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      The role of CRP and ATG9B expression in clear cell renal cell carcinoma

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          Abstract

          The purpose of the study is to investigate the correlation between the expression of C-reactive protein ( CRP) and autophagy-related 9B ( ATG9B) and pathological features of clear cell renal cell carcinoma (CCRCC) patients. We also intended to explore the effects of manipulated expression of CRP and ATG9B on the apoptosis and cell cycle progression of CCRCC cell line. ATG9B expression in CCRCC tissues and adjacent renal tissues was analyzed by immunohistochemistry (IHC). Gene expression was determined at transcription and translational levels using real-time quantitative PCR (RT-qPCR) and Western blot. The association between CRP/ATG9B expression and clinical-pathological parameters including age, gender, pathological grades, TNM stage and distant metastasis of the patients was assessed by correlation analysis. siRNA and overexpression plasmids construction were used to manipulate the expression of CRP in human CCRCC cell line 786-O. Cell apoptosis and cell cycle progression were determined using flow cytometry (FCM) and Hoechst 33258 staining. CRP expression correlates with ATG9B expression. The expression of CRP and ATG9B are significantly correlated with TNM staging, distant metastasis, and survival time of CCRCC patients. A high-level of CRP indicates a poor overall survival (OS). In addition, CRP expression influences cell cycle and apoptosis of CCRCC cells. The study reveals that CRP might be a CCRCC development promoter. In addition, there is a close relationship between CRP and ATG9B in CCRCC carcinogenesis.

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          Most cited references31

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          C-Reactive Protein Is an Important Biomarker for Prognosis Tumor Recurrence and Treatment Response in Adult Solid Tumors: A Systematic Review

          Purpose A systematic literature review was done to determine the relationship between elevated CRP and prognosis in people with solid tumors. C-reactive protein (CRP) is a serum acute phase reactant and a well-established inflammatory marker. We also examined the role of CRP to predict treatment response and tumor recurrence. Methods MeSH (Medical Subject Heading) terms were used to search multiple electronic databases (PubMed, EMBASE, Web of Science, SCOPUS, EBM-Cochrane). Two independent reviewers selected research papers. We also included a quality Assessment (QA) score. Reports with QA scores <50% were excluded. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) methodology was utilized for this review (S1 PRISMA Checklist). Results 271 articles were identified for final review. There were 45% prospective studies and 52% retrospective. 264 had intermediate QA score (≥50% but <80%); Seven were adequate (80% -100%); A high CRP was predictive of prognosis in 90% (245/271) of studies—80% of the 245 studies by multivariate analysis, 20% by univariate analysis. Many (52%) of the articles were about gastrointestinal malignancies (GI) or kidney malignancies. A high CRP was prognostic in 90% (127 of 141) of the reports in those groups of tumors. CRP was also prognostic in most reports in other solid tumors primary sites. Conclusions A high CRP was associated with higher mortality in 90% of reports in people with solid tumors primary sites. This was particularly notable in GI malignancies and kidney malignancies. In other solid tumors (lung, pancreas, hepatocellular cancer, and bladder) an elevated CRP also predicted prognosis. In addition there is also evidence to support the use of CRP to help decide treatment response and identify tumor recurrence. Better designed large scale studies should be conducted to examine these issues more comprehensively.
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            TRPM3 and miR-204 establish a regulatory circuit that controls oncogenic autophagy in clear cell renal cell carcinoma.

            Autophagy promotes tumor growth by generating nutrients from the degradation of intracellular structures. Here we establish, using shRNAs, a dominant-negative mutant, and a pharmacologic inhibitor, mefenamic acid (MFA), that the Transient Receptor Potential Melastatin 3 (TRPM3) channel promotes the growth of clear cell renal cell carcinoma (ccRCC) and stimulates MAP1LC3A (LC3A) and MAP1LC3B (LC3B) autophagy. Increased expression of TRPM3 in RCC leads to Ca(2+) influx, activation of CAMKK2, AMPK, and ULK1, and phagophore formation. In addition, TRPM3 Ca(2+) and Zn(2+) fluxes inhibit miR-214, which directly targets LC3A and LC3B. The von Hippel-Lindau tumor suppressor (VHL) represses TRPM3 directly through miR-204 and indirectly through another miR-204 target, Caveolin 1 (CAV1).
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              Coordinated regulation of autophagy by p38alpha MAPK through mAtg9 and p38IP.

              Autophagy, a lysosomal degradation pathway, is essential for homeostasis, development, neurological diseases, and cancer. Regulation of autophagy in human disease is not well understood. Atg9 is a transmembrane protein required for autophagy, and it has been proposed that trafficking of Atg9 may regulate autophagy. Mammalian Atg9 traffics between the TGN and endosomes in basal conditions, and newly formed autophagosomes in response to signals inducing autophagy. We identified p38IP as a new mAtg9 interactor and showed that this interaction is regulated by p38alpha MAPK. p38IP is required for starvation-induced mAtg9 trafficking and autophagosome formation. Manipulation of p38IP and p38alpha alters mAtg9 localization, suggesting p38alpha regulates, through p38IP, the starvation-induced mAtg9 trafficking to forming autophagosomes. Furthermore, we show that p38alpha is a negative regulator of both basal autophagy and starvation-induced autophagy, and suggest that this regulation may be through a direct competition with mAtg9 for binding to p38IP. Our results provide evidence for a link between the MAPK pathway and the control of autophagy through mAtg9 and p38IP.
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                Author and article information

                Journal
                Biosci Rep
                Biosci. Rep
                ppbioscirep
                BSR
                Bioscience Reports
                Portland Press Ltd.
                0144-8463
                1573-4935
                18 September 2017
                15 November 2017
                22 December 2017
                : 37
                : 6
                : BSR20171082
                Affiliations
                [1 ]Department of Urology, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264000, Shandong, China
                [2 ]Department of Organ Transplantation, the affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264000, Shandong, China
                [3 ]Department of Urology, Liaocheng People’s Hospital, Liaocheng 252000, Shandong, China
                [4 ]Department of Urology, Guanxian Center Hospital, Liaocheng 252500, Shandong, China
                [5 ]Department of Pediatrics, Liaocheng People’s Hospital, Liaocheng 252000, Shandong, China
                [6 ]Department of Urology, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
                Author notes
                Correspondence: Zhonghua Xu ( zhouxinjyk@ 123456163.com )
                [*]

                These authors contributed equally to this work.

                Article
                10.1042/BSR20171082
                5686392
                28923830
                b6692547-4d04-48dd-bf56-9bc28ce54b75
                © 2017 The Author(s).

                This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).

                History
                : 20 July 2017
                : 11 September 2017
                : 13 September 2017
                Page count
                Pages: 12
                Categories
                Research Articles
                Research Article
                22
                39

                Life sciences
                atg9b,clear cell renal cell carcinoma (ccrcc),crp,cell apoptosis
                Life sciences
                atg9b, clear cell renal cell carcinoma (ccrcc), crp, cell apoptosis

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