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Zhang CY, Zhang R, Zhang L, Wang ZM, Sun HZ, Cui ZG, Zheng HC. Regenerating gene 4 promotes chemoresistance of colorectal cancer by affecting lipid droplet synthesis and assembly. World J Gastroenterol 2023; 29:5104-5124. [PMID: 37744296 PMCID: PMC10514755 DOI: 10.3748/wjg.v29.i35.5104] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 08/10/2023] [Accepted: 08/25/2023] [Indexed: 09/14/2023] Open
Abstract
BACKGROUND Regenerating gene 4 (REG4) has been proved to be carcinogenic in some cancers, but its manifestation and possible carcinogenic mechanisms in colorectal cancer (CRC) have not yet been elucidated. Our previous study found that the drug resistance of CRC cells may be closely linked to their fat metabolism. AIM To explore the role of REG4 in CRC and its association with lipid droplet formation and chemoresistance. METHODS We conducted a meta-analysis and bioinformatics and pathological analyses of REG4 expression in CRC. The effects of REG4 on the phenotypes and related protein expression were also investigated in CRC cells. We detected the impacts of REG4 on the chemoresistance and lipid droplet formation in CRC cells. Finally, we analyzed how REG4 regulated the transcription and proteasomal degradation of lipogenic enzymes in CRC cells. RESULTS Compared to normal mucosa, REG4 mRNA expression was high in CRC (P < 0.05) but protein expression was low. An inverse correlation existed between lymph node and distant metastases, tumor-node-metastasis staging or short overall survival and REG4 mRNA overexpression (P < 0.05), but vice versa for REG4 protein expression. REG4-related genes included: Chemokine activity; taste receptors; protein-DNA and DNA packing complexes; nucleosomes and chromatin; generation of second messenger molecules; programmed cell death signals; epigenetic regulation and DNA methylation; transcription repression and activation by DNA binding; insulin signaling pathway; sugar metabolism and transfer; and neurotransmitter receptors (P < 0.05). REG4 exposure or overexpression promoted proliferation, antiapoptosis, migration, and invasion of DLD-1 cells in an autocrine or paracrine manner by activating the epidermal growth factor receptor-phosphoinositide 3-kinase-Akt-nuclear factor-κB pathway. REG4 was involved in chemoresistance not through de novo lipogenesis, but lipid droplet assembly. REG4 inhibited the transcription of acetyl-CoA carboxylase 1 (ACC1) and ATP-citrate lyase (ACLY) by disassociating the complex formation of anti-acetyl (AC)-acetyl-histone 3-AC-histone 4-inhibitor of growth protein-5-si histone deacetylase;-sterol-regulatory element binding protein 1 in their promoters and induced proteasomal degradation of ACC1 or ACLY. CONCLUSION REG4 may be involved in chemoresistance through lipid droplet assembly. REG4 reduces expression of de novo lipid synthesis key enzymes by inhibiting transcription and promoting ubiquitination-mediated proteasomal degradation.
