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      Circular RNA circ-ACACA regulates proliferation, migration and glycolysis in non-small-cell lung carcinoma via miR-1183 and PI3K/PKB pathway

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          Abstract

          Non-small cell lung carcinoma (NSCLC) accounts for 85% of all lung cancers and the five-year survival rate is ~1% in the late stage. Circular RNAs (circRNAs) were reported to be involved in the progression of diverse human cancers. However, the role of circ-ACACA in NSCLC progression remains elusive. Quantitative polymerase chain reaction was conducted to detect the expression levels of circ-ACACA and microRNA (miR)-1183 in NSCLC tissues and cells. A Cell Counting Kit-8 assay and transwell assay were employed to check proliferation and migration, respectively. Metabolic alternations in NSCLC cells were monitored by the Seahorse XFe96 analyzer. The protein levels of cellular myelocytomatosis, matrix metallopeptidase 9, glucose transporter 1, phosphatase and tensin homolog, phosphoinositide 3-kinases (PI3K), phosphorylated PI3K (p-PI3K), protein kinase B (PKB) and p-PKB in samples were measured by western blotting. The interaction between circ-ACACA and miR-1183 was predicted by circular RNA Interactome, which was verified by dual-luciferase reporter assay, RNA immunoprecipitation assay and RNA pull-down assay. Xenograft tumor model was established to investigate the biological roles of circ-ACACA in vivo. The level of circ-ACACA was markedly upregulated in NSCLC tissues and cells, which was contrary to the expres-sion of miR-1183. Knockdown of circ-ACACA inhibited proliferation and migration of NSCLC cells and also reduced the glycolysis rate. In addition, miR-1183 was a target of circ-ACACA and its downregulation reversed circ-ACACA silencing-mediated inhibitory impact on NSCLC progression. Further studies indicated that circ-ACACA regulated the PI3K/PKB pathway through interacting with miR-1183 and downregulation of circ-ACACA suppressed tumor growth. Knockdown of circ-ACACA impeded NSCLC progression by sponging miR-1183 and inactivating the PI3K/PKB signaling pathway.

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          Most cited references14

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          Regulation of microRNA function in animals

          Since their serendipitous discovery in nematodes, microRNAs (miRNAs) have emerged as key regulators of biological processes in animals. These small RNAs form complex regulatory networks in cell development, differentiation and homeostasis. Deregulation of miRNA function is associated with an increasing number of human diseases, particularly cancer. Recent discoveries have expanded our understanding of how miRNAs are regulated. Here we review the mechanisms that modulate miRNA activity, their stability and their localization through alternative processing, sequence editing, post-translational modifications of Argonaute proteins, viral factors, transport from the cytoplasm and regulation of miRNA–target interactions. We conclude by discussing intriguing open questions to be answered by future research.
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            The enhancement of glycolysis regulates pancreatic cancer metastasis

            Pancreatic ductal adenocarcinoma is prone to distant metastasis and is expected to become the second leading cause of cancer-related death. In an extremely nutrient-deficient and hypoxic environment resulting from uncontrolled growth, vascular disturbances and desmoplastic reactions, pancreatic cancer cells utilize "metabolic reprogramming" to satisfy their energy demand and support malignant behaviors such as metastasis. Notably, pancreatic cancer cells show extensive enhancement of glycolysis, including glycolytic enzyme overexpression and increased lactate production, and this is caused by mitochondrial dysfunction, cancer driver genes, specific transcription factors, a hypoxic tumor microenvironment and stromal cells, such as cancer-associated fibroblasts and tumor-associated macrophages. The metabolic switch from oxidative phosphorylation to glycolysis in pancreatic cancer cells regulates the invasion-metastasis cascade by promoting epithelial-mesenchymal transition, tumor angiogenesis and the metastatic colonization of distant organs. In addition to aerobic glycolysis, oxidative phosphorylation also plays a critical role in pancreatic cancer metastasis in ways that remain unclear. In this review, we expound on the intracellular and extracellular causes of the enhancement of glycolysis in pancreatic cancer and the strong association between glycolysis and cancer metastasis, which we expect will yield new therapeutic approaches targeting cancer metabolism.
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              Leptomeningeal metastases in non-small-cell lung cancer.

              Leptomeningeal metastasis is a complication of advanced non-small-cell lung cancer (NSCLC). Diagnosis and monitoring of leptomeningeal metastasis are challenging, and are based on neurological, radiographic, and cerebrospinal fluid findings. Substantial progress has been made in several key aspects of management of leptomeningeal metastasis, including improved characterisation of the genetic profiles, generation of clinically relevant animal models, advances in cerebrospinal fluid liquid biopsy with improved cytology and genotyping analysis, and the development of therapeutic agents with greater CNS penetration. This Review discusses cumulative data on multiple treatment modalities with a particular focus on recent advances in molecularly targeted therapies in subtypes of patients with leptomeningeal metastasis from NSCLC. Future research is needed to further understand the biology of leptomeningeal metastasis and the mechanisms of resistance to treatment.
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                Author and article information

                Journal
                Int J Mol Med
                Int. J. Mol. Med
                IJMM
                International Journal of Molecular Medicine
                D.A. Spandidos
                1107-3756
                1791-244X
                June 2020
                24 March 2020
                24 March 2020
                : 45
                : 6
                : 1814-1824
                Affiliations
                Department of Oncology, Liaocheng People's Hospital, Liaocheng, Shandong 252000, P.R. China
                Author notes
                Correspondence to: Mr. Xialei Yao, Department of Oncology, Liaocheng People's Hospital, 67 Dongchang West Road, Liaocheng, Shandong 252000, P.R. China, E-mail: cehaom@ 123456163.com
                Article
                ijmm-45-06-1814
                10.3892/ijmm.2020.4549
                7169939
                32236577
                8888822c-0ca4-4fc9-be34-e3239d1ec12d
                Copyright: © Wu et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs 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
                : 25 October 2019
                : 24 January 2020
                Categories
                Articles

                non-small cell lung carcinoma, circular-acaca, mir-1183, phosphoinositide 3-kinase,protein kinase b pathway

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