Role of pyruvate kinase M2 in regulating sepsis (Review).

Glycolysis occurs in all living organisms as a form of energy supply. Pyruvate kinase M2 (PKM2) is one of the rate­limiting enzymes in the glycolytic process. PKM2 is considered to serve an important role in several terminal diseases, including sepsis. However, to the best of our knowledge, the specific mechanistic role of PKM2 in sepsis remains to be systematically summarised. Therefore, the present review aims to summarise the roles of PKM2 in sepsis progression. In addition, potential treatment strategies for patients with sepsis are discussed. The present review hopes to lay the groundwork for studying the role of PKM2 and developing therapeutic strategies against metabolic disorders that occur during sepsis.

A combined immune and exosome-related risk signature as prognostic biomakers in acute myeloid leukemia.

OBJECTIVES: Acute myeloid leukemia (AML) is one of the common hematological diseases with low survival rates. Studies have highlighted the dysregulated expression of immune-related and exosome-related genes (ERGs) in cancers. Nevertheless, it remains to be determined whether combining these genes have a prognostic significance in AML. METHODS: Immune-ERG profiles for 151 AML patients from TCGA were analyzed. A risk model was constructed and optimized through the combination of univariate Cox regression and LASSO regression analysis. GEO datasets were utilized as the external validation for the robustness of the risk model. In addition, we performed KEGG and GO enrichment analyses to investigate the role played by these genes in AML. The variations in immune cell infiltrations among risk groups were assessed through four algorithms. Expression of hub gene in specific cell was analyzed by single-cell RNA seq. RESULTS: A total of 85 immune-ERGs associated with prognosis were identified, enabling the construction of a risk model for AML. The risk model based on five immune-ERGs (CD37, NUCB2, LSP1, MGST1, and PLXNB1) demonstrated a correlation with the clinical outcomes. Additionally, age, FAB classification, cytogenetics risk, and risk score were identified as independent prognostic factors. The five immune-ERGs exhibited correlations with cytokine-cytokine receptor interaction, and antigen processing and presentation. Notably, the risk model demonstrated significant associations with immune responses and the expression of immune checkpoints. CONCLUSIONS: An immune-ERG-based risk model was developed to effectively predict prognostic outcomes for AML patients. There is potential for immune therapy in AML targeting the five hub genes.

Gab2 promotes cancer stem cell like properties and metastatic growth of ovarian cancer via downregulation of miR-200c.

Scaffolding adaptor Gab2 is overexpressed in a subset of high-grade ovarian cancer. Our published work shows that Gab2 via PI3K enhances migratory behaviors and epithelial to mesenchymal transition (EMT) features of ovarian cancer cells in vitro. However, it is still unclear how Gab2/PI3K pathway reuglates EMT characteristics and whether Gab2 promotes the growth of ovarian cancer stem cell (CSC)-like population and metastatic growth. In this study, we examined the effects of Gab2 expression on CSC-like cell growth using Aldefluor and tumorshpere assays commonly used for assessing ovarian cancer cells with CSC properties. Gab2 overexpression increased the number of ALDH+ cells and tumorsphere formation in two different ovarian cancer cell lines OVCAR5 and OVCAR8, whereas knockdown of Gab2 decreased the number of ALDH+ cells and tumorsphere formation in Caov-3 cells. Furthermore, Gab2 promoted metastatic tumor growth of OVCAR5 in nude mice. Mechanistically, we uncovered that Gab2 via PI3K specifically inhibited miR-200c expression. miR-200c downregulation contributed to the Gab2-enhanced cell migratory behaviors, EMT properties, and the expansion of ALDH+ cells and tumorspheres. Furthermore, Gab2 promoted CD44 expression and cell migration/invasion through miR-200c downregulation. Our findings support a model that Gab2-PI3K pathway via miR-200c downregulation promotes CD44 expression, EMT characteristics, and CSC-like cell growth. Therapies involving miR-200c or targeting CD44 should help treat ovarian cancer with high Gab2 expression.

Shp1 positively regulates EGFR signaling by controlling EGFR protein expression in mammary epithelial cells.

SH2-domain containing protein tyrosine phosphatase 1 (Shp1/PTPN6) is mainly expressed in hematopoietic cells and acts a negative signaling regulator. Although Shp1 is also expressed in epithelial cells, the function of shp1 in normal epithelial is still less well understood, especially in regulating the growth of epithelial cells. In this study, different shRNAs and siRNAs against Shp1 were used to knockdown Shp1 expression in MCF10A, an immortalized mammary epithelial cell line. Shp1 knockdown resulted in inhibited cell growth in part due to lower percentage of MCF10A cells entering into S phase and reduced cyclin D1 expression. Accordingly, EGF-induced tyrosyl phosphorylation of EGFR and Stat5 was significantly inhibited in cells with Shp1 knockdown compared with control whereas EGF-induced Akt and Erk phosphorylation was not affected by Shp1 knockdown. Further analysis revealed that Shp1 knockdown lead to decreased EGFR protein expression without affecting EGFR mRNA expression or increasing EGFR protein degradation. Our data indicate that Shp1 functions as a positive regulator and acts in a novel mechanism through promoting EGFR protein expression in mammary epithelial cells.