we established a nomogram containing the clinical stage and PR risk score to predict the survival rates of HCC patients. The prognostic value of the PR model was successfully validated in ICGC and GSE14520 cohorts. Moreover, high PR risk conferred the decreased infiltration level of CD8+ T cells and weakened the activities of “cytolytic activity” pathways. As for therapeutic correlation, a high PR risk score seemed to imply a poor efficacy of PD-1/L1 inhibitors and sorafenib. Finally, the overexpression of WNK1 could promote the proliferation, migration, and invasion of HC cells. Conclusions: The PR risk score was closely related to the prognosis, antitumor immune process, therapeutic outcomes, and malignant progression of HCC. WNK1, the core regulator of pyroptosis, possesses pro-oncogenic abilities, showing promise as a novel treatment target.
Highlights
Hepatocellular carcinoma (HCC) is the fourth common digestive tumor with a non-negligibly high malignancy
Biological functional analyses indicated that these genes were enriched in “pyroptosis,” “programmed cell death,” “apoptosis,” etc. pathways (Figure 2C), which solidly proved the plausibility of our PR gene set
Consulting some crucial immunological research (Cassetta and Pollard 2018; Castro et al, 2018; Farhood et al, 2019; Cornel et al, 2020; Sadeghzadeh et al, 2020; Stocker et al, 2020; Wculek et al, 2020), we found that the affected immune cells and immune signaling pathways have been proven to intimately participate in the regulation of antitumor immunity and the immune tolerance (Table 2)
Summary
Hepatocellular carcinoma (HCC) is the fourth common digestive tumor with a non-negligibly high malignancy. In 2021, the estimated new cases of HCC in America reached 42,230, and its cancer-related mortality was as high as 6% (Siegel et al, 2021). The median survival of HCC patients in China is only 23 months, while that in Japan, the region with the best prognostic outcomes, is less than 60 months (Yang et al, 2019). As the first-line systemic therapy for HCC, the median OS of patients who receive either sorafenib or nivolumab is only 10.8 and 13.8 months, respectively (El-Khoueiry et al, 2017; Keating 2017). Pyroptosis, an inflammatory form of programmed cell death (PCD), sheds new light on cancer treatment. Pyroptosis, an inflammatory form of programmed cell death, provides new ideas for anticancer treatment. The roles of pyroptosis-related (PR) genes (PRGs) in HCC remain elusive
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