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Affiliation(s)
- Cong-Yu Zhang
- Cancer Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
| | - Rui Zhang
- Department of Colorectal Surgery, Liaoning Cancer Hospital, Shenyang 110042, Liaoning Province, China
| | - Li Zhang
- Department of Oncology, The Affiliated Hospital of Chengde Medical University, Chengde 067000, Hebei Province, China
| | - Zi-Mo Wang
- Cancer Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
| | - Hong-Zhi Sun
- Cancer Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
| | - Zheng-Guo Cui
- Department of Environmental Health, University of Fukui School of Medical Sciences, Fukui 910-1193, Japan
| | - Hua-Chuan Zheng
- Cancer Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
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Kim K, Ko SJ, Cho SH, Kim J, Park JW. Herbal medicine, Banxia-xiexin tang, for functional dyspepsia: a systematic review and meta-analysis. Front Pharmacol 2023; 14:1130257. [PMID: 37274096 PMCID: PMC10235465 DOI: 10.3389/fphar.2023.1130257] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 05/04/2023] [Indexed: 06/06/2023] Open
Abstract
Background: The demand for complementary and alternative medicine for the management of functional dyspepsia (FD) is increasing due to the insufficient efficacy of conventional treatment options. In Asia, the Chinese herbal medicine formula Banxia-xiexin tang (BXT) has been used to treat FD. Methods: We searched 11 digital medical databases on 1 September 2021. Randomized controlled trials (RCTs) that investigated the efficacy of BXT or combination therapy (BXT plus Western medicines) for FD were selected. The outcome parameters were total clinical efficacy rate (TCE), motilin level, symptom checklist-90-revised (SCL-90-R), and visual analog scale (VAS) for dyspepsia and adverse events. Cochrane risk of bias tool 2.0 (RoB 2) was used for the quality assessment of included studies. Results: The meta-analysis comprised 57 RCTs with 5,525 participants. BXT was more efficacious, with a higher TCE than Western medicine. Combination therapy (BXT plus Western medicine) also resulted in a higher TCE than Western medicine. Combination therapy improved motilin levels and psychological symptoms to a greater extent than Western medicine, evidenced by a higher SCL-90-R score. However, no significant difference in VAS scores was observed between the BXT and placebo groups. BXT and combination therapy were associated with fewer adverse events than Western medicine or placebo. Conclusion: Our findings suggest that BXT and its combination therapy may be an effective and safe alternative treatment for FD. More RCTs with better methodologies are required to strengthen this evidence. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019123285], identifier [CRD42019123285].
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Affiliation(s)
- Keumji Kim
- Department of Internal Korean Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea
- Department of Clinical Korean Medicine, Graduate School of Kyung Hee University, Seoul, Republic of Korea
| | - Seok-Jae Ko
- Department of Internal Korean Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea
- Department of Clinical Korean Medicine, Graduate School of Kyung Hee University, Seoul, Republic of Korea
- Department of Gastroenterology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Soo Ho Cho
- Department of Internal Korean Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea
| | - Jinsung Kim
- Department of Clinical Korean Medicine, Graduate School of Kyung Hee University, Seoul, Republic of Korea
- Department of Gastroenterology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Jae-Woo Park
- Department of Internal Korean Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea
- Department of Clinical Korean Medicine, Graduate School of Kyung Hee University, Seoul, Republic of Korea
- Department of Gastroenterology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
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Zheng HC, Xue H, Zhang CY. REG4 promotes the proliferation and anti-apoptosis of cancer. Front Cell Dev Biol 2022; 10:1012193. [PMID: 36172286 PMCID: PMC9511136 DOI: 10.3389/fcell.2022.1012193] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 08/26/2022] [Indexed: 11/27/2022] Open
Abstract
Regenerating islet-derived 4 (REG4) gene was discovered by high-throughput sequencing of ulcerative colitis cDNA libraries. REG4 is involved in infection and inflammation by enhancing macrophage polarization to M2, via activation of epidermal growth factor receptor (EGFR)/Akt/cAMP-responsive element binding and the killing inflammatory Escherichia coli, and closely linked to tumorigenesis. Its expression was transcriptionally activated by caudal type homeobox 2, GATA binding protein 6, GLI family zinc finger 1, SRY-box transcription factor 9, CD44 intracytoplasmic domain, activating transcription factor 2, and specificity protein 1, and translationally activated by miR-24. REG4 can interact with transmembrane CD44, G protein-coupled receptor 37, mannan and heparin on cancer cells. Its overexpression was observed in gastric, colorectal, pancreatic, gallbladder, ovarian and urothelial cancers, and is closely linked to their aggressive behaviors and a poor prognosis. Additionally, REG4 expression and recombinant REG4 aggravated such cellular phenotypes as tumorigenesis, proliferation, anti-apoptosis, chemoradioresistance, migration, invasion, peritoneal dissemination, tumor growth, and cancer stemness via EGFR/Akt/activator protein-1 and Akt/glycogen synthase kinase three β/β-catenin/transcription factor 4 pathways. Sorted REG4-positive deep crypt secretory cells promote organoid formation of single Lgr5 (+) colon stem cells by Notch inhibition and Wnt activation. Histologically, REG4 protein is specifically expressed in neuroendocrine tumors and signet ring cell carcinomas of the gastrointestinal tract, pancreas, ovary, and lung. It might support the histogenesis of gastric intestinal–metaplasia–globoid dysplasia–signet ring cell carcinoma. In this review, we summarized the structure, biological functions, and effects of REG4 on inflammation and cancer. We conclude that REG4 may be employed as a biomarker of tumorigenesis, subsequent progression and poor prognosis of cancer, and may be a useful target for gene therapy.
