LncRNA MAFG-AS1 affects the tumorigenesis of breast cancer cells via the miR-574-5p/SOD2 axis.

Amounting evidence suggested that long non coding RNAs (lncRNAs) played vital roles in the progression of various cancers. The aim of this study is to examine the biological roles and underlying mechanisms of lncRNA MAFG-AS1 in the tumorigenesis of breast cancer (BC) cells. Here we showed that downregulation of MAFG-AS1 inhibited the viability, migration, and invasion of BC cells. Mechanism investigation showed that inhibition of MAFG-AS1 induced apoptosis via the intrinsic apoptotic pathway and overexpression of Bcl-2 could inhibited it. Further, MAFG-AS1 acts as a sponge of miR-574-5p which directly binds to SOD2 mRNA. Re-expression of SOD2 using a 3'-UTR mutant SOD2 reversed the effects of silencing of MAFG-AS1 on BC cells. Finally, downregulation of MAFG-AS1 inhibited the growth of tumour in vivo. Together, MAFG-AS1 acts as an oncogene via regulation of miR-574-5p/SOD2 axis in BC cells.

Metformin and FTY720 Synergistically Induce Apoptosis in Multiple Myeloma Cells.

BACKGROUND/AIMS: Patients with multiple myeloma (MM) invariably relapse with chemotherapy-resistant disease, underscoring the need for new therapeutic options that bypass these resistance mechanisms. Metformin is a widely prescribed antidiabetic drug with direct antitumor activity against various tumor cell lines. FTY720, also known as fingolimod, is an immune-modulating agent approved by the FDA as oral medication to treat the relapsing form of multiple sclerosis (MS). In recent years, FTY720 has attracted attention due to its anti-tumor activity. To explore an optimized combinational therapy, interactions between metformin and FTY720 were examined in MM cells. METHODS: MTT assays were employed to assess the viability of MM cells. An apoptotic nucleosome assay was employed to measure apoptosis. Loss of mitochondrial membrane potential (MMP, ΔΨm) and cellular levels of ROS were measured by flow cytometry. qRT-PCR was used to analyze the expression of mRNAs. Western blotting assays were applied to measure the levels of proteins involved in different signaling pathways. RESULTS: Coadministration of metformin and FTY720 synergistically inhibited the proliferation of MM cells. Increased levels of apoptosis, activation of caspase-3 and cleavage of PARP were detected after cotreatment with metformin and FTY720. These events were associated with modulation of Bcl-2 proteins, loss of MMP, ER stress induction, and inhibition of the PI3K/AKT/mTOR signaling pathway. The metformin/FTY720 regimen markedly induced ROS generation; moreover, apoptosis, ER stress and inhibition of PI3K/AKT/ mTOR were attenuated by the ROS scavenger NAC. CONCLUSIONS: Exposure to metformin in combination with FTY720 potently induces apoptosis in MM cells in a ROS-dependent manner, suggesting that a strategy combining these agents warrants further investigation in MM.

Long noncoding RNA linc-ITGB1 promotes cell migration and invasion in human breast cancer.

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer-related death in women globally. Its high morbidity and mortality, as well as its elevated tendency to metastasize to other organs, warrant the urgency to find new biomarkers for breast cancer diagnosis and treatment. The specific roles of long noncoding RNA linc-ITGB1 on cell proliferation and metastasis in breast cancer were explored in this study. The expression of linc-ITGB1 was significantly upregulated in both clinical breast cancer tissues and cultured breast cancer cell lines. The linc-ITGB1 knockdown with specific short hairpin RNA (shRNA) decreased cell proliferation and colony formation in vitro. Tumor growth in vivo was also inhibited by linc-ITGB1 depletion. In addition, linc-ITGB1 depletion caused cell accumulation in the G0/G1 phase. Breast cancer cell lines with linc-ITGB1 depletion exhibited decreased migration and invasion abilities compared with the control cells. Furthermore, the linc-ITGB1 knockdown decreased the expression of mesenchymal markers N-cadherin and vimentin while increasing the expression of the epithelial marker E-cadherin. Key cell cycle regulators Cdc25C and Cyclin B1 were also decreased by the linc-ITGB1 knockdown. These data suggest that linc-ITGB1 promotes breast cancer progression by inducing cell cycle arrest and interrupting the epithelial-to-mesenchymal transition process.

miR-139-5p Was Identified as Biomarker of Different Molecular Subtypes of Breast Carcinoma.

