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miR-141 and miR-146b-5p are two important tumor suppressor microRNAs, which control several cancer-related genes and processes. In the present report, we have shown that these microRNAs bind specific sites at the 3'-untranslated region (UTR) of the mRNA-binding protein AUF1, leading to its down-regulation. This inverse correlation between the levels of these microRNAs and AUF1 has been identified in various osteosarcoma cell lines. Additionally, we present clear evidence that AUF1 promotes mesenchymal features in osteosarcoma cells and that miR-141 and miR-146b-5p suppress this prometastatic process through AUF1 repression. Indeed, both microRNAs suppressed the invasion/migration and proliferation abilities of osteosarcoma cells through inhibiting the AKT protein kinase in an AUF1-dependent manner. We have also shown that AUF1 binds to and stabilizes the mRNA of the AKT activator phosphoinositide-dependent kinase-1 (PDK1). Furthermore, miR-141 and miR-146b-5p positively regulate the epithelial markers (E-cadherin and Epcam) and repress the mesenchymal markers (N-cadherin, Vimentin, Twist2, and ZEB1). These effects were mediated via the repression of the epithelial-to-mesenchymal inducer ZEB1 through targeting AUF1, which binds the 3'-UTR of the ZEB1 mRNA and reduces its turnover. These results indicate that at least some tumor suppressor functions of miR-141 and miR-146b-5p are mediated through the repression of the oncogenic potentials of AUF1. Therefore, these 3'-UTR-directed post-transcriptional gene expression regulators constitute promising new targets for diagnostic and/or therapeutic interventions., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)

Circulating oncomiRs are highly stable diagnostic, prognostic, and therapeutic tumor biomarkers, which can reflect the status of the disease and response to cancer therapy. miR-141 is an oncomiR, which is overexpressed in advanced prostate cancer patients, whereas its expression is at the normal levels in the early stages of the disease. On the other hand, miR-21 is significantly elevated in the early stage, but not in the advanced prostate cancer. Here, we have demonstrated simultaneous detection of exogenous miR-21 and miR-141 from human body fluids including blood, urine and saliva using nanographene oxide. Our system enables us to specifically and reliably detect each oncomiR at different fluorescence emission channels from a large population of RNAs extracted from body fluids. We were also able to determine the content and the ratio of the miR-21 and miR-141 in 10 different miRNA cocktails composed of various, but unknown, concentrations of both oncomiRs. A strong agreement (around 90%) between the experimental results and the actual miRNA compositions was observed. Moreover, we have demonstrated that overexpressed miR-21 or miR-141 increases the fluorescence only at their signature wavelengths of 520 and 670 nm, respectively. The approach in this study combines two emerging fields of nanographene in biomedicine and the role of circulating miRNAs in cancer. Our strategy has the potential to address the current challenges in diagnosis, prognosis and staging of prostate cancer with a non- or minimally invasive approach.

Background and Objectives: Surgery is the standard treatment for colorectal cancer (CRC), and adjuvant chemotherapy has been shown to be effective in stage III but less so in stage II. We have analyzed the expression of the miR-200 family in tissue samples from resected CRC patients and correlated our findings with survival to adjuvant treatment with fluoropyrimidines., Methods: Tumor tissue samples were obtained from 127 surgically resected patients with stage I-III CRC. miRNA detection was performed using TaqMan MicroRNA assays., Results: High levels of miR-200a and miR-200c were associated with longer overall survival, while high levels of miR-429 correlated with longer overall and disease-free survival (DFS). In the subgroup of 56 patients treated with fluoropyrimidines and in the smaller subgroup of 32 stage II patients treated with fluoropyrimidines, those with high levels of miR-200a, miR-200c, miR-141, or miR-429 had significantly longer overall and DFS. Low miR-429 levels were identified as an independent prognostic marker. High levels of miR-429 combined with 5-fluorouracil inhibited cell invasion in LOVO cells., Conclusions: miR-200a, miR-200c, miR-141, and miR-429 expression levels may identify CRC patients, including those with stage II disease, who are most likely to benefit from adjuvant chemotherapy., (© 2014 Wiley Periodicals, Inc.)

HOTAIR is a long non-coding RNA that interacts with the polycomb repressive complex and suppresses its target genes. HOTAIR has also been demonstrated to promote malignancy. MicroRNA-141 (miR-141) has been reported to play a role in the epithelial to mesenchymal transition process, and the expression of miR-141 is inversely correlated with tumorigenicity and invasiveness in several human cancers. We found that HOTAIR expression is inversely correlated to miR-141 expression in renal carcinoma cells. HOTAIR promotes malignancy, including proliferation and invasion, whereas miR-141 suppresses malignancy in human cancer cells. miR-141 binds to HOTAIR in a sequence-specific manner and suppresses HOTAIR expression and functions, including proliferation and invasion. Both HOTAIR and miR-141 were associated with the immunoprecipitated Ago2 (Argonaute2) complex, and the Ago2 complex cleaved HOTAIR in the presence of miR-141. These results demonstrate that HOTAIR is suppressed by miR-141 in an Ago2-dependent manner.

Background/aim: Increased levels of microRNAs in serum/plasma have been identified in various malignancies. We aimed to investigate serum levels of miR-26a-1 and miR-141 in patients undergoing prostate biopsy clinical suspicious for prostate cancer (PCA) in a prospective multi-center study., Patients and Methods: Pre-biopsy serum samples of 170 patients were collected in three different study Centres. Serum RNA was isolated, and microRNA lev-els were quantified using real-time PCR. Relative miR-26a -1 and miR-141 levels were determined using RNU1-4 and SNORD43 as reference genes., Results: After exclusion of pa-tients with metastatic prostate cancer (n=9) and isolation failures (n=28), 133 patients (prostate cancer n=54, non-malignant n=79) were used for further analysis. The levels of miR-26a-1 and miR-141 were similar in patients with positive and negative biopsies. We observed a significant increase of miR-141 in patients with higher Gleason Score., Conclusion: The analysis of circulating microRNAs does not seem to help identify patients with cancer undergoing prostate biopsy. However, their levels may be useful to identify patients with high-risk prostate cancer.

The mouse incisor is a remarkable tooth that grows throughout the animal's lifetime. This continuous renewal is fueled by adult epithelial stem cells that give rise to ameloblasts, which generate enamel, and little is known about the function of microRNAs in this process. Here, we describe the role of a novel Pitx2:miR-200c/141:noggin regulatory pathway in dental epithelial cell differentiation. miR-200c repressed noggin, an antagonist of Bmp signaling. Pitx2 expression caused an upregulation of miR-200c and chromatin immunoprecipitation assays revealed endogenous Pitx2 binding to the miR-200c/141 promoter. A positive-feedback loop was discovered between miR-200c and Bmp signaling. miR-200c/141 induced expression of E-cadherin and the dental epithelial cell differentiation marker amelogenin. In addition, miR-203 expression was activated by endogenous Pitx2 and targeted the Bmp antagonist Bmper to further regulate Bmp signaling. miR-200c/141 knockout mice showed defects in enamel formation, with decreased E-cadherin and amelogenin expression and increased noggin expression. Our in vivo and in vitro studies reveal a multistep transcriptional program involving the Pitx2:miR-200c/141:noggin regulatory pathway that is important in epithelial cell differentiation and tooth development.