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Affiliation(s)
- Hua-Chuan Zheng
- Department of Oncology and Central Laboratory, The Affiliated Hospital of Chengde Medical University, Chengde, China
- *Correspondence: Hua-Chuan Zheng,
| | - Hang Xue
- Department of Oncology and Central Laboratory, The Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Cong-Yu Zhang
- Cancer Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
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Takasawa S, Tsuchida C, Sakuramoto-Tsuchida S, Uchiyama T, Makino M, Yamauchi A, Itaya-Hironaka A. Upregulation of REG IV gene in human intestinal epithelial cells by lipopolysaccharide via downregulation of microRNA-24. J Cell Mol Med 2022; 26:4710-4720. [PMID: 35946046 PMCID: PMC9443949 DOI: 10.1111/jcmm.17498] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 07/03/2022] [Accepted: 07/06/2022] [Indexed: 01/10/2023] Open
Abstract
The pathophysiology of inflammatory bowel diseases (IBD) reflects a balance between mucosal injury and reparative mechanisms. Some regenerating gene (Reg) family members (REG Iα, REG Iβ and REG IV) are expressed in Crohn's disease (CD) and ulcerative colitis (UC) and involved as proliferative mucosal factors in IBD. We revealed that REG Iα and REG Iβ were induced in cell culture system by IL‐6/IL‐22. Although REG IV was upregulated in IBD biopsy samples, the upregulation of REG IV was not at all induced in cell culture by autoimmune‐related cytokines such as IL‐6, IL‐22 and TNFα. Here, we analysed REG IV expression in LS‐174 T and HT‐29 human intestinal epithelial cells by real‐time RT–PCR and elisa. REG IV expression was induced by lipopolysaccharide (LPS). However, LPS did not activate REG IV promoter activity. As the LPS‐induced upregulation of REG IV was considered to be regulated post‐transcriptionally, we searched targeted microRNA (miR), which revealed that REG IV mRNA has a potential target sequence for miR‐24. We measured the miR‐24 level of LPS‐treated cells and found that the level was significantly lower. The LPS‐induced increase of REG IV mRNA was abolished by the introduction of miR‐24 mimic but not by non‐specific control RNA.
