Diffuse Large B-Cell Lymphoma With Cardiac Invasion Presented as Acute Myocardial Infarction and Left Ventricular Hypertrophy: A Case Report.

Primary cardiac lymphoma is an exceedingly rare malignant tumor, with diffuse large B-cell lymphoma (DLBCL) being the most prevalent histological subtype. This disease has non-specific clinical manifestations, making early diagnosis crucial. However, DLBCL diagnosis is commonly delayed, and its prognosis is typically poor. Herein, we report the case of a 51-year-old male patient with DLBCL who presented with recurrent chest tightness for 4 months as the primary clinical symptom. The patient was admitted to the hospital and diagnosed with acute myocardial infarction and left ventricular hypertrophy with heart failure. Echocardiography revealed a progression from left ventricular thickening to local pericardial thickening and adhesion in the inferior and lateral walls of the left ventricle. Finally, pathological analysis of myocardial biopsy confirmed the diagnosis of DLBCL. After treatment with the R-CHOP chemotherapy regimen, the patient's chest tightness improved, and he was discharged. After 2 months, the patient succumbed to death owing to sudden ventricular tachycardia, ventricular fibrillation, and decreased blood pressure despite rescue efforts. Transthoracic echocardiography is inevitable for the early diagnosis of DLBCL, as it can narrow the differential and guide further investigations and interventions, thereby improving the survival of these patients.

CCDC65, a Gene Knockout that leads to Early Death of Mice, acts as a potentially Novel Tumor Suppressor in Lung Adenocarcinoma.

CCDC65 is a member of the coiled-coil domain-containing protein family and was only reported in gastric cancer by our group. We first observed that it is downregulated in lung adenocarcinoma based on the TCGA database. Reduced CCDC65 protein was shown as an unfavorable factor promoting the clinical progression in lung adenocarcinoma. Subsequently, CCDC65-/- mice were found possibly dead of hydrocephalus. Compared with the CCDC65+/+ mice, the downregulation of CCDC65 in CCDC65+/- mice significantly increased the formation ability of lung cancer induced by urethane. In the subsequent investigation, we observed that CCDC65 functions as a tumor suppressor repressing cell proliferation in vitro and in vivo. Molecular mechanism showed that CCDC65 recruited E3 ubiquitin ligase FBXW7 to induce the ubiquitination degradation of c-Myc, an oncogenic transcription factor in tumors, and reduced c-Myc binding to ENO1 promoter, which suppressed the transcription of ENO1. In addition, CCDC65 also recruited FBXW7 to degrade ENO1 protein by ubiquitinated modulation. The downregulated ENO1 further reduced the phosphorylation activation of AKT1, which thus inactivated the cell cycle signal. Our data demonstrated that CCDC65 is a potential tumor suppressor by recruiting FBWX7 to suppress c-Myc/ENO1-induced cell cycle signal in lung adenocarcinoma.

CCDC65 as a new potential tumor suppressor induced by metformin inhibits activation of AKT1 via ubiquitination of ENO1 in gastric cancer.

The coiled-coil domain containing protein members have been well documented for their roles in many diseases including cancers. However, the function of the coiled-coil domain containing 65 (CCDC65) remains unknown in tumorigenesis including gastric cancer. Methods: CCDC65 expression and its correlation with clinical features and prognosis of gastric cancer were analyzed in tissue. The biological role and molecular basis of CCDC65 were performed via in vitro and in vivo assays and a various of experimental methods including co-immunoprecipitation (Co-IP), GST-pull down and ubiquitination analysis et al. Finally, whether metformin affects the pathogenesis of gastric cancer by regulating CCDC65 and its-mediated signaling was investigated. Results: Here, we found that downregulated CCDC65 level was showed as an unfavourable factor in gastric cancer patients. Subsequently, CCDC65 or its domain (a.a. 130-484) was identified as a significant suppressor in GC growth and metastasis in vitro and in vivo. Molecular basis showed that CCDC65 bound to ENO1, an oncogenic factor has been widely reported to promote the tumor pathogenesis, by its domain (a.a. 130-484) and further promoted ubiquitylation and degradation of ENO1 by recruiting E3 ubiquitin ligase FBXW7. The downregulated ENO1 decreased the binding with AKT1 and further inactivated AKT1, which led to the loss of cell proliferation and EMT signal. Finally, we observed that metformin, a new anti-cancer drug, can significantly induce CCDC65 to suppress ENO1-AKT1 complex-mediated cell proliferation and EMT signals and finally suppresses the malignant phenotypes of gastric cancer cells. Conclusion: These results firstly highlight a critical role of CCDC65 in suppressing ENO1-AKT1 pathway to reduce the progression of gastric cancer and reveals a new molecular mechanism for metformin in suppressing gastric cancer. Our present study provides a new insight into the mechanism and therapy for gastric cancer.

Glycyrrhizic acid ameliorates myocardial ischemia-reperfusion injury in rats through inhibiting endoplasmic reticulum stress.

The purpose of this study was to investigate the role of glycyrrhizic acid (GA) in regulating myocardial ischemia-reperfusion injury (MIRI) in rats as well as the underlying mechanism. H9c2 cells were subjected to hypoxia/re-oxygenation (H/R) to mimic the MIRI in vitro, while a rat model of ischemia-reperfusion (I/R) was constructed by occlusion of the left anterior descending coronary artery for 0.5 h followed by 2 h of reperfusion. While flow cytometry and TUNEL assay were performed to analyze apoptosis in cells and myocardial tissue, echocardiography, hematoxylin and eosin staining, and Masson's trichrome staining were conducted to evaluate cardiac function and pathological changes, respectively. The levels of serum CK, CK-MB, LDH, AST, TNF-α, and IL-6 as well as the contents of MDA and SOD in tissues were measured by ELISA, while Western blot analysis was performed to detect the expression of endoplasmic reticulum stress (ERS)-related proteins. GA treatment significantly reduced apoptosis in H9c2 cells, while it alleviated left ventricular dysfunction, fibrosis and myocardial apoptosis, down-regulated the levels of CK, CK-MB, LDH, AST, TNF-α, IL-6, and MDA, and up-regulated SOD levels in I/R rats. Moreover, GA treatment led to a decrease in the expression of CHOP, GRP78, and p-PERK in both H/R cells and I/R rats. This study demonstrates that cardioprotective role of GA in MIRI may involve the attenuation of ERS-induced apoptosis and inflammation, potentially providing an alternative strategy for intervention of MIRI.

miR-1254 induced by NESG1 inactivates HDGF/DDX5-stimulated nuclear translocation of ß-catenin and suppresses NPC metastasis.

Nasopharyngeal carcinoma (NPC) is one of the most common malignant tumors in Chinese and other Southeast Asians. We aimed to explore the precise mechanism for NESG1 in NPC for understanding the pathogenesis of NPC. Transwell, Boyden assays, and wounding healing were respectively performed for cell metastasis. The microRNA (miRNA) microarray and luciferase reporter assays were designed to clarify NESG1-modulated miRNAs and miR-1254-targeted protein. Western blotting assays examined the pathways regulated by miR-1254, the (Hepatoma-Derived Growth Factor) HDGF/DDX5 complex, and NESG1. The chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), and co-immunoprecipitation (coIP) assays were used to explore the DNA-protein complex and protein-protein complex. NESG1 suppressed NPC migration and invasion via Wnt/ß-catenin signaling. Further, miR-1254 was confirmed as a positive downstream modulator of NESG1 reducing metastatic abilities of NPC cells in vivo and in vitro. Transduction of HDGF significantly restored cell migration and invasion ability in miR-1254-overexpressing NPC cells. In clinical samples, miR-1254 expression was negatively correlated with HDGF and positively correlated with NESG1 expression. miR-1254 acts as an independent prognostic factor for NPC, which was induced by NESG1 to suppress NPC metastasis via inactivating Wnt/ß-catenin pathway and its downstream EMT signals.

Normoxia is not favorable for maintaining stemness of human endothelial progenitor cells.

The in vitro expansion of endothelial progenitor cells (EPCs) is necessary for obtaining sufficient amounts of cells for clinical applications. However, EPC expansion is conventionally carried out under non-physiologic oxygen concentrations (normoxia, ~20% O2). We compared the effects of normoxic and hypoxic culture on the stemness of expanded EPCs. Human EPCs were cultured under hypoxia (1% O2) or normoxia (~20% O2), respectively. Cell proliferation, colony formation, in vitro angiogenesis, and the migration ability of the expanded EPCs were compared. To explore the underlying mechanism, whole transcriptome RNA sequencing (RNA-seq) was also performed to select differentially expressed genes (DEGs), which were then partially validated by western blotting. EPCs cultured under normoxia showed reduced proliferation, colony formation, in vitro angiogenesis, and migration abilities and a higher proportion of senescent cells compared with those cultured under hypoxia. A total of 48 DEGs were identified by transcriptome RNA-seq. Further bioinformatics analysis revealed that six pathways were enriched, among which the p53 signaling pathway. Finally, we confirmed the differential expression of the p53 pathway by Western blot analysis. Compared with hypoxia, normoxia is not favorable for maintaining the stemness of human EPCs. Several signaling pathways, including the p53 signaling pathway implicate in reducing stemness of EPCs under normoxia.

miR-296-3p Negatively Regulated by Nicotine Stimulates Cytoplasmic Translocation of c-Myc via MK2 to Suppress Chemotherapy Resistance.

This study aimed to identify mechanisms by which microRNA 296-3p (miR-296-3p) functions as a tumor suppressor to restrain nasopharyngeal carcinoma (NPC) cell growth, metastasis, and chemoresistance. Mechanistic studies revealed that miR-296-3p negatively regulated by nicotine directly targets the oncogenic protein mitogen-activated protein kinase-activated protein kinase-2 (Mapkapk2) (MK2). Suppression of MK2 downregulated Ras/Braf/Erk/Mek/c-Myc and phosphoinositide-3-kinase (PI3K)/Akt/c-Myc signaling and promoted cytoplasmic translocation of c-Myc, which activated miR-296-3p expression by a feedback loop. This ultimately inhibited cell cycle progression, epithelial-to-mesenchymal transition (EMT), and chemoresistance of NPC. In addition, nicotine as a key component of tobacco was observed to suppress miR-296-3p and thus elevate MK2 expression by inducing PI3K/Akt/c-Myc signaling. In clinical samples, reduced miR-296-3p as an unfavorable factor was inversely correlated with MK2 and c-Myc expression. These results reveal a novel mechanism by which miR-296-3p negatively regulated by nicotine directly targets MK2-induced Ras/Braf/Erk/Mek/c-Myc or PI3K/AKT/c-Myc signaling to stimulate its own expression and suppress NPC cell proliferation and metastasis. miR-296-3p may thus serve as a therapeutic target to reverse chemotherapy resistance of NPC.