Pyroptosis-Related Risk Signature Exhibits Distinct Prognostic, Immune, and Therapeutic Landscapes in Hepatocellular Carcinoma

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.

Identification of Immune-Related Subtypes and Construction of a Novel Prognostic Model for Bladder Urothelial Cancer

“…In the end, we demonstrated that the risk score could be employed as a standalone indicator judging the prognosis of BLCA, and the HR value of risk score was much higher than HR value of age and tumor stage, which indicated that it was more meaningful to evaluate the BLCA patients’ prognosis by risk score than by age and tumor stage. Similar results have been reported in other cancer studies [ 54 , 55 ]. A nomogram is recognized as a convenient method to speculate the survival probability of patients [ 56 , 57 , 58 ].…”

Focal adhesion kinase confers lenvatinib resistance in hepatocellular carcinoma via the regulation of lysine‐deficient kinase 1

“…Interestingly, WNK1 triggers the progression and invasion of HCC cell lines and xenograft tumors via its interaction with lncRNAs in the tumor microenvironment 64 . On the other hand, inhibition of WNK1 diminished its stimulative capabilities on proliferation, invasion, and migration in HCC cells, which is suggested to be mediated via activating AMPK and autophagy 32,65 . Nonetheless, the functional significance of WNK1 in lenvatinib resistance in HCC was neither reported nor anticipated.…”

“…64 On the other hand, inhibition of WNK1 diminished its stimulative capabilities on proliferation, invasion, and migration in HCC cells, which is suggested to be mediated via activating AMPK and autophagy. 32,65 Nonetheless, the functional significance of WNK1 in lenvatinib resistance in HCC was neither reported nor anticipated.…”

Identification and Validation of Necroptosis-Related LncRNA Signature in Hepatocellular Carcinoma for Prognosis Estimation and Microenvironment Status

“…HCC cells with different drug sensitivity were used for in vitro validation. We compared the C-index values of several latest prediction signatures in HCC with ours ( Lin et al, 2022 ; Miao et al, 2022 ; Ye et al, 2022 ; Zhao et al, 2022 ; Zhou et al, 2022 ) ( Supplementary Figure S2 ). Genes in the prediction signature are listed in Supplementary File S4 .…”