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Affiliation(s)
- Shin Takasawa
- Department of Biochemistry, Nara Medical University, Kashihara, Japan
| | | | | | - Tomoko Uchiyama
- Department of Biochemistry, Nara Medical University, Kashihara, Japan.,Department of Diagnostic Pathology, Nara Medical University, Kashihara, Japan
| | - Mai Makino
- Department of Biochemistry, Nara Medical University, Kashihara, Japan
| | - Akiyo Yamauchi
- Department of Biochemistry, Nara Medical University, Kashihara, Japan
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OKAMOTO H, TAKASAWA S. Okamoto model for necrosis and its expansions, CD38-cyclic ADP-ribose signal system for intracellular Ca 2+ mobilization and Reg (Regenerating gene protein)-Reg receptor system for cell regeneration. PROCEEDINGS OF THE JAPAN ACADEMY. SERIES B, PHYSICAL AND BIOLOGICAL SCIENCES 2021; 97:423-461. [PMID: 34629354 PMCID: PMC8553518 DOI: 10.2183/pjab.97.022] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 06/22/2021] [Indexed: 05/03/2023]
Abstract
In pancreatic islet cell culture models and animal models, we studied the molecular mechanisms involved in the development of insulin-dependent diabetes. The diabetogenic agents, alloxan and streptozotocin, caused DNA strand breaks, which in turn activated poly(ADP-ribose) polymerase/synthetase (PARP) to deplete NAD+, thereby inhibiting islet β-cell functions such as proinsulin synthesis and ultimately leading to β-cell necrosis. Radical scavengers protected against the formation of DNA strand breaks and inhibition of proinsulin synthesis. Inhibitors of PARP prevented the NAD+ depletion, inhibition of proinsulin synthesis and β-cell death. These findings led to the proposed unifying concept for β-cell damage and its prevention (the Okamoto model). The model met one proof with PARP knockout animals and was further extended by the discovery of cyclic ADP-ribose as the second messenger for Ca2+ mobilization in glucose-induced insulin secretion and by the identification of Reg (Regenerating gene) for β-cell regeneration. Physiological and pathological events found in pancreatic β-cells have been observed in other cells and tissues.
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Affiliation(s)
- Hiroshi OKAMOTO
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
- Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Shin TAKASAWA
- Department of Biochemistry, Nara Medical University, Kashihara, Nara, Japan
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Xing H, Chen X, Han Y. Role of regenerating gene IA expression on local invasion and survival in nasopharyngeal carcinoma. Biol Res 2017; 50:37. [PMID: 29162157 PMCID: PMC5699201 DOI: 10.1186/s40659-017-0142-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 10/31/2017] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Regenerating gene IA (REGIA) plays an important role in tissue regeneration and tumors prognosis of epithelium origin. However, the role of REGIA in nasopharyngeal carcinoma (NPC) is unclear. This study aims to investigate the expression and function of REG1A in NPC. RESULTS We have found that there was 63 patients with REGIA positive expression of 155 patients in this study (40.65%). The positive expression rate of REGIA was 30.50, 44.44 and 47.83% in stage T2, T3 and T4 patients, respectively. The REGIA expression was significantly difference in T2 and T4 stage tumors or T2 and T3-T4 stage. The positive expression rate of REGIA was found to be higher in patients with cervical lymph node persistence than those with cervical lymph node complete regression. Patients with negative REGIA expression had a better overall survival and free survival than those with REGIA positive expression. In addition, according to the univariate and multivariate analysis, the REGIA expression was an independent adverse prognostic factor for NPC patients. CONCLUSION REGIA expression was a useful biomarker in NPC patients for assessing T stage and survival.
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Affiliation(s)
- Haijie Xing
- Department of Otorhinolaryngology Head and Neck Surgery, Guang Ming New District People's Hospital, No.4253 Songbai rode, ShenZhen, 518106, China. .,Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Xinhua Hospital, Hainan Medical College, Haikou, 570311, China.
