glutaminase and Stomach-Neoplasms

Abnormal 5-methylcytosine (m5C) methylation has been proved to be closely related to gastric carcinogenesis, progression, and prognosis. Dysregulated long noncoding RNAs (lncRNAs) participate in a variety of biological processes in cancer. However, to date, m5C-methylated lncRNAs are rarely researched in gastric cancer (GC). Here, we found that RNA cytosine-C(5)-methyltransferase (NSUN2) was upregulated in GC and high NSUN2 expression was associated with poor prognosis. NR_033928 was identified as an NSUN2-methylated and upregulated lncRNA in GC. Functionally, NR_033928 upregulated the expression of glutaminase (GLS) by interacting with IGF2BP3/HUR complex to promote GLS mRNA stability. Increased glutamine metabolite, α-KG, upregulated NR_033928 expression by enhancing its promoter 5-hydroxymethylcytosine (hm5C) demethylation. In conclusion, our results revealed that NSUN2-methylated NR_033928 promoted GC progression and might be a potential prognostic and therapeutic target for GC.

Topics: Cell Proliferation; Glutaminase; Glutamine; Humans; RNA, Long Noncoding; RNA, Messenger; Stomach Neoplasms

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal).\ \ This article has been retracted at the request of Editor-in-Chief and the authors. The journal was initially contacted by the corresponding author to request the retraction of the article because the author claimed that part of the paper was outsourced to a third-party company who offered them the “wrong picture”. During the investigation, the Editor became aware of allegations about this article on Pubpeer.\ \ Figure 7E is similar to Figure 7F from the article published by Xiaoping Pan, Chen Wang, Yan Li, Lida Zhu and Ti Zhang in Life Sciences, 214, (2018) 124-135 https://doi.org/10.1016/j.lfs.2018.10.064, a similar portion of Figure 6D from the article published by Qiang Wang, Yi Yan, Jie Zhang, Peng Guo, Yuqing Xing, Yong Wang, Fawei Qin and Qingyun Zeng in Biomedicine & Pharmacotherapy, 104, (2018) 28-35 https://doi.org/10.1016/j.biopha.2018.05.013, portions of Figure 6C from the article published by Jun Zou, Yamei Wang, Mingdi Liu, Xiushu Huang, Wenjian Zheng, Qian Gao, Haijing Wang in Cell Biochemistry and Function, 36, (2018) 303-311 https://doi.org/10.1002/cbf.3349, portions of Figure 8C from the article published by Kaili Liu, Hui Gao, Qiaoyun Wang , Longyuan Wang, Bin Zhang , Zhiwu Han, Xuehong Chen, Mei Han, and Mingquan Gao in Cancer Science, 109, (2018) 1369-1381 https://doi.org/10.1111/cas.13575, portions of Figure 8D of the article published by Xiangyang Dou, Meihua Wang, Tao Zhang and Jiapei Yao in The Anatomical Record, 303, (2020) 3117-3128 https://doi.org/10.1002/ar.24324, portions of Figure 6F from the article published by Xuezhu Lin, Mingquan Gao, Ailing Zhang, Jingjie Tong, Xiaoyi Zhang, Quanzhong Su, Zhihong Yang, Hui Gao and Guohui Jiang in Life Sciences 239, (2019) 117074 https://doi.org/10.1016/j.lfs.2019.117074, portions of 6F from the article published by Luping Wang, Lu Yun, Xiaojun Wang, Liying Sha, Luning Wang, Yingying Sui and Hui Zhang in Life Sciences, 218, (2019) 16-24 https://doi.org/10.1016/j.lfs.2018.12.023, and portions of Figure 7F from the article published by Dong Li, Xiaoyan Li , Genqu Li , Yan Meng , Yanghong Jin , Shuang Shang , Yanjie Li in Life Sciences, 216, (2019) 259-270 https://doi.org/10.1016/j.lfs.2018.11.032.\ \ The journal requested the authors to provide the raw data. However, the authors were not able to fulfill this request and therefore the Edito

Topics: Animals; Apoptosis; Cell Proliferation; Emodin; Female; Gene Expression Regulation, Neoplastic; Glucosides; Glutaminase; Humans; Iron; Lipid Peroxidation; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNAs; Reactive Oxygen Species; Stomach Neoplasms; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

To screen the novel biomarkers for gastric cancer and to determine the values of glutaminase 1 (GLS1) and gamma-glutamylcyclotransferase (GGCT) for detecting gastric cancer.. A discovery group of four paired gastric cancer tissue samples are labeled with Isobaric tag for relative and absolute quantitation agents and identified with LC-ESI-MS/MS. A validation group of 168 gastric cancer samples and 30 healthy controls are used to validate the expression of GLS1 and GGCT.. Four hundred and thirty-one proteins are found differentially expressed in gastric cancer tissues. Of these proteins, GLS1 and GGCT are found overexpressed in gastric cancer patients, with sensitivity of 75.6% (95% CI: 69-82.2%) and specificity of 81% (95% CI: 75-87%) for GLS1, and with sensitivity of 63.1% (95% CI: 55.7-71.5%) and specificity of 60.7% (95% CI: 53.3-68.2%) for GGCT. The co-expression of GLS1 and GGCT in gastric cancer tissues has sensitivity of 78.1% (95% CI: 70.1-86.1%) and specificity of 86.5% (95% CI: 79.5-93.4%). Moreover, both GLS1 and GGCT present higher expression of 82.6% (95% CI: 68.5-99.4%) and 73.9% (95% CI: 54.5-93.3%) in lymph node metastasis specimen than those in non-lymph node metastasis specimen. The areas under ROC curves are up to 0.734 for the co-expression of GLS1 and GGCT in gastric cancer. The co-expression of GLS1 and GGCT is strongly associated with histological grade, lymph node metastasis, and TNM stage Ⅲ/Ⅳ.. The present study provides the quantitative proteomic analysis of gastric cancer tissues to identify prognostic biomarkers of gastric cancer. The co-expression level of GLS1 and GGCT is of great clinical value to serve as diagnostic and therapeutic biomarkers for early gastric cancer.

