Blog
About

1
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Molecular Pathogenesis of Gene Regulation by the miR-150 Duplex: miR-150-3p Regulates TNS4 in Lung Adenocarcinoma

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Based on our miRNA expression signatures, we focused on miR-150-5p (the guide strand) and miR-150-3p (the passenger strand) to investigate their functional significance in lung adenocarcinoma (LUAD). Downregulation of miR-150 duplex was confirmed in LUAD clinical specimens. In vitro assays revealed that ectopic expression of miR-150-5p and miR-150-3p inhibited cancer cell malignancy. We performed genome-wide gene expression analyses and in silico database searches to identify their oncogenic targets in LUAD cells. A total of 41 and 26 genes were identified as miR-150-5p and miR-150-3p targets, respectively, and they were closely involved in LUAD pathogenesis. Among the targets, we investigated the oncogenic roles of tensin 4 ( TNS4) because high expression of TNS4 was strongly related to poorer prognosis of LUAD patients (disease-free survival: p = 0.0213 and overall survival: p = 0.0003). Expression of TNS4 was directly regulated by miR-150-3p in LUAD cells. Aberrant expression of TNS4 was detected in LUAD clinical specimens and its aberrant expression increased the aggressiveness of LUAD cells. Furthermore, we identified genes downstream from TNS4 that were associated with critical regulators of genomic stability. Our approach (discovery of anti-tumor miRNAs and their target RNAs for LUAD) will contribute to the elucidation of molecular networks involved in the malignant transformation of LUAD.

          Related collections

          Most cited references 37

          • Record: found
          • Abstract: found
          • Article: not found

          Passenger-strand cleavage facilitates assembly of siRNA into Ago2-containing RNAi enzyme complexes.

          In the Drosophila and mammalian RNA interference pathways, siRNAs direct the protein Argonaute2 (Ago2) to cleave corresponding mRNA targets, silencing their expression. Ago2 is the catalytic component of the RNAi enzyme complex, RISC. For each siRNA duplex, only one strand, the guide, is assembled into the active RISC; the other strand, the passenger, is destroyed. An ATP-dependent helicase has been proposed first to separate the two siRNA strands, then the resulting single-stranded guide is thought to bind Ago2. Here, we show that Ago2 instead directly receives the double-stranded siRNA from the RISC assembly machinery. Ago2 then cleaves the siRNA passenger strand, thereby liberating the single-stranded guide. For siRNAs, virtually all RISC is assembled through this cleavage-assisted mechanism. In contrast, passenger-strand cleavage is not important for the incorporation of miRNAs that derive from mismatched duplexes.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            Regulatory mechanisms of microRNA expression

            MicroRNAs (miRs, miRNAs) are small molecules of 18–22 nucleotides that serve as important regulators of gene expression at the post-transcriptional level. One of the mechanisms through which miRNAs regulate gene expression involves the interaction of their “seed” sequences primarily with 3′-end and more rarely with 5′-end, of mRNA transcribed from target genes. Numerous studies over the past decade have been devoted to quantitative and qualitative assessment of miRNAs expression and have shown remarkable changes in miRNA expression profiles in various diseases. Thus, profiling of miRNA expression can be an important tool for diagnostics and treatment of disease. However, less attention has been paid towards understanding the underlying reasons for changes in miRNA expression, especially in cancer cells. The purpose of this review is to analyze and systematize current data that explains reasons for changes in the expression of miRNAs. The review will cover both transcriptional (changes in gene expression and promoter hypermethylation) and post-transcriptional (changes in miRNA processing) mechanisms of regulation of miRNA expression, as well as effects of endogenous (hormones, cytokines) and exogenous (xenobiotics) compounds on the miRNA expression. The review will summarize the complex multilevel regulation of miRNA expression, in relation to cell type, physiological state of the body and various external factors.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              Dual-strand tumor-suppressor microRNA-145 (miR-145-5p and miR-145-3p) coordinately targeted MTDH in lung squamous cell carcinoma

              Patients with lung adenocarcinoma may benefit from recently developed molecular targeted therapies. However, analogous advanced treatments are not available for patients with lung squamous cell carcinoma (lung SCC). The survival rate of patients with the advanced stage of lung SCC remains poor. Exploration of novel lung SCC oncogenic pathways might lead to new treatment protocols for the disease. Based on this concept, we have identified microRNA- (miRNA) mediated oncogenic pathways in lung SCC. It is well known that miR-145-5p (the guide strand) functions as a tumor suppressor in several types of cancer. However, the impact of miR-145-3p (the passenger strand) on cancer cells is still ambiguous. Expression levels of miR-145-5p and miR-145-3p were markedly reduced in cancer tissues, and ectopic expression of these miRNAs inhibited cancer cell aggressiveness, suggesting that both miR-145-3p as well as miR-145-5p acted as antitumor miRNAs. We identified seven putative target genes (MTDH, EPN3, TPD52, CYP27B1, LMAN1, STAT1 and TXNDC12) that were coordinately regulated by miR-145-5p and miR-145-3p in lung SCC. Among the seven genes, we found that metadherin (MTDH) was a direct target of these miRNAs. Kaplan–Meier survival curves showed that high expression of MTDH predicted reduced survival of lung SCC patients. We investigated pathways downstream from MTDH by using genome-wide gene expression analysis. Our data showed that several anti-apoptosis and pro-proliferation genes were involved in pathways downstream from MTDH in lung SCC. Taken together, both strands of miR-145, miR-145-5p and miR-145-3p are functional and play pivotal roles as antitumor miRNAs in lung SCC.
                Bookmark

                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                30 April 2019
                May 2019
                : 11
                : 5
                Affiliations
                [1 ]Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan; k8574402@ 123456kadai.jp (S.M.); keim@ 123456m.kufm.kagoshima-u.ac.jp (K.M.); akifumiuchida7883@ 123456gmail.com (A.U.); k8173956@ 123456kadai.jp (H.S.); kuma@ 123456m2.kufm.kagoshima-u.ac.jp (T.K.); taka3741@ 123456m2.kufm.kagoshima-u.ac.jp (T.S.); inoue-pulm@ 123456umin.net (H.I.)
                [2 ]Department of Functional Genomics, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan; yasutaka1205@ 123456olive.plala.or.jp (Y.Y.); naoko-k@ 123456hospital.chiba-u.jp (N.K.)
                [3 ]Department of Biochemistry and Genetics, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan; moriya.shogo@ 123456chiba-u.jp
                Author notes
                [* ]Correspondence: naoseki@ 123456faculty.chiba-u.jp ; Tel.: +81-43-226-2971
                Article
                cancers-11-00601
                10.3390/cancers11050601
                6562801
                31052206
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                Categories
                Article

                tns4, lung adenocarcinoma, mir-150-3p, mir-150-5p, microrna

                Comments

                Comment on this article