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Loss of Alanine-Glyoxylate and Serine-Pyruvate Aminotransferase

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Loss of Alanine-Glyoxylate and Serine-Pyruvate Aminotransferase Sun et al. J Transl Med (2019) 17:390 https://doi.org/10.1186/s12967-019-02138-5 Journal of Translational Medicine RESEARCH Open Access Loss of alanine-glyoxylate and serine-pyruvate aminotransferase expression accelerated the progression of hepatocellular carcinoma and predicted poor prognosis Yufeng Sun1,2†, Wenchao Li3,6†, Shiqi Shen1†, Xuejing Yang4, Bing Lu5, Xiaojing Zhang5, Peng Lu1, Yi Shen3* and Juling Ji1* Abstract Background: Accumulated studies reported abnormal gene expression profles of hepatocellular carcinoma (HCC) by cDNA microarray. We tried to merge cDNA microarray data from diferent studies to search for stably changed genes, and to fnd out better diagnostic and prognostic markers for HCC. Methods: A systematic review was performed by searching publications indexed in Pubmed from March 1, 2001 to July 1, 2016. Studies that reporting cDNA microarray profles in HCC, containing both tumor and nontumor data and published in English-language were retrieved. The diferentially expressed genes from eligible studies were summa- rized and ranked according to the frequency. High frequency genes were subjected to survival analyses. The expres- sion and prognostic value of alanine-glyoxylate and serine-pyruvate aminotransferase (AGXT) was further evaluated in HCC datasets in Oncomine and an independent HCC tissue array cohort. The role of AGXT in HCC progression was evaluated by proliferation and migration assays in a human HCC cell line. Results: A total of 43 eligible studies that containing 1917 HCC patients were included, a list of 2022 non redun- dant abnormally expressed genes in HCC were extracted. The frequencies of reported genes were ranked. We fnally obtained a list of only fve genes (AGXT; ALDOB; CYP2E1; IGFBP3; TOP2A) that were diferentially expressed in tumor and nontumor tissues across studies and were signifcantly correlated to HCC prognosis. Only AGXT had not been reported in HCC. Reduced expression of AGXT refected poor diferentiation of HCC and predicts poor survival. Knock- ing down of AGXT enhanced cell proliferation and migration of HCC cell line. Conclusions: The present study supported the feasibility and necessity of systematic review on discovering new and reliable biomarkers for HCC. We also identifed a list of high frequency prognostic genes and emphasized a critical role of AGXT deletion during HCC progression. Keywords: Hepatocellular carcinoma, Systematic review, Alanine-glyoxylate and serine-pyruvate aminotransferase, Diagnostic marker, Prognostic marker *Correspondence: [email protected]; [email protected] †Yufeng Sun, Wenchao Li and Shiqi Shen contributed equally to this work 1 Department of Pathology, Medical School of Nantong University, Nantong, China 3 Department of Epidemiology and Medical Statistics, Public Health School of Nantong University, Nantong, China Full list of author information is available at the end of the article © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sun et al. J Transl Med (2019) 17:390 Page 2 of 16 Background Terms were chose as the key words, including hepato- Liver cancer is the third leading cause of cancer death and cellular carcinoma, liver neoplasms, gene expression the sixth most common cancer worldwide [1]. Hepatocel- profling, human, gene expression regulation, oligonu- lular carcinoma (HCC) accounts for 70–85% of the total cleotide array sequence analysis. Date of publications liver cancer burden. Te accurate diagnosis and proper was restricted to July 2016. Besides, the literature must treatment of HCC is particularly challenging. Options for be published in English language. In addition to use HCC treatment remain limited, surgical resection is con- (((((((carcinoma, hepatocellular[MeSH Terms]) AND sidered the only “curative treatment”. But HCC patients liver neoplasms[MeSH Terms]) AND gene expression do not have overt symptoms in the early stages, 80% of profling[MeSH Terms]) AND human[MeSH Terms]) patients have widespread HCC at the time of diagnosis AND gene expression regulation[MeSH Terms]) AND and are not candidates for surgical treatment. Even with oligonucleotide array sequence analysis[MeSH Terms])) surgical resection, the 5-year survival rate is poor (about AND (“1781/01/01”[Date-MeSH]: “2016/06/30”[Date- 38%) [2]. MeSH]) as the search strategy to obtain literatures, we Accumulated data from high-throughput analyses by also reviewed the bibliographies of eligible studies as cDNA microarray provide an accurate landscape of gene well as those of relevant review articles to identify addi- expression in HCC, and revealed a lot of pathogenic and tional studies not captured by our database searches. To prognostic genes for HCCs, thus enabled us to deline- identify all potentially eligible studies, two investigators ate some of the key events that might dominate tumor independently conducted structured searches in selected development and progression. Hopefully, translation of databases. this knowledge into new targets and biomarkers might impact HCC decision making, and ultimately improve Study inclusion criteria patient’s outcomes [3]. However, these studies were per- Eligible studies were included in the systematic review formed with diferent platforms and in diferent popula- if they met the following criteria: (1) they were gene tions, the suggested diagnostic markers and potential expression studies in hepatocellular carcinoma; (2) they therapeutic targets for HCC varied across studies, hence used tissue samples obtained from surgically resected prevented the application of these fndings. It’s the high tumor and corresponding non-tumor or normal tissues time to merge these cDNA microarray data from dif- in human for comparison; (3) validation of method and ferent studies using diferent platforms, to search those sample set were reported; (4) clinical and experimental widely and stably changed genes, and to fnd out better study. Articles were excluded based on the following cri- diagnostic markers and potential therapeutic targets for teria: (1) review articles or letters; (2) non-liver cancer; HCC. (3) non-gene expression profle; (4) non-human tissue In the present study, we performed a systematic review samples. of studies that reported cDNA microarray data for both tumor and nontumor liver tissues of HCC patients and Data extraction came up with a list of fve genes that were diferentially From the full text and corresponding additional infor- expressed in tumor and nontumor tissues across diferent mation, the following items were eligible to collect and studies and were signifcantly correlated to HCC progno- record for each study: authors, year of publication, region, sis. Among the fve genes, except for alanine-glyoxylate selection number and characteristics of recruited liver and serine-pyruvate aminotransferase (AGXT) which is cancer patients, the members of abnormally expressed an essential gene involved in glyoxylate detoxifcation, genes in liver cancer. Two investigators (K. D. and YL. the other four genes were well documented in HCC. J.) independently evaluated and extracted the data with Here, we reported that AGXT was involved in the pro- the inclusion criteria. Conficts in study selection at this gression of HCC and loss of AGXT expression predicted stage were resolved by consensus, referring back to the poor prognosis of HCC. AGXT might be a novel diag- original article in consultation with the principal. nostic and prognostic marker and a potential therapeutic target for HCC. Gene statistics and screening For genes that have multiple names/synonyms, we Methods standardized the gene name for later work by using Data sources and search strategy widely accepted and used HGNC database (https :// Literature retrieval was originally performed with www.genen ames.org/). Frequency and composition PubMed, a free search engine accessing primarily the analysis of the abnormally expressed genes in hepa- MEDLINE database of references and abstracts on life tocellular carcinomas were conducted by IBM SPSS sciences and biomedical topics. Te relevant Mesh Statistics 20.0 software (Endicott, New York, NY). Sun et al. J Transl Med (2019) 17:390 Page 3 of 16 Te genes presented in more than four studies were respectively. Te staining scores were evaluated indepen- regarded as high frequent genes. Te expression of dently by two pathologists who were blinded to the clini- the high frequent genes in other malignant tumors cal outcomes. were obtained from Oncomine (https ://www.oncom ine.org/). To identify a prognostic gene list across dif- Cell culture ferent studies, the prognostic value of these high fre- Human HCC cell lines were cultured in Dulbecco’s quent genes were evaluated by survival risk prediction Modifed Eagle’s Medium (DMEM) (Gibco, CA, USA) in a previously described cohort of 247 Chinese HCC supplemented with 10% fetal bovine serum (FBS, Gibco, patients with publicly available Afymetrix U133A Carlsbad, USA) in a 5% CO2 atmosphere at 37 °C. array data (National Center for Biotechnology
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