| | - Xiangdong Chen
- Department of Otolaryngology Head and Neck Surgery, Affiliated Hospital of Shenzhen University, Shenzhen, 518055, Guangdong Province, China
| | - Yaofeng Han
- Department of Epidemiology, Public Health College of Xiamen University, Xiamen, 361005, Fujian, China
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Leinartaité L, Svenningsson P. Folding Underlies Bidirectional Role of GPR37/Pael-R in Parkinson Disease. Trends Pharmacol Sci 2017. [PMID: 28629580 DOI: 10.1016/j.tips.2017.05.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Since conformational flexibility, which is required for the function of a protein, comes at the expense of structural stability, many proteins, including G-protein-coupled receptors (GPCRs), are under constant risk of misfolding and aggregation. In this regard GPR37 (also named PAEL-R and ETBR-LP-1) takes a prominent role, particularly in relation to Parkinson disease (PD). GPR37 is a substrate for parkin and accumulates abnormally in autosomal recessive juvenile parkinsonism, contributing to endoplasmic reticulum stress and death of dopaminergic neurons. GPR37 also constitutes a core structure of Lewy bodies, demonstrating a more general involvement in PD pathology. However, if folded and matured properly, GPR37 seems to be neuroprotective. Moreover, GPR37 modulates functionality of the dopamine transporter and the dopamine D2 receptor and stimulates dopamine neurotransmission. Here we review the multiple roles of GPR37 with relevance to potential disease modification and symptomatic therapies of PD and highlight unsolved issues in this field.
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Affiliation(s)
- Lina Leinartaité
- Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, SE-171 76, Stockholm, Sweden.
| | - Per Svenningsson
- Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, SE-171 76, Stockholm, Sweden.
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Chen S, Gou WF, Zhao S, Niu ZF, Zhao Y, Takano Y, Zheng HC. The role of the REG4 gene and its encoding product in ovarian epithelial carcinoma. BMC Cancer 2015; 15:471. [PMID: 26077911 PMCID: PMC4469329 DOI: 10.1186/s12885-015-1435-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Accepted: 05/13/2015] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Although its biological function remains poorly understood, REG4 is reported to be a potent activator of the EGFR/Akt/AP-1 signaling pathway in colon cancer cells and closely linked with the inhibition of apoptosis. METHODS SKOV3 cells were transfected with a REG4-expressing plasmid or treated with recombinant REG4. We then analyzed proliferation, cell cycle, apoptosis, invasion and metastasis or expression of related molecules. REG4 expression was examined in normal ovarian tissue, benign and borderline tumors, and cancers by immunohistochemistry or real-time PCR. RESULTS REG4 overexpression and the recombinant protein inhibited cell apoptosis, enhanced G2/S progression, proliferation, migration and invasion. Furthermore, expression of Wnt5a, p70s6k, survivin and VEGF expression was increased, while Bax expression was decreased at both the mRNA and protein levels compared to control or mock cells (P<0.05). REG4 mRNA levels were higher in benign tumors and primary cancer compared to those in normal ovarian tissue (P<0.05) while, REG4 protein expression was higher in all three tumor types than that in normal ovarian tissue (P<0.05). Higher REG4 mRNA expression was observed in mucinous carcinomas than serous carcinomas (P<0.05), and in well- and moderately-differentiated carcinomas than poorly-differentiated carcinomas (P<0.05). Survival analysis revealed an inverse relationship between REG4 expression and cumulative or relapse-free survival rates of the patients with ovarian cancer as an independent factor (P<0.05). CONCLUSIONS Our findings indicate that aberrant REG4 expression plays an essential role in early ovarian carcinogenesis and is closely linked to mucinous ovarian tumors, differentiation and adverse prognosis of ovarian cancer by modulating proliferation, apoptosis, migration and invasion.
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Affiliation(s)
- Shuo Chen
- Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China.
| | - Wen-Feng Gou
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, China Medical University, Shenyang, 110001, China.
| | - Shuang Zhao
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, China Medical University, Shenyang, 110001, China.
| | - Zhe-Feng Niu
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, China Medical University, Shenyang, 110001, China.
| | - Yang Zhao
- Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China.
| | - Yasuo Takano
- Clinical Cancer Institute, Kanagawa Cancer Center, Yokohama, 241-0815, Japan.
| | - Hua-Chuan Zheng
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, China Medical University, Shenyang, 110001, China.
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Wu L, Li G, Feng D, Qin H, Gong L, Zhang J, Zhang Z. MicroRNA-21 expression is associated with overall survival in patients with glioma. Diagn Pathol 2013; 8:200. [PMID: 24326156 PMCID: PMC3933412 DOI: 10.1186/1746-1596-8-200] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2013] [Accepted: 12/04/2013] [Indexed: 12/12/2022] Open
Abstract
Background MicroRNA-21 has been proved to be associated with glioma proliferation and invasion; thus, we sought to clarify the clinical value of miR-21 expression in glioma tissues with WHO grade I to IV. Methods One hundred and fifty-two pairs of human gliomas and non-neoplastic brain tissues were evaluated using real-time PCR. The association of miR-21 expression with clinicopathological factors or the prognosis of glioma patients was also analyzed. In this study, survival analysis was performed using the Kaplan-Meier method and Cox’s proportional hazards model. Results MiR-21 was more greatly expressed in glioma tissues compared to the corresponding non-neoplastic brain tissues (P < 0.001). This observed high miR-21 expression was significantly associated with high pathological grades and the Karnofsky performance score of glioma patients. In addition, overall patient survival for those with low miR-21 expression was significantly longer than those patients with high miR-21 expression (P < 0.001). Moreover, multivariate Cox regression analysis indicated that miR-21 might be an independent prognostic marker for glioma patient survival. Conclusions Our data show that miR-21 may be a candidate independent marker for gliomas, especially those with high pathological grades, and this could also be a potential therapeutic target for molecular glioma therapy. Virtual slide The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1445749171109834.
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Affiliation(s)
| | | | | | | | | | - Jian Zhang
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Cancer Biology, the Fourth Military Medical University, Xi'an, China.
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Li G, Jin T, Liang H, Zhang Z, He S, Tu Y, Yang H, Geng T, Cui G, Chen C, Gao G. RTEL1 tagging SNPs and haplotypes were associated with glioma development. Diagn Pathol 2013; 8:83. [PMID: 23683922 PMCID: PMC3661361 DOI: 10.1186/1746-1596-8-83] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2013] [Accepted: 05/12/2013] [Indexed: 01/08/2023] Open
Abstract
As glioma ranks as the first most prevalent solid tumors in primary central nervous system, certain single-nucleotide polymorphisms (SNPs) may be related to increased glioma risk, and have implications in carcinogenesis. The present case-control study was carried out to elucidate how common variants contribute to glioma susceptibility. Ten candidate tagging SNPs (tSNPs) were selected from seven genes whose polymorphisms have been proven by classical literatures and reliable databases to be tended to relate with gliomas, and with the minor allele frequency (MAF)>5% in the HapMap Asian population. The selected tSNPs were genotyped in 629 glioma patients and 645 controls from a Han Chinese population using the multiplexed SNP MassEXTEND assay calibrated. Two significant tSNPs in RTEL1 gene were observed to be associated with glioma risk (rs6010620, P=0.0016, OR: 1.32, 95% CI: 1.11-1.56; rs2297440, P=0.001, OR: 1.33, 95% CI: 1.12-1.58) by χ2 test. It was identified the genotype "GG" of rs6010620 acted as the protective genotype for glioma (OR, 0.46; 95% CI, 0.31-0.7; P=0.0002), while the genotype "CC" of rs2297440 as the protective genotype in glioma (OR, 0.47; 95% CI, 0.31-0.71; P=0.0003). Furthermore, haplotype "GCT" in RTEL1 gene was found to be associated with risk of glioma (OR, 0.7; 95% CI, 0.57-0.86; Fisher's P=0.0005; Pearson's P=0.0005), and haplotype "ATT" was detected to be associated with risk of glioma (OR, 1.32; 95% CI, 1.12-1.57; Fisher's P=0.0013; Pearson's P=0.0013). Two single variants, the genotypes of "GG" of rs6010620 and "CC" of rs2297440 (rs6010620 and rs2297440) in the RTEL1 gene, together with two haplotypes of GCT and ATT, were identified to be associated with glioma development. And it might be used to evaