Transcription factor E2F3 activates CDC25B to regulate DNA damage and promote mitoxantrone resistance in stomach adenocarcinoma.

BACKGROUND: CDC25B, as a member of the cell cycle regulating protein family, is located in the cytoplasm and is involved in the transition of the cell cycle and mitosis. CDC25B is highly expressed in various tumors and is a newly discovered oncogene. This study aimed to investigate the impact of CDC25B on mitoxantrone resistance in stomach adenocarcinoma (STAD) and its possible mechanisms. METHODS: This study analyzed the expression of CDC25B and its potential transcription factor E2F3 in STAD, as well as the IC50 values of tumor tissues by bioinformatics analysis. Expression levels of CDC25B and E2F3 in STAD cells were measured by qRT-PCR. MTT was utilized to evaluate cell viability and IC50 values of STAD cells, and comet assay was utilized to analyze the level of DNA damage in STAD cells. Western blot was used to analyze the expression of DNA damage-related proteins. The targeting relationship between E2F3 and CDC25B was validated by dual-luciferase and ChIP assays. RESULTS: Bioinformatics analysis and molecular experiments showed that CDC25B and E2F3 were highly expressed in STAD, and CDC25B was enriched in the mismatch repair and nucleotide excision repair pathways. The IC50 values of tumor tissues with high expression of CDC25B were relatively high. Dual-luciferase and ChIP assays confirmed that CDC25B could be transcriptionally activated by E2F3. Cell experiments revealed that CDC25B promoted mitoxantrone resistance in STAD cells by regulating DNA damage. Further research found that low expression of E2F3 inhibited mitoxantrone resistance in STAD cells by DNA damage, but overexpression of CDC25B reversed the impact of E2F3 knockdown on mitoxantrone resistance in STAD cells. CONCLUSION: This study confirmed a novel mechanism by which E2F3/CDC25B mediated DNA damage to promote mitoxantrone resistance in STAD cells, providing a new therapeutic target for STAD treatment.

The effect of intermittent versus continuous enteral feeding for critically ill patients: a meta-analysis of randomized controlled trials.

Objectives: The appropriate strategy for enteral feeding in critically ill patients still remains controversial. Therefore, we conducted this meta-analysis to compare the effect of intermittent versus continuous enteral feeding method for critically ill patients. Methods: Electronic databases including PubMed, Embase, Scopus, and Cochrane Library were searched up to April 10th, 2023 for randomized controlled trials evaluating the effect of intermittent versus continuous enteral feeding for critically ill patients. The primary outcomes were feeding intolerances, including diarrhea, vomiting, distension, constipation, gastric retention, and aspiration pneumonia. The secondary outcomes were mortality in intensive care unit (ICU), length of stay in ICU, and achievement of nutritional goal. Results: Thirteen studies with a total of 884 patients were analyzed in this meta-analysis. Overall, the use of intermittent enteral feeding was associated with higher incidence of diarrhea (OR 1.66, 95%CI 1.13 to 2.43, I2 = 16%) and distension (OR 2.29, 95%CI 1.16 to 4.51, I2 = 0%), lower incidence of constipation (OR 0.58, 95%CI 0.37 to 0.90, I2 = 0%), and longer length of ICU stay (MD 1.09, 95%CI 0.53 to 1.64, I2 = 0%). Moreover, no significant difference was identified for other outcome measures. Conclusion: In critically ill patients, the implementation of intermittent enteral feeding was associated with higher incidence of diarrhea and distension, longer length of ICU stay, but lower occurrence of constipation. Nevertheless, the absence of sufficient high-quality randomized controlled clinical trials precludes any definitive conclusions regarding the optimal approach to enteral feeding in this population. There is an imperative need for more studies to further assess the efficacy of the two enteral feeding strategies.

Construction of a Prognostic Evaluation Model for Stomach Adenocarcinoma on the Basis of Immune-Related lncRNAs.

Progression, prognosis, and therapeutic strategy of stomach adenocarcinoma (STAD) have a close connection with tumor microenvironment (TME). Thus, it is pivotal to delve into the TME and immune-related genes, which may bring possibilities for improving patient's prognosis. TCGA-STAD dataset was analyzed to acquire differentially expressed lncRNAs in tumor samples, which were overlapped with the immune-related lncRNA datasets in the ImmLnc database. Twenty-six lncRNAs related to STAD immunity and patient's prognosis were acquired by univariate Cox analysis. Following lncRNA expression patterns, STAD samples could be classified into two clusters with completely different immune patterns. We performed multivariate Cox regression analysis on lncRNAs to identify 7-feature lncRNAs and constructed a corresponding prognostic model. The model validity was verified by survival analysis and ROC curve in validation and training sets. To explore connection between model and TME and tumor drug resistance, this study analyzed differences in immune cell infiltration between samples from high- and low-risk groups and then revealed immune cells follicular helper with significant differences in tumor tissue infiltration. Analysis of resistance to chemotherapeutic drugs revealed that samples in the high-risk group had resistance to cisplatin, doxorubicin, bleomycin, and gemcitabine. Through univariate and multivariate Cox analyses, we manifested that risk score could be an independent prognostic factor. Combining risk score and clinical factors, a nomogram was constructed to accurately predict patient's prognosis. This model can effectively predict prognosis, TME, and drug resistance of STAD patients, which may provide a reference for tumor development evaluation and precise treatment for clinical STAD.

lncRNA DSCR8 mediates miR-137/Cdc42 to regulate gastric cancer cell proliferation, invasion, and cell cycle as a competitive endogenous RNA.

