Ezrin, one of the ezrin-radixin-moesin (ERM) proteins, is involved in the formation of cell membrane processes and has been implicated in the promotion of cancer proliferation and metastasis. However, the possible role of ezrin in hepatocellular carcinoma (HCC) metastasis and glycolysis reprogramming has remained unclear. In this study, we found that ezrin was upregulated in HCC tissues, and its overexpression was linked with HCC patients' aggressive tumor characteristics and poor prognosis. Functional experiments further revealed that ezrin overexpression promoted HCC cell proliferation, epithelial-to-mesenchymal transition (EMT) progression and angiogenesis. In addition, by measuring glucose consumption, lactate production, ATP levels and the expression of glucose metabolism-related markers in HCC cells, we investigated whether ezrin regulated glucose metabolism. Moreover, 2-deoxy-D-glucose (2-DG) affected ezrin-mediated proliferation, migration and EMT of HCC cells, which suggested that ezrin may, at least in part, promote HCC progression by regulating glycolysis reprogramming. Based on our results, we proposed that ezrin was involved in HCC progression and may be a valid prognostic marker.

T lymphoma invasion and metastasis 1 (Tiam1) as a tumor-associated gene specifically activates Rho-like GTPases Rac1 and implicates in the invasive phenotype of many cancers. Altering the glycolytic pathway is foreseen as a sound approach to trigger cancer regression. However, the mechanism of Tiam1 in breast cancer (BC) glycolysis reprogramming remains to be clarified. Here, we reported the Tiam1 high expression and prognostic significance in BC. In vitro and in vivo experimental assays identified the functional role of Tiam1 in promoting BC cell proliferation, metastasis and glycolysis reprogramming. Mechanistically, we showed for the first time that Tiam1 could interact with the crucial glycolytic enzyme phosphofructokinase, liver type (PFKL) and promote the evolution of BC in a PFKL-dependent manner. Moreover, miR-21-5p was found to exacerbate the BC proliferation and aggression by targeting Tiam1. Altogether, our study highlights the critical role of Tiam1 in BC development and that the miR-21-5p/Tiam1/PFKL signaling pathway may serve as a target for new anti-BC therapeutic strategies.

Background: The necessity of platinum-doublet chemotherapy in first-line immunotherapy for non-squamous non-small cell lung cancer (nsqNSCLC) with programmed death-ligand 1 (PD-L1) expression on less than 50% of tumor cells remains poorly investigated. Biomarkers predicting this necessity can guide chemotherapy-free treatment to minimize unnecessary toxicity. Methods: Treated with immune checkpoint inhibitor monotherapy (ICI-mono), chemotherapy, or combination (ICI-chemo), 790 low PD-L1-expressing nsqNSCLCs (in-house: n=83; public: n=707) were analyzed for development and validation of the interaction score for additional chemotherapy (ISAC). Transcriptomic (public, n=11) and multiplex immunofluorescence data (in-house, n=100) were analyzed to evaluate the immune microenvironment. Results: ICI-chemo, compared with ICI-mono, tended to prolong progression-free survival (PFS; HR=0.72, p=0.004) and overall survival (OS; HR=0.77, p=0.071) as first-line therapy in low PD-L1-expressing nsqNSCLCs. The added value of chemotherapy was observed in the ISAC-low subgroup (PFS: HR=0.48, p<0.001; OS: HR=0.53, p=0.001) rather than the ISAC-high subgroup (PFS: HR=1.08, p=0.65; OS: HR=1.14, p=0.56). This predictive utility was independent of tumor mutational burden and PD-L1 expression, indicated by subgroup and multivariable analyses. A high ISAC was associated with adaptive immune resistance reflected by more proinflammatory (eg, CD8⁺ T cells and M1 macrophages) rather than anti-inflammatory tumor-infiltrating immune cells (eg, M2 macrophages) and high expression of immune checkpoints except for PD-L1 (eg, programmed cell death protein-1). Conclusion: A high ISAC was identified as a significant predictor for virtually no added value of platinum-doublet chemotherapy for first-line ICI treatment in low PD-L1-expressing nsqNSCLC. Our findings may help refine personalized therapeutic strategies for nsqNSCLC, thereby improving efficacy and reducing undue toxicity.

Objective: We aimed to explore the role of structural maintenance of chromosomes 4 (SMC4) in malignant progression and immunology of colon adenocarcinoma (COAD). Methods: The expression, genetic and protein features, and immune cell infiltration of SMC4 in pan-cancer were provided by public databases and websites. The protein expression of SMC4 in COAD tissues was screened by immunohistochemical assay. Si-RNA-mediated transfection was performed in COAD cells and the proliferation viability was measured using MTT, colony formation and EdU assays. Cell autophagy was detected by AO staining, western blots, and immunofluorescence staining. The migratory ability was determined using scratch and transwell assays. The expression of epithelial-to-mesenchymal transition (EMT) markers and transcriptional factors were detected using western blots. Results: The expression of SMC4 was upregulated in pan-cancer and had relationships with prognosis, TMB, and MSI of cancer patients. Particularly, SMC4 protein was highly expressed in COAD tissues and correlated with poor prognosis of patients. Depletion of SMC4 inhibited cell proliferation, induced autophagy, and decreased migration through EMT progression in COAD cells. In addition, SMC4 was associated with infiltration of neutrophils, M2 macrophages, and CD4 + T cells in COAD, and had positive association with M2 macrophage markers and immune checkpoints. Conclusion: SMC4 was correlated with patients’ poor prognosis, proliferation, metastasis, and immune cell infiltrates, and might function as a potential diagnosis and prognostic biomarker in COAD.