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      MicroRNA‐92b‐3p is a prognostic oncomiR that targets TSC1 in clear cell renal cell carcinoma

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          Abstract

          Although several studies have reported that microRNA (miR)‐92b‐3p is involved in various cellular processes related to carcinogenesis, its physiological role in clear cell renal cell carcinoma (ccRCC) remains unclear. To clarify the role of miR‐92b‐3p in ccRCC, we compared miR‐92b‐3p expression levels in ccRCC tissues and adjacent normal renal tissues. Significant upregulation of miR‐92b‐3p was observed in ccRCC tissues. Overexpression of miR‐92b‐3p using a miRNA mimic promoted proliferation, migration, and invasion activities of ACHN cells. Functional inhibition of miR‐92b‐3p by a hairpin miRNA inhibitor suppressed Caki‐2 cell growth and invasion activities in vitro. Mechanistically, it was found that miR‐92b‐3p directly targeted the TSC1 gene, a known upstream regulator of mTOR. Overexpression of miR‐92b‐3p decreased the protein expression of TSC1 and enhanced the downstream phosphorylation of p70S6 kinase, suggesting that the mTOR signaling pathway was activated by miR‐92b‐3p in RCC cells. Importantly, a multivariate Cox proportion hazard model, based on TNM staging and high levels of miR‐92b‐3p, revealed that miR‐92b‐3p expression (high vs. low hazard ratio, 2.86; 95% confidence interval, 1.20‐6.83; P = .018) was a significant prognostic factor for overall survival of ccRCC patients with surgical management. Taken together, miR‐92b‐3p was found to act as an oncomiR, promoting cell proliferation by downregulating TSC1 in ccRCC.

          Abstract

          MicroRNA‐92b‐3p was found to act as an oncomiR, promoting cell proliferation by downregulating TSC1 in clear cell renal cell carcinoma, and predicts poor patient overall survival.

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          Most cited references16

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          A complex interplay between Akt, TSC2 and the two mTOR complexes.

          Akt/PKB (protein kinase B) both regulates and is regulated by the TSC (tuberous sclerosis complex) 1-TSC2 complex. Downstream of PI3K (phosphoinositide 3-kinase), Akt phosphorylates TSC2 directly on multiple sites. Although the molecular mechanism is not well understood, these phosphorylation events relieve the inhibitory effects of the TSC1-TSC2 complex on Rheb and mTORC1 [mTOR (mammalian target of rapamycin) complex] 1, thereby activating mTORC1 in response to growth factors. Through negative-feedback mechanisms, mTORC1 activity inhibits growth factor stimulation of PI3K. This is particularly evident in cells and tumours lacking the TSC1-TSC2 complex, where Akt signalling is severely attenuated due, at least in part, to constitutive activation of mTORC1. An additional level of complexity in the relationship between Akt and the TSC1-TSC2 complex has recently been uncovered. The growth-factor-stimulated kinase activity of mTORC2 [also known as the mTOR-rictor (rapamycin-insensitive companion of mTOR) complex], which normally enhances Akt signalling by phosphorylating its hydrophobic motif (Ser(473)), was found to be defective in cells lacking the TSC1-TSC2 complex. This effect on mTORC2 can be separated from the inhibitory effects of the TSC1-TSC2 complex on Rheb and mTORC1. The present review discusses our current understanding of the increasingly complex functional interactions between Akt, the TSC1-TSC2 complex and mTOR, which are fundamentally important players in a large variety of human diseases.
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            miR-92b-3p acts as a tumor suppressor by targeting Gabra3 in pancreatic cancer

