Background: Nowadays, microRNAs (miRNAs) attract much attention in regulating anticancer drug resistance in cancers including multiple myeloma (MM). Bortezomib is the first-line choice in MM treatment, and bortezomib resistance caused by aberrant DNA repair leads to the recurrence and therapeutic failure of MM. Objective: Our study aims to identify a miRNA that overcomes bortezomib resistance in MM. Methods: We established bortezomib-resistant MM cell lines, and screened several miRNAs that have aberrant expressions in MM cell lines. The expression of DNA-repair-related proteins were assessed by western blot, and cell viability was determined by the MTT assay in bortezomib-resistant cell lines. The binding between miRNAs and 3ʹ-UTR of APE1 mRNA was confirmed by luciferase reporter assay. The mouse bortezomib-resistant xenograft was established to verify the therapeutic effect of miRNA overexpression. Results: miR-520g and miR-520h were significantly downregulated in bortezomib-resistant MM cell lines, and overexpression of miR-520g and miR-520h together inhibited expression of homologous recombination-related protein Rad51 and cell viability of bortezomib-resistant MM cells in vitro by binding with 3ʹ-UTR of APE1 mRNA. Combined overexpression of miR-520g and miR-520h inhibited bortezomib-resistant MM tumor growth in vivo. Conclusion: Our findings demonstrated that combined overexpression of miR-520g and miR-520h overcomes bortezomib resistance in MM through inhibition of DNA repair, offering a promising therapeutic target for MM treatment.

Glioblastoma is a malignant brain tumor characterized by rapid growth, diffuse invasion and therapeutic resistance. We recently used microRNA expression profiles to subclassify glioblastoma into five genetically and clinically distinct subclasses, and showed that microRNAs both define and contribute to the phenotypes of these subclasses. Here we show that miR-29a activates a multi-faceted growth and invasion program that promotes glioblastoma aggressiveness. microRNA expression profiles from 197 glioblastomas were analyzed to identify the candidate miRNAs that are correlated to glioblastoma aggressiveness. The candidate miRNA, miR-29a, was further studied in vitro and in vivo. Members of the miR-29 subfamily display increased expression in the two glioblastoma subclasses with the worst prognoses (astrocytic and neural). We observed that miR-29a is among the microRNAs that are most positively-correlated with PTEN copy number in glioblastoma, and that miR-29a promotes glioblastoma growth and invasion in part by targeting PTEN. In PTEN-deficient glioblastoma cells, however, miR-29a nevertheless activates AKT by downregulating the metastasis suppressor, EphB3. In addition, miR-29a robustly promotes invasion in PTEN-deficient glioblastoma cells by repressing translation of the Sox4 transcription factor, and this upregulates the invasion-promoting protein, HIC5. Indeed, we identified Sox4 as the most anti-correlated predicted target of miR-29a in glioblastoma. Importantly, inhibition of endogenous miR-29a decreases glioblastoma growth and invasion in vitro and in vivo, and increased miR-29a expression in glioblastoma specimens correlates with decreased patient survival. Taken together, these data identify miR-29a as a master regulator of glioblastoma growth and invasion.

Background: Acyl-CoA dehydrogenase long chain (ACADL) was revealed to have a correlation with malignant progression of cancer. However, whether ACADL plays a role in clinical therapy remains unclear. The clinicopathological role of ACADL in esophageal squamous cell carcinoma (ESCC) will be discussed in this study. Materials and methods: The expression of ACADL was analyzed via real-time PCR and Western blotting to assess mRNA and protein levels in ESCC cell lines and normal esophageal epithelial cells (NEECs), in six paired ESCC tumors and relative normal tissues. Furthermore, immunohistochemical staining was performed on 135 paraffin-embedded ESCC specimens to assess ACADL expression. The clinicopathological significance of ACADL expression was further investigated via survival analysis and Cox regression analysis. Results: ACADL was found to be markedly upregulated in ESCC cell lines when compared with NEECs. Moreover, various experiments such as quantitative real-time PCR, Western blot, and immunohistochemical analyses all revealed that ACADL expression was increased in all six paired ESCC tumors and matched normal tissues. Furthermore, immunohistochemical analysis revealed an increased level of ACADL protein expression in all 135 paraffin-embedded samples from ESCC patients, which increased with disease progression. Conclusion: We demonstrated that ACADL is overexpressed in ESCC, both in cell lines and clinical specimens. ACADL is found to be a vital regulator in ESCC progression and can predict a worse outcome for ESCC patients, suggesting that ACADL might be a valuable molecule to be targeted for clinical therapy of ESCC treatment.

Background: Mitochondrial fission regulator 2 (MTFR2) has been reported to promote proliferation, migration and invasion in tumors; however, little is known about its function in breast cancer. Thus, we investigated the effect of MTFR2 expression on prognosis of breast cancer. Methods: The expression of MTFR2 in breast cancer tissues was detected by immunohistochemistry, and overall survival (OS) and recurrence free survival (RFS) were evaluated by the Log rank test and Cox model. Results: We found that MTFR2 expression was significantly associated with clinical stage (P< 0.001), T classification (P=0.005), N classification (P=0.001), M classification (P=0.041), HER2 expression (P= 0.001), and molecular subtypes (P=0.002), respectively. Compared with low MTFR2 expression, the patients with higher expression of MTFR2 exhibited significantly shorter OS and RFS (All P < 0.001). Both univariate and multivariate analyses showed that MTFR2 was an independent prognostic factor for OS (HR, 2.8, 95% CI 1.1– 6.8, P = 0.023) and RFS (HR, 2.8, 95% CI 1.2– 6.4, P = 0.015) in breast cancer patients. Moreover, in HER2 positive and TNBC subtype, the associations between high MTFR2 expression and poor OS and RFS were more pronounced. Conclusion: Taken together, our results demonstrated that high MTFR2 expression was associated with poor prognosis of breast cancer patients, and such an association was more pronounced in the patients with aggressive tumors. Therefore, MTFR2 expression might be a potentially important prognostic biomarker and clinical target for patients with breast cancer.

Objective: This study aimed to identify immune infiltration characteristics and new immunological diagnostic biomarkers in the cerebrovascular tissue of moyamoya disease (MMD) using bioinformatics analysis.Methods: GSE189993 and GSE141022 were downloaded from the GEO database. Differentially expressed gene and PPI analysis were performed. After performing WGCNA, the most significant module associated with MMD was obtained. Next, functional pathways according to GSEA, GO, and KEGG were enriched for the aforementioned core genes obtained from PPI and WGCNA. Additionally, immune infiltration, using the CIBERSORT deconvolution algorithm, immune-related biomarkers, and the relationship between these genes, was further explored. Finally, diagnostic accuracy was verified with ROC curves in the validation dataset GSE157628.Results: A total of 348 DEGs were screened, including 89 downregulated and 259 upregulated genes. The thistle^l module was detected as the most significant module associated with MMD. Functional analysis of the core genes was chiefly involved in the immune response, immune system process, protein tyrosine kinase activity, secretory granule, and so on. Among 13 immune-related overlapping genes, 4 genes (BTK, FGR, PTPN11, and SYK) were identified as potential diagnostic biomarkers, where PTPN11 showed the highest specificity and sensitivity. Meanwhile, a higher proportion of eosinophils, not T cells or B cells, was demonstrated in the specific immune infiltration landscape of MMD.Conclusion: Immune activities and immune cells were actively involved in the progression of MMD. BTK, FGR, PTPN11, and SYK were identified as potential immune diagnostic biomarkers. These immune-related genes and cells may provide novel insights for immunotherapy in the future.