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      Everolimus inhibits the proliferation and migration of epidermal growth factor receptor-resistant lung cancer cells A549 via regulating the microRNA-4328/phosphatase and tensin homolog signaling pathway

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          Abstract

          Lung cancer is the most common cancer type worldwide, and investigating novel therapeutics methods for the treatment of chemoresistant lung cancer are of notable clinical significance. Reverse transcription-quantitative polymerase chain reaction and western blotting assays were performed to analyze the expression levels of phosphatase and tensin homolog (PTEN) and microRNA-4328 (miR-4328), and Cell Counting Kit-8 (CCK-8) and Transwell migration assays were conducted to evaluate the proliferation and migration of A549 cells, respectively. Everolimus was observed to upregulate the expression of PTEN and inhibit the proliferation and migration of A549 cells in a dose-dependent manner. The knockdown of PTEN abolished the effects of everolimus on the proliferation and migration of A549 cells, and everolimus was demonstrated to upregulate PTEN, and inhibit the proliferation and migration of A549 cells via downregulating miR-4328. Collectively, the results of the present study indicate that everolimus inhibited the proliferation and migration of EGFR-resistant A549 lung cancer cells via regulating the miR-4328/PTEN signaling pathway.

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          ENETS Consensus Guidelines Update for the Management of Distant Metastatic Disease of Intestinal, Pancreatic, Bronchial Neuroendocrine Neoplasms (NEN) and NEN of Unknown Primary Site

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            PTEN: Tumor Suppressor and Metabolic Regulator

            Phosphatase and Tensin Homolog deleted on Chromosome 10 (PTEN) is a dual phosphatase with both protein and lipid phosphatase activities. PTEN was first discovered as a tumor suppressor with growth and survival regulatory functions. In recent years, the function of PTEN as a metabolic regulator has attracted significant attention. As the lipid phosphatase that dephosphorylates phosphatidylinositol-3, 4, 5-phosphate (PIP3), PTEN reduces the level of PIP3, a critical 2nd messenger mediating the signal of not only growth factors but also insulin. In this review, we introduced the discovery of PTEN, the PTEN-regulated canonical and nuclear signals, and PTEN regulation. We then focused on the role of PTEN and PTEN-regulated signals in metabolic regulation. This included the role of PTEN in glycolysis, gluconeogenesis, glycogen synthesis, lipid metabolism as well as mitochondrial metabolism. We also included how PTEN and PTEN regulated metabolic functions may act paradoxically toward insulin sensitivity and tumor metabolism and growth. Further understanding of how PTEN regulates metabolism and how such regulations lead to different biological outcomes is necessary for interventions targeting at the PTEN-regulated signals in either cancer or diabetes treatment.
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              Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus.

              Personalized cancer medicine is based on the concept that targeted therapies are effective on subsets of patients whose tumors carry specific molecular alterations. Several mammalian target of rapamycin (mTOR) inhibitors are in preclinical or clinical trials for cancers, but the molecular basis of sensitivity or resistance to these inhibitors among patients is largely unknown. Here we have identified oncogenic variants of phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA) and KRAS as determinants of response to the mTOR inhibitor everolimus. Human cancer cells carrying alterations in the PI3K pathway were responsive to everolimus, both in vitro and in vivo, except when KRAS mutations occurred concomitantly or were exogenously introduced. In human cancer cells with mutations in both PIK3CA and KRAS, genetic ablation of mutant KRAS reinstated response to the drug. Consistent with these data, PIK3CA mutant cells, but not KRAS mutant cells, displayed everolimus-sensitive translation. Importantly, in a cohort of metastatic cancer patients, the presence of oncogenic KRAS mutations was associated with lack of benefit after everolimus therapy. Thus, our results demonstrate that alterations in the KRAS and PIK3CA genes may represent biomarkers to optimize treatment of patients with mTOR inhibitors.
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                Author and article information

                Journal
                Oncol Lett
                Oncol Lett
                OL
                Oncology Letters
                D.A. Spandidos
                1792-1074
                1792-1082
                November 2019
                19 September 2019
                19 September 2019
                : 18
                : 5
                : 5269-5276
                Affiliations
                [1 ]Department of Thoracic Surgery, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, Yunnan 650118, P.R. China
                [2 ]Department of Palliative Medicine and Palliative Medicine Research Center, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, Yunnan 650118, P.R. China
                [3 ]School of Medicine, Yunnan University, Kunming, Yunnan 650091, P.R. China
                [4 ]Department of Gynecology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Center, Kunming, Yunnan 650118, P.R. China
                Author notes
                Correspondence to: Dr Jing Yu, Department of Gynecology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Center, 519 Kunzhou Road, Kunming, Yunnan 650118, P.R. China, E-mail: yujing12071@ 123456sina.com
                Dr Gaofeng Li, Department of Thoracic Surgery, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, 519 Kunzhou Road, Kunming, Yunnan 650118, P.R. China, E-mail: ligaofeng2541@ 123456sina.com
                [*]

                Contributed equally

                Article
                OL-0-0-10887
                10.3892/ol.2019.10887
                6781784
                ffc79540-5376-4e56-b686-cc26cb97f5ac
                Copyright: © Xiang 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
                : 01 February 2018
                : 19 September 2019
                Categories
                Articles

                Oncology & Radiotherapy
                lung cancer,phosphatase and tensin homolog,microrna-4328,proliferation,migration

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