Topics: Biomarkers, Tumor; Chromatography, Liquid; Female; gamma-Glutamylcyclotransferase; Gene Expression Regulation, Developmental; Gene Expression Regulation, Neoplastic; Glutaminase; Glutamine; Humans; Male; Mass Spectrometry; Neoplasm Proteins; Proteomics; Stomach Neoplasms

The aim of this study was to analyze the significance of glucose metabolism-related enzymes in the proliferation of gastric cancer under hypoxia. Four hypoxia-resistant gastric cancer cell lines and four parent cell lines were used. Reverse transcription-PCR was used to evaluate the mRNA expression levels of the following metabolism-related enzymes: pyruvate kinase isozyme M2 (PKM2), glutaminase (GLS), enolase 1 (ENO1), glucose-6-phosphate dehydrogenase (G6PDH), and PKM1. The effects of these enzymes on the proliferation of gastric cancer cells were examined using siRNAs, shikonin as a PKM2 inhibitor, or BPTES as a GLS inhibitor, in vitro and in vivo. Levels of both PKM2 and GLS mRNA were significantly high in all hypoxia-resistant cell lines, compared with those of their parent cells. Knockdown of PKM2 and GLS significantly decreased the proliferation of all hypoxia-resistant cells. The combination of siPKM2 and siGLS significantly decreased proliferation compared with treatment by siPKM2 or siGLS alone. The knockdown of ENO1, G6PDH, or PKM1 did not decrease the proliferation of all hypoxia-resistant cells. Combination treatment using shikonin and BPTES inhibited the proliferation of all hypoxia-resistant cancer cells more than that by either agent alone. The in vivo study indicated that the tumor size treated by the combination of shikonin and BPTES was significantly smaller than that of vehicle-treated group. These findings suggested that PKM2 and GLS might play important roles in the proliferation of hypoxic gastric cancer cells. A combination of PKM2 and GLS inhibitors could be therapeutically promising for the treatment of gastric cancer.

Topics: Animals; Antineoplastic Agents; Carrier Proteins; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Glutaminase; Humans; Membrane Proteins; Mice; Mice, Inbred BALB C; Mice, Nude; Stomach Neoplasms; Thyroid Hormone-Binding Proteins; Thyroid Hormones; Xenograft Model Antitumor Assays

Glutamine (Gln) is a crucial metabolite in cancer cells of different origin, and the expression and activity of different isoforms of the Gln-degrading enzyme, glutaminase (GA), have variable implications for tumor growth and metabolism. Human glutaminases are encoded by two genes: the GLS gene encodes the kidney-type glutaminases, KGA and GAC, while the GLS2 gene encodes the liver-type glutaminases, GAB and LGA. Recent studies suggest that the GAC isoform and thus high GAC/KGA ratio, are characteristic of highly proliferating tumors, while GLS2 proteins have an inhibitory effect on tumor growth. Here we analyzed the expression levels of distinct GA transcripts in 7 gastroenteropancreatic neuroendocrine tumors (GEP-NETs) with low proliferation index and 7 non-neoplastic tissues. GEP-NETs overexpressed KGA, while GAC, which was the most abundant isoform, was not different from control. The expression of the GLS2 gene showed tendency towards elevation in GEP-NETs compared to control. Collectively, the expression pattern of GA isoforms conforms to the low proliferative capacity of GEP-NETs encompassed in this study.

Topics: Adult; Cell Proliferation; Cell Survival; Gene Expression Regulation, Neoplastic; Gene Silencing; Glutaminase; Humans; Intestinal Neoplasms; Middle Aged; Neuroendocrine Tumors; Pancreatic Neoplasms; Protein Isoforms; RNA, Messenger; Stomach Neoplasms

Free glutamine content and phosphate-dependent glutaminase activity were studied in the biopsy specimens from the tissue of ulcer, polyps, carcinoma and the surrounding gastric mucosa of patients with precancerous diseases and carcinoma of the stomach. The glutamine content in carcinoma was not significantly different from that in the normal gastric mucosa. The glutamine level in the gastric mucosa remote from the tumour was considerably higher than normal. In case of polyposis of the stomach glutamine was present in the polyps and absent in the remote gastric mucosa. A marked glutaminase activity was revealed in the carcinoma of the stomach, but its level did not differ from the normal or in the case of precancerous diseases.

Topics: Gastric Mucosa; Gastritis; Glutaminase; Glutamine; Humans; Polyps; Precancerous Conditions; Stomach Neoplasms; Stomach Ulcer