Abstract
Breast cancer, the most common malignant tumor in women, has become a worldwide burden for family and society. MicroRNAs (miRNAs or miRs) are recognized as critical mediators of cancer-related processes, since they have the ability to coordinately suppress multiple target genes. In this study, we aim to find out specific miRNAs involved in the progression of breast cancer and explore the underlying molecular mechanism. Bioinformatics analysis suggested miR-301 as a differentially overexpressed miRNA in breast cancer, which was confirmed by expression determination. Functional assays were employed to explore the effect of miR-301 and its downstream effectors cytoplasmic polyadenylation element-binding protein 1 (CPEB1), SIRT1, and SOX2 on malignant phenotypes of breast cancer. The interaction among these factors was explained using luciferase and RNA immunoprecipitation (RIP) assays. In addition, the in vivo impact of miR-301 on breast cancer was assessed by cellular tumorigenicity in nude mice. We found that miR-301 overexpression restricted CPEB1 level and further promoted cell proliferation, metastasis, and cell cycle progression and impeded apoptosis. Moreover, CPEB1 regulated breast cancer development by mediating the SIRT1/SOX2 pathway. Further, miR-301 overexpression accelerated tumor formation in nude mice. Our results indicate that miR-301 overexpression accelerates the progression of breast cancer through the CPEB1/SIRT1/SOX2 axis.
Highlights
Breast cancer is the most common cancer in females with an increasing incidence rate throughout the globe.[1,2] Nearly 11% of the worldwide breast cancer cases occur in China, where it is the sixthleading cause of cancer-related deaths among females.[3]
3,554 differential genes were obtained by analyzing the breast cancer database in The Cancer Genome Atlas (TCGA) database using the online tool GEPIA, of which 2,133 genes were significantly lowly expressed in breast cancer, and the predicted miR-301a candidate target genes were intersected with the significantly downregulated genes in TCGA (Figure 1E), and the candidate target gene GPEB1 was obtained
Previous studies indicated that cytoplasmic polyadenylation elementbinding protein 1 (CPEB1) can moderate the expression of SIRT1 12, whereas SIRT1 can have an effect on the expression of SOX2.13,14 highly expressed SIRT1 was found in breast cancer.[15]
Summary
Breast cancer is the most common cancer in females with an increasing incidence rate throughout the globe.[1,2] Nearly 11% of the worldwide breast cancer cases occur in China, where it is the sixthleading cause of cancer-related deaths among females.[3]. The aberrant regulatory interaction of microRNA (miRNA)-mRNA that mediates the malignant phenotypes of cancer cells may provide novel targets and therapies to limit development of malignancies, including breast cancer.[6] miRNAs are small noncoding RNAs existing in both nucleus and cytoplasm, repressing gene expression by binding to their target mRNAs via complementary sequences of the 30 untranslated region (30 UTR).[7] Among different breast cancer subtypes, the specific miRNA signatures are shown as either oncogenes or tumor suppressor genes.[8] In the present study, differentially expressed miRNAs and their target genes related to breast cancer were predicted through bioinformatic analyses, where microRNA (miR)-301 and cytoplasmic polyadenylation elementbinding protein 1 (CPEB1) were chosen for subsequent experiments. There is only one study suggesting that miR-301 mediates breast cancer through transcriptional regulation of target mRNAs, including PTEN, FoxF2, BBC3, and Col2A1.9 Still, the involved downstream regulatory signaling pathways have not been fully established. It is reasonable to hypothesize that the regulation of miR-301 on CPEB1 may play a potential role in the development of breast cancer
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