lncRNA DSCR8 (Down syndrome critical region 8) is involved in progression of many cancers, but its specific role in gastric cancer (GC) is still unclear. Here, qRT-PCR detected upregulated expression of DSCR8 and Cdc42 and downregulated expression of miR-137 in GC. The protein expression level of Cdc42 in GC was upregulated as tested by western blot. Statistical analysis showed that DSCR8 was closely associated with some malignant clinicopathological features (such as tumor size, metastasis, and stage) in GC patients. Fluorescence in situ hybridization showed that DSCR8 was localized in the nucleus and cytoplasm. Dual-luciferase reporter gene, RNA immunoprecipitation, and biotin pull-down assays showed that DSCR8 could bind to miR-137 could bind to Cdc42. In vitro and in vivo assays showed that DSCR8 could promote proliferation, invasion, and the cycle of GC cells and inhibit cell apoptosis. In addition, a rescue experiment showed that DSCR8 regulated progression of GC cells via miR-137. Furthermore, DSCR8 regulated Cdc42 in GC cells by inhibiting miR-137. Taken together, these data indicated that DSCR8 could adsorb miR-137 to reduce its inhibitory effect on Cdc42 expression, thereby promoting the progression of GC cells and regulating the cell cycle. These results provide a novel direction for DSCR8 as a target of GC.

Integrative bioinformatics analysis of KPNA2 in six major human cancers.

BACKGROUND: Malignant tumors were considered as the leading causes of cancer-related mortality globally. More and more studies found that dysregulated genes played an important role in carcinogenesis. The aim of this study was to explore the significance of KPNA2 in human six major cancers including non-small cell lung cancer (NSCLC), gastric cancer, colorectal cancer, breast cancer, hepatocellular carcinoma, and bladder cancer based on bioinformatics analysis. METHODS: The data were collected and comprehensively analyzed based on multiple databases. KPNA2 mRNA expression in six major cancers was investigated in Oncomine, the human protein atlas, and GEPIA databases. The mutation status of KPNA2 in the six major cancers was evaluated by online data analysis tool Catalog of Somatic Mutations in Cancer (COSMIC) and cBioPortal. Co-expressed genes with KPNA2 were identified by using LinkedOmics and made pairwise correlation by Cancer Regulome tools. Protein-protein interaction (PPI) network relevant to KPNA2 was constructed by STRING database and KEGG pathway of the included proteins of the PPI network was explored and demonstrated by circus plot. Survival analysis-relevant KPNA2 of the six cancers was performed by GEPIA online data analysis tool based on TCGA database. RESULTS: Compared with paired normal tissue, KPNA2 mRNA was upregulated in all of the six types of cancers. KPNA2 mutations, especially missense substitution, were widely identified in six cancers and interact with different genes in different cancer types. Genes involved in PPI network were mainly enriched in p53 signaling pathway, cell cycle, viral carcinogenesis, and Foxo signaling pathway. KPNA2 protein was mainly expressed in nucleoplasm and cytosol in cancer cells. Immunohistochemistry assay indicated that KPNA2 protein was also positively expressed in nucleoplasm with brownish yellow staining. Overall survival (OS) and progression free survival (PFS) were different between KPNA2 high and low expression groups. CONCLUSIONS: KPNA2 was widely dysregulated and mutated in carcinomas and correlated with the patients prognosis which may be potential target for cancer treatment and biomarker for prognosis.

Implication from thyroid function decreasing during chemotherapy in breast cancer patients: chemosensitization role of triiodothyronine.

BACKGROUND: Thyroid hormones have been shown to regulate breast cancer cells growth, the absence or reduction of thyroid hormones in cells could provoke a proliferation arrest in G0-G1 or weak mitochondrial activity, which makes cells insensitive to therapies for cancers through transforming into low metabolism status. This biological phenomenon may help explain why treatment efficacy and prognosis vary among breast cancer patients having hypothyroid, hyperthyroid and normal function. Nevertheless, the abnormal thyroid function in breast cancer patients has been considered being mainly caused by thyroid diseases, few studied influence of chemotherapy on thyroid function and whether its alteration during chemotherapy can influence the respose to chemotherapy is still unclear. So, we aimed to find the alterations of thyroid function and non-thyroidal illness syndrome (NTIS) prevalence druing chemotherapy in breast cancer patients, and investigate the influence of thyroid hormones on chemotherapeutic efficacy. METHODS: Thyroid hormones and NTIS prevalence at initial diagnosis and during chemotherapy were analyzed in 685 breast diseases patients (369 breast cancer, 316 breast benign lesions). The influence of thyroid hormones on chemotherapeutic efficacy was evaluated by chemosensitization test, to compare chemotherapeutic efficacy between breast cancer cells with chemotherapeutics plus triiodothyronine (T3) and chemotherapeutics only. RESULTS: In breast cancer, NTIS prevalence at the initial diagnosis was higher and increased during chemotherapy, but declined before the next chemotherapeutic course. Thyroid hormones decreased signigicantly during chemotherapy. T3 can enhance the chemosensitivity of MCF-7 to 5-Fu and taxol, with progression from G0-G1 phase to S phase. The similar chemosensitization role of T3 were found in MDA-MB-231. We compared chemotherapeutic efficacy among groups with different usage modes of T3, finding pretreatment with lower dose of T3, using higher dose of T3 together with 5-Fu or during chemotherapy with 5-Fu were all available to achieve chemosensitization, but pretreatment with lower dose of T3 until the end of chemotherapy may be a safer and more efficient therapy. CONCLUSIONS: Taken together, thyroid hormones decreasing during chemotherapy was found in lots of breast cancer patients. On the other hand, thyroid hormones can enhance the chemotherapeutic efficacy through gatherring tumor cells in actively proliferating stage, which may provide a new adjuvant therapy for breast cancer in furture, especially for those have hypothyroidism during chemotherapy.