Identification of a Pyroptosis-Related Prognostic Signature Combined With Experiments in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with poor prognosis. There is a necessary search for improvement in diagnosis and treatment methods to improve the prognosis. Some useful prognostic markers of HCC are still lacking. Pyroptosis is a type of programmed cell death caused by the inflammasome. It is still unknown whether pyroptosis-related genes (PRGs) are involved in the prognosis in HCC. The gene expression and clinical data of LIHC (liver hepatocellular carcinoma) patients were downloaded from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium database (ICGC). In this study, we identified 40 PRGs that were differentially expressed between LIHC and normal liver tissues. Based on the TCGA-LIHC cohort, a 9-gene prediction model was established with the Least absolute shrinkage and selection operator (LASSO)-penalized Cox regression. The risk score was calculated according to the model in the TCGA-LIHC cohort and the ICGC-LIHC cohort. Utilizing the median risk score from the TCGA cohort, LIHC patients from the ICGC-LIHC cohort were divided into two risk subgroups. The Kaplan-Meier (KM) survival curves demonstrated that patients with lower risk scores had significantly favorable overall survival (OS). Combined with the clinical characteristics, the risk score was an independent factor for predicting the OS of LIHC patients in both the TCGA-LIHC cohort and the ICGC-LIHC cohort. Functional enrichment and immune function analysis were carried out. Furthermore, a nomogram based on risk score, age, gender, and tumor stage was used to predict mortality of patients with LIHC. Moreover, KM survival analysis was performed for 9 genes in the risk model, among which CHMP4A, SCAF11, and GSDMC had significantly different results and the ceRNA network was constructed. Based on the core role of SCAF11, we performed loss-of-function experiments to explore the function of SCAF11 in vitro. Suppression of SCAF11 expression inhibited the proliferation, attenuated the migration and invasion, and induced apoptosis of liver cancer cell lines. In conclusion, the pyroptosis-related model and nomogram can be utilized for the clinical prognostic prediction in LIHC. This study has demonstrated for the first time that SCAF11 promotes the progression of liver cancer.

A Prognostic Signature Consisting of Pyroptosis-Related Genes and SCAF11 for Predicting Immune Response in Breast Cancer.

Pyroptosis, characterized as an inflammasome-mediated cell death pathway, may be participated in tumorigenesis and progression. However, the underlying molecular function and mechanism of pyroptosis in BRCA remain unclear. In our study, we aimed to develop a prognostic signature in BRCA based on pyroptosis-associated genes. Data was downloaded from TCGA database, and then we screened 760 female BRCA samples and 104 normal breast tissues as the training set. Seven pyroptosis-related genes (CASP9, GPX4, IL18, NLRC4, SCAF11, TIRAP, and TNF) were identified as the pyroptosis-related prognostic model for BRCA using LASSO Cox regression. We subsequently tested the prognostic value of pyroptosis-associated gene signature in a validation set, GSE 20685. Time-dependent receiver operating characteristic analysis demonstrated the credible predictive capacity of this pyroptosis-associated gene signature. The area under the curves were 0.806 at 3 years, 0.787 at 5 years, 0.775 at 8 years, and 0.793 at 10 years in the training set, and 0.824 at 5 years, 0.808 at 8 years, and 0.790 at 10 years in the validation set. Furthermore, there are currently few data on SCAF11 regulating pyroptosis. To clarify this issue, we performed integrative bioinformatics and experimental analysis. Knocking down SCAF11 possessed an anti-cancer effect in terms of inhibiting cell viability and suppressing colony-formation in in-vitro functional assays. Meanwhile, the biological functions of SCAF11 in BRCA were further validated with several algorithms, such as Xiantao tool, LinkedOmics, GEPIA2, and TISIDB. These findings indicated that the expression of SCAF11 was significantly correlated with diverse tumor-infiltrating lymphocytes (TILs), including T central memory cell (Tcm), and type 2 T helper cell (Th2), etc. Functional enrichment analysis suggested that co-expression genes of SCAF11 primarily participated in inflammation and immune-related signaling pathways, such as oxidative phosphorylation, antimicrobial humoral response, and immunoglobulin complex. Moreover, SCAF11 expression was positively correlated with several immune checkpoints, including PD-L1, B7H3, and PDCD1LG2. Taken together, this study uncovered that pyroptosis-associated gene signature might be applied as an effective independent predictor in patients with BRCA. The pyroptosis-related gene SCAF11 might play potential roles in the regulation of immune microenvironment in BRCA.

Cold atmospheric plasmas target breast cancer stemness via modulating AQP3-19Y mediated AQP3-5K and FOXO1 K48-ubiquitination.

Cold atmospheric plasma (CAP) is selective against many cancers with little side effect, yet its molecular mechanism remains unclear. Through whole transcriptome sequencing followed by assays in vitro, in vivo and using clinical samples, we propose CAP as a promising onco-therapy targeting cancer stemness via the AQP3/FOXO1 axis. CAP-generated reactive species penetrated cells via AQP3 and suppressed RPS6KA3, a shared kinase of AQP3 and FOXO1. Reduced AQP3-19Y phosphorylation suppressed SCAF11-mediated AQP3-5K K48-ubiquitination that led to sabotaged FOXO1 stability. Inhibited FOXO1 phosphorylation retarded its regulatory activities in maintaining cancer stemness including ALDH1 and IL6. Enhanced anti-cancer efficacy was observed through combining CAP with Atorvastatin in vitro and in vivo. We propose CAP as a 'selective' onco-therapeutic against cancer stemness, with the AQP3/FOXO1 axis being one molecular mechanism. We report SCAF11 as an E3 ubiquitin ligase of both AQP3 and FOXO1, identify AQP3-5K as an AQP3 K48-ubiquitination site, and emphasize the essential role of AQP3-19Y in this process. We reposition Atorvastatin into the onco-therapeutic portfolio by synergizing it with CAP towards enhanced efficacy. We anticipate the efficacy of CAP in targeting malignancies of high stemness alone or as an adjuvant therapy towards the hope of ultimate cancer cure.

Expanding the SRI domain family: a common scaffold for binding the phosphorylated C-terminal domain of RNA polymerase II.

The SRI domain is a small three-helix domain originally discovered near the C-terminus of both histone methyltransferase SETD2 and helicase RECQL5. The SRI domain binds to the C-terminal repeat domain of the largest subunit of RNA polymerase II, allowing SETD2 and RECQL5 to regulate various mechanisms associated with RNA transcription. Using original tools to detect common patterns in distantly related sequences, we have identified SRI domains in several additional proteins, most of which are involved in RNA metabolism. Combining sequence analysis with structural prediction, we show that this domain family is more diverse than previously thought and we predict critical structural and functional features.