miR-31-5p suppresses myocardial hypertrophy by targeting Nfatc2ip.

Cardiac hypertrophy, worldwide known as an adaptive functional compensatory state of myocardial stress, is mainly believed to proceed to severe heart diseases, even to sudden death. Emerging studies have explored the microRNA alteration during hypertrophy. However, the mechanisms of microRNAs involved in cardiac hypertrophy are still uncertain. We studied young rats to establish abdominal aorta coarctation (AAC) for 4 weeks. With the significant downregulated cardiac function and upregulated hypertrophic biomarkers, AAC-induced rats showed enlarged myocardiocytes and alterations in microRNAs, especially downregulated miR-31-5p. miR-31-5p targets the 3'UTR of Nfatc2ip and inhibits myocardial hypertrophy in vitro and in vivo. Furthermore, we verified that Nfatc2ip is necessary and sufficient for cardiac hypertrophy in neonatal rat cardiomyocytes. Moreover, we found miR-31-5p inhibited the colocalization of Nfatc2ip and hypertrophic gene ß-Mhc. Luciferase assay and ChiP-qPCR test demonstrated that Nfatc2ip binded to the core-promoter of ß-Mhc and enhanced its transcriptional activity. Above all, our study found a new pathway, mir-31-5p/Nfatc2ip/ß-Mhc, which is involved in cardiac hypertrophy, suggesting a potential target for intervention of cardiac hypertrophy.

Lumican is a potential predictor on the efficacy of concurrent chemoradiotherapy in cervical squamous cell carcinoma.

Purpose: To identify new novel biomarkers for predicting the efficacy of concurrent chemoradiotherapy(CCRT) in cervical squamous cell carcinoma(CESC). Methods: Gene expression datasets GSE56363, GSE5787, and GSE168009 were analyzed to identify candidate genes to predict the efficacy of CCRT in CESC. Single-cell RNA sequencing (scRNA-seq) data from GSE168652 and CESC patients in The Cancer Genome Atlas(TCGA) were systematically analyzed to explore possible molecular mechanisms. Kaplan-Meier evaluated the correlation between LUM (Lumican) and prognostic significance. The expression of LUM protein in biopsy tissues before CCRT was detected by immunohistochemistry in 15 CESC patients. Results: LUM mRNA levels were significantly upregulated in nonresponders of CESC.patients receiving CCRT and positively correlated with poor therapeutic effect. Furthermore, high expression of LUM influenced the immune microenvironment in CESC patient-derived organoids treated with CCRT. LUM overexpression in CESC cells induced resistance to CCRT, potentially via immune landscape modulation. Gene Set Enrichment Analysis (GSEA) revealed that possible mechanisms underlying resistance to CCRT might involve the PARs and IL1 signaling pathway affecting the immune landscape. Conclusions: High LUM expression is correlated with poor efficacy in CESC patients receiving CCRT, possibly through the PARs and IL1 signaling pathway affecting the immune landscape.

Downregulation of MACC1 facilitates the reversal effect of verapamil on the chemoresistance to active metabolite of irinotecan in human colon cancer cells.

The aim of this study is to investigate the reversal effect of verapamil (VER) on chemoresistance to irinotecan (CPT-11) in human colon cancer cells and relevant mechanisms. Cell counting kit-8 (CCK-8) test and colony-forming unit (CFU) experiment results show that VER strengthens the sensitivity of human colon cancer cell line HT29 to CPT-11 but has a small effect on SW480 cells. High-throughput transcriptome sequencing, RT-PCR, and Western blot results show that the inhibition of metastasis-associated in colon cancer-1 (MACC1) expression by VER is the key factor for reversal effect on chemoresistance to CPT-11. Transfection experiments further show that VER can reverse the resistance of human colon cancer cells to SN-38, the active metabolite of CPT-11, when MACC1 is overexpressed. The nude mouse transplantation tumor experiment provides an in vivo proof that VER can strengthen sensitivity to CPT-11 in drug-resistant human colon cancer cells, and the effect might be related to the inhibited expression of MACC1. In summary, VER might strengthen the reversal effect of VER on chemoresistance to CPT-11 in human colon cancer cells and facilitate the apoptosis of human colon cancer cells by downregulating MACC1 expression.

Role of Aurora-A in Ovarian Cancer: A Meta-Analysis.

BACKGROUND: Recently, several studies have examined associations between Aurora-A expression and clinical outcome in patients with ovarian cancer, but yielded conflicting results with respect to survival. Therefore, the aim of this study was to evaluate the prognostic significance of Aurora-A in ovarian cancer by performing a meta-analysis. METHODS: PubMed, Cochrane library, Web of Science, Embase, Medline and Chinese BioMed Database (CBM) databases were searched systematically and only articles in which Aurora-A expression was detected by immunohistochemical staining were included. Hazard ratios (HRs) with 95% confidence intervals (CIs) were extracted and pooled for overall survival (OS) and disease-free survival (DFS). RESULTS: Our results show that the pooled HR for OS was 1.40 (95% CI 0.82-1.98, p < 0.01) by univariate analysis in 7 articles (1,028) and 0.32 (95% CI 0.04-0.615, p = 0.23) by multivariate analysis in 3 studies (155). The association between Aurora-A expression and DFS was also statistically significant in 5 studies (HR = 1.14, 95% CI 0.50-1.78, p < 0.01). CONCLUSION: This present meta-analysis suggests that the Aurora-A expression may be associated with poor prognosis in patients with ovarian cancer. Furthermore, studies of larger scale and well-matched regimes are warranted to confirm the findings in the future.

CCNB2 overexpression is a poor prognostic biomarker in Chinese NSCLC patients.

Cyclin B2 (CCNB2), a member of cyclin family proteins, serves a key role in progression of G2/M transition. The clinical value of CCNB2 in non-small cell lung cancer is still unknown. The aim of our study is to identify the role of CCNB2 in NSCLC patients. The status of CCNB2 in NSCLC tissues and normal lung tissues was observed in Gene Expression Omnibus (GEO: GSE19804). CCNB2 mRNA and protein expressions were detected in NSCLC and normal lung tissues by using Real-time PCR and immunohistochemistry. The association of CCNB protein expression with clinical characteristics of 186 NSCLC patients was analyzed by immunohistochemistry. Based on microarray data (GEO: GSE19804), we observed that CCNB2 was significantly overexpressed in NSCLC tissues compared with paired adjacent normal lung tissue. Furthermore, we verified mRNA and protein levels of CCNB2 expression were both increased in NSCLC tissues. We found high levels of CCNB2 protein were positively associated with the status of differentiated degree, tumor size, lymph node metastasis, distant metastasis, and clinical stage. Meanwhile, CCNB2 protein overexpression was an independent unfavorable prognostic factor for the overall survival of patients with NSCLC. In conclusion, overexpression of CCNB2 protein is associated with clinical progression and poor prognosis in NSCLC.

[Development of a lung cancer vaccine by transfecting dendritic cells with rAAV/CEA].

OBJECTIVE: To study the feasibility of preparing a therapeutic lung cancer vaccine by transfecting dendritic cells (DCs) with adeno-associated virus vector carrying carcino-embryonic antigen gene (rAAV/CEA). METHODS: Adherent cells (monocytes) isolated from the peripheral blood of a healthy donor were infected with rAAV/CEA virus stock or pulsed with CEA peptide (control). The monocytes in both groups were induced into mature DCs with recombinant human GM-CSF, IL-4 and TNF-α. At day 7 of induction, the mature DCs were harvested and mixed with T lymphocytes. T cell proliferation stimulated by the DCs was assessed with (3)H-thymidine uptake, and the expression of IL-4, IFN-γ, CD8, CD4, CD25 and CD69 in cytotoxic T lymphocytes (CTL) was analyzed with flow cytometry. The cytotoxicity of the CTL against the target CEA-positive lung cancer A549 cells was tested by (51)Cr releasing assay. RESULTS: The DCs transfected with rAAV/CEA strongly stimulated the proliferation of the T cell populations, and the induced CTL showed high expressions of CD8, CD69 and IFN-γ. The transfected DCs exhibited a high killing ability of CEA-positive lung cancer cells, and the killing showed a CEA antigen specificity and was limited by MHC I. These results suggested the ability of rAAV/CEA-transfected DCs in generating specific cellular immunity in vitro. CONCLUSION: It is feasible to prepare therapeutic lung cancer vaccines by transfecting DCs with rAAV/CEA.