            Background MicroRNAs (miRNAs) can act as oncogenes or tumor suppressors by controlling cell proliferation, differentiation, metastasis and apoptosis, and miRNA dysregulation is involved in the development of pancreatic cancer (PC). Our previous study demonstrated that Gabra3 plays critical roles in cancer progression. However, whether Gabra3 is regulated by miRNAs in PC remains unknown. Methods The expression levels of miR-92b-3p and Gabra3 were measured by quantitative PCR (qPCR), immunoblotting, in situ hybridization (ISH) and immunohistochemistry (IHC). The proliferation rate of PC cells was detected by MTS assay. Wound-healing and transwell assays were used to examine the invasive abilities of PC cells. Dual-luciferase reporter assays were used to determine how miR-92b-3p regulates Gabra3. Xenograft mouse models were used to assess the role of miR-92b-3p in PC tumor formation in vivo. Results Here, we provide evidence that miR-92b-3p acted as a tumor suppressor in PC by regulating Gabra3 expression. MiR-92b-3p expression levels were lower in PC tissues than corresponding noncancerous pancreatic (CNP) tissues and were associated with a poor prognosis in PC patients. MiR-92b-3p overexpression suppressed the proliferation and invasion of PC cells in both in vivo and in vitro models. Conversely, miR-92b-3p knockdown induced an aggressive phenotype in PC cells. Mechanistically, miR-92b-3p overexpression suppressed Gabra3 expression, which then led to the inactivation of important oncogenic pathways, including the AKT/mTOR and JNK pathways. Conclusion Our results suggest that miR-92b-3p acted as a tumor suppressor by targeting Gabra3-associated oncogenic pathways; these results provide novel insight into future treatments for PC patients. Electronic supplementary material The online version of this article (10.1186/s12943-017-0723-7) contains supplementary material, which is available to authorized users.
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              MiR-92b regulates the cell growth, cisplatin chemosensitivity of A549 non small cell lung cancer cell line and target PTEN.

              MicroRNAs (miRNAs) have emerged to play important roles in tumorigenesis and drug resistance of human cancer. Fewer studies were explored the roles of miR-92b on human lung cancer cell growth and resistance to cisplatin (CDDP). In this paper, we utilized real-time PCR to verify miR-92b was significantly up-regulated in non-small cell lung cancer (NSCLC) tissues compared to matched adjacent normal tissues. In vitro assay demonstrated that knock-down of miR-92b inhabits cell growth and sensitized the A549/CDDP cells to CDDP. Furthermore, we found miR-92b could directly target PTEN, a unique tumor suppressor gene, which was downregulated in lung cancer tissues compared to the matched adjacent normal tissues. These data indicate that the miR-92b play an oncogene roles by regulates cell growth, cisplatin chemosensitivity phenotype, and could serve as a novel potential maker for NSCLC therapy. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                uemura@uro.med.osaka-u.ac.jp
                Journal
                Cancer Sci
                Cancer Sci
                10.1111/(ISSN)1349-7006
                CAS
                Cancer Science
                John Wiley and Sons Inc. (Hoboken )
                1347-9032
                1349-7006
                19 February 2020
                April 2020
                : 111
                : 4 ( doiID: 10.1111/cas.v111.4 )
                : 1146-1155
                Affiliations
                [ 1 ] Department of Urology Osaka University Graduate School of Medicine Suita Japan
                [ 2 ] Department of Urological Immuno‐Oncology Osaka University Graduate School of Medicine Suita Japan
                [ 3 ] Laboratory of Molecular and Cellular Physiology Osaka University Graduate School of Pharmaceutical Sciences Suita Japan
                Author notes
                [*] [* ] Correspondence

                Motohide Uemura, Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan.

                Email: uemura@ 123456uro.med.osaka-u.ac.jp

                Author information
                https://orcid.org/0000-0001-8445-6205
                https://orcid.org/0000-0002-4701-5635
                https://orcid.org/0000-0002-8681-1407
                https://orcid.org/0000-0001-9369-4264
                Article
                CAS14325
                10.1111/cas.14325
                7156823
                31975504
                c3a20190-a1e8-42e0-aab9-310a64ed7d89
                © 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 03 October 2019
                : 27 December 2019
                : 06 January 2020
                Page count
                Figures: 5, Tables: 3, Pages: 10, Words: 5518
                Funding
                Funded by: Japan Society for the Promotion of Science , open-funder-registry 10.13039/501100000646;
                Award ID: Grant number: A16H069540
                Categories
                Original Article
                Original Articles
                Carcinogenesis
                Custom metadata
                2.0
                April 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.0 mode:remove_FC converted:15.04.2020

                Oncology & Radiotherapy
                ccrcc,mir‐92b‐3p,oncomir,proliferation,tsc1
                Oncology & Radiotherapy
                ccrcc, mir‐92b‐3p, oncomir, proliferation, tsc1

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