CPEB2 Suppresses Hepatocellular Carcinoma Epithelial-Mesenchymal Transition and Metastasis through Regulating the HIF-1α/miR-210-3p/CPEB2 Axis.

Hepatocellular carcinoma (HCC) is a prevalent and high-mortality cancer worldwide, and its complexity necessitates novel strategies for drug selection and design. Current approaches primarily focus on reducing gene expression, while promoting gene overexpression remains a challenge. In this work, we studied the effect of cytoplasmic polyadenylation element binding protein 2 (CPEB2) in HCC by constructing tissue microarrays (TAMs) from 90 HCC cases and corresponding para-cancerous tissues. Our analysis showed that CPEB2 expression was significantly reduced in HCC tissues, and its low expression was associated with a higher recurrence risk and poorer prognosis in patients with head and neck cancer. CPEB2 was found to regulate HCC epithelial-mesenchymal transition (EMT) and metastasis through the HIF-1α/miR-210-3p/CPEB2 feedback circuit. Using the RNA binding protein immunoprecipitation (RIP) assay, we demonstrated that miR-210 directly governs the expression of CPEB2. The inverse relationship between CPEB2 expression and miR-210-3p in HCC tissues suggested that this regulatory mechanism is directly linked to HCC metastasis, EMT, and clinical outcomes. Moreover, utilizing the SM2miR database, we identified drugs that can decrease miR-210-3p expression, consequently increasing CPEB2 expression and providing new insights for drug development. In conclusion, our findings illustrated a novel HIF-1α/miR-210-3p/CPEB2 regulatory signaling pathway in HCC and highlighted the potential of enhancing CPEB2 expression through targeting miR-210-3p as a novel predictive biomarker and therapeutic strategy in HCC, as it is modulated by the HIF-1α/miR-210-3p/CPEB2 feedback circuit.

The ufmylation modification of ribosomal protein L10 in the development of pancreatic adenocarcinoma.

Pancreatic adenocarcinoma (PAAD) is the most malignant cancer with a high mortality rate. Despite the association of ribosomal protein L10 (RPL10) with PAAD and previous reports on RPL26 ufmylation, the relationship between RPL10 ufmylation and PAAD development remains unexplored. Here, we report the dissection of ufmylating process of RPL10 and potential roles of RPL10 ufmylation in PAAD development. The ufmylation of RPL10 was confirmed in both pancreatic patient tissues and cell lines, and specific modification sites were identified and verified. Phenotypically, RPL10 ufmylation significantly increased cell proliferation and stemness, which is principally resulted from higher expression of transcription factor KLF4. Moreover, the mutagenesis of ufmylation sites in RPL10 further demonstrated the connection of RPL10 ufmylation with cell proliferation and stemness. Collectively, this study reveals that PRL10 ufmylation plays an important role to enhance the stemness of pancreatic cancer cells for PAAD development.

Clinical application of thioredoxin reductase as a novel biomarker in liver cancer.

Hepatic cancer is often amenable to surgery, including percutaneous ablation, trans-arterial chemoembolization. However, in metastatic cases, surgery is often not an effective option. Chemotherapy as a conventional clinical method for treatment of malignant diseases may be useful in such cases, but it is likewise not always able to slow or halt progression, therefore novel approaches for treatment of hepatic cancer are needed. Current research suggests that molecular tumor markers (TM) can play a crucial role for diagnosis and prognostic evaluation of malignancies, and TM such as AFP, CEA, CA19-9 have been reported in many malignant diseases. Thioredoxin reductase (TrxR), a type of anti-oxidant biomarker, has become a TM of significant interest. However, little is known about the above TM and TrxR activity in liver cancer. Therefore, this paper aimed to assess these TM with regards to diagnosis and and monitoring treatment efficacy in both primary and metastatic liver cancer. Our results showed TrxR had superior performance for discriminating between liver cancer patients and healthy controls than AFP, CEA, and CA19-9. TrxR also exhibited superior performance for assessing benefits of chemotherapy regardless if patients had PLC or MLC. Meanwhile, due to diagnostic efficiency of unresponsive chemotherapy patients, TrxR also showed a higher activity levels than other general markers in liver metastasis patients. Our results suggest that application of TrxR in combination with other tumor markers may maximize the efficiency of diagnosis and assessment of therapeutic efficiency, and provide new insights for the clinical application of TrxR as a candidate biomarker for liver cancer.

Nomograms to predict overall and cancer-specific survival in patients with upper tract urothelial carcinoma: a large population-based study.

BACKGROUND: To develop and validate survival nomograms for predicting the overall survival (OS) and cancer-specific survival (CSS) in upper tract urothelial carcinoma (UTUC) patients. METHOD: Patients diagnosed with UTUC from 2010 to 2015 in the Surveillance, Epidemiology, and End Results (SEER) database were retrospectively enrolled. Clinical characteristics and survival outcomes were respectively collected from the included patients. Then, eligible patients were divided into the training cohort and the validation cohort. Additionally, survival nomograms were developed based on the results of multivariate Cox analysis in the training cohort. Furthermore, Kaplan-Meier (KM) survival curves were generated to assess the actual effect of each variable. Lastly, the nomograms were validated using the concordance index (C-index), the area under the receiver operating characteristic (ROC) curve and calibration curves. RESULTS: Totally, 3,556 patients were included, with 2,492 in the training cohort and 1,064 in the validation cohort. No significant differences were detected in comparisons in clinical characteristics between two cohorts. Based on the results of uni- and multivariate Cox regression analysis, seven factors (age, TNM stage, use of surgery/radiation and marital status) for OS and six factors (age, TNM stage and use of surgery/radiation) for CSS were selected to develop the survival nomograms. The C-index for OS and CSS was 0.763 and 0.793 in the training cohort, and 0.759 and 0.784 in the validation cohort. Additionally, the 3- and 5-year AUCs for OS were 0.808 and 0.780 in the training cohort, and 0.785 and 0.778 in the validation group. As for CSS, it was 0.833 and 0.803 in the training cohort, and 0.815 and 0.810 in the validation cohort. Lastly, the calibration curves indicated a good consistency between the actual survival and the predictive survival. CONCLUSIONS: It was the first time to conduct survival models for UTUC patients with predictive performance. It might be valuable of clinical application and further exploration with more studies in the future.

Human gingiva-derived mesenchymal stem cells alleviate inflammatory bowel disease via IL-10 signalling-dependent modulation of immune cells.

Current evidence indicates that inflammatory bowel disease (IBD) is caused primarily by impaired mucosal immunity, resulting in an imbalance between epithelial barrier function and tissue inflammation. Human gingiva-derived mesenchymal stem cells (GMSCs) exhibit immunomodulatory and anti-inflammatory effects in a variety of immunity- and inflammation-associated diseases. However, the role of GMSCs in treating IBD has not been elucidated. Our study, therefore, examined the therapeutic effect and mechanism of GMSCs in a murine colitis model of IBD. Our results indicate that the infusion of GMSCs significantly prolonged survival and relieved symptoms. Phenotype analyses showed that the frequencies of NK1.1+ and CD11b+ cells, as well as CD4 T cells in the spleen, were suppressed in GMSC-treated mice compared with the PBS- or fibroblast-treated control groups. Additionally, GMSC treatment markedly increased the numbers of interleukin (IL)-10+ regulatory T cells, reduced the secretion of pro-inflammatory cytokines, and increased production of anti-inflammatory cytokines. A mechanistic study revealed that anti-IL-10R antibody abolished the protective effect of GMSCs compared with mice treated with anti-IgG antibody. Thus, our results indicate that GMSCs play a critical role in alleviating colitis by modulating inflammatory immune cells via IL-10 signalling.

HIF-1α-induced miR-23a∼27a∼24 cluster promotes colorectal cancer progression via reprogramming metabolism.

Tumor cells switch metabolic profile from oxidative phosphorylation to glycolysis in a hypoxic environment for survival and proliferation. The mechanisms governing this metabolic switch, however, remain incompletely understood. Here, we show that three miRNAs in the miR-23a∼27a∼24 cluster, miR-23a, miR-27a and miR-24, are the most upregulated miRNA cluster in colorectal cancer (CRC) under hypoxia. Gain- and loss-of-function assays, a human glucose metabolism array and gene pathway analyses confirm that HIF-1α-induced miR-23a∼27a∼24 cluster collectively regulate glucose metabolic network through regulating various metabolic pathways and targeting multiple tricarboxylic acid cycle (TCA)-related genes. In specific, miR-24/VHL/HIF-1α in CRC form a double-negative feedback loop, which in turn, promotes the cellular transition to the 'high HIF-1α/miR-24 and low VHL' state and facilitates cell survival. Our findings reveal that the miR-23a∼27a∼24 cluster is critical regulator switching CRC metabolism from oxidative phosphorylation to glycolysis, and controlling their expression can suppress colorectal cancer progression.