Located on chromosome 11q13.4, miR-139-5p has been confirmed by several studies as a possible attractive biomarker for cancer, including breast cancer, but its mechanism of correlation in different molecular subtypes of breast cancer has not been reported. In this study, comprehensive bioinformatics analysis was used to evaluate the expression of miR-139-5p in different molecular subtypes of breast cancer (luminal A, luminal B, HER2-enriched, and basal-like). The target genes of miR-139-5p were predicted by using an online database TargetScan and miRDB, and three key genes, FBN2, MEX3A, and TPD52, were screened in combination with differentially expressed genes in different molecular subtypes of breast cancer. The expression of the three genes was verified separately, and the genes were analyzed for pathway and functional enrichment. Bone marrow mesenchymal stem cells (BMSC) are another kind of highly plastic cell population existing in bone marrow besides hematopoietic stem cells. BMSC can affect the proliferation and migration of cancer cells, promote the metastasis and development of cancer, and regulate the tumor microenvironment by secreting exosome mirnas, thus affecting the malignant biological behavior of tumor cells. Finally, human bone marrow mesenchymal stem cells exosomes were obtained by ultracentrifugation, and the morphology of exosomes was observed by transmission electron microscopy. The expression of miR-139-5p in normal breast cells MCF-10A, human breast cancer cell line MDA-MB-231 cells, and BMSCs-derived exosomes were compared; the exosomes and MDA-MB-231 cells were co-cultured to observe their effects on the proliferation of the MDA-MB-231 cells. Human bone marrow mesenchymal stem cell-derived exosomes inhibited the growth of breast cancer cells and promoted the expression of FBN2, MEX3A, and TPD52 by transporting miR-139-5p.

DIRAS3, GPR171 and RAC2 were identified as the key molecular patterns associated with brain metastasis of breast cancer.

Objective: Brain metastasis is a primary cause of morbidity and mortality in breast cancer patients. Therefore, elucidation and understanding of the underlying mechanisms are essential for the development of new therapeutic strategies. Methods: Differential gene analysis was performed for those with and without distant metastasis in The Cancer Genome Atlas (TCGA) database and those with and without recurrence in the brain in the dataset GSE12276. The differentially expressed genes procured from the two databases were intersected to obtain the intersecting genes associated with brain metastasis. Thereafter, the intersecting genes were subjected to LASSO model construction to screen for prognostic genes. The expression of the obtained genes in metastatic breast cancer was observed, and survival analysis was performed. Finally, GSEA analysis of the obtained genes was performed, and the relationship between them and immune cells was explored. Results: A total of 335 differential genes for the occurrence of distant metastases were obtained based on the TCGA database. A total of 1070 differential genes for recurrence to the brain were obtained based on the dataset GSE12276. The Venn diagram showed 24 intersecting genes associated with brain metastasis. The LASSO prognostic model contained a total of five genes (GBP2, GPR171, DIRAS3, RAC2, and CACNA1D). Expression difference analysis showed that GBP2, GPR171, DIRAS3, and RAC2 were significantly down-regulated in expression in metastatic breast cancer compared with primary breast cancer tumors. Only GPR171, DIRAS3, and RAC2 were strongly correlated with the overall survival of breast cancer patients. Their correlation analysis with immune cells showed that the correlation coefficient between the expression levels of DIRAS3 and immune cells was low, and the expression levels of GPR171 and RAC2 were more closely correlated with B cells and macrophages. Conclusions: The expression of DIRAS3, GPR171 and RAC2, genes associated with brain metastasis, was reduced in metastatic breast cancer, and GPR171 was found to promote brain metastasis of breast cancer cells by inducing B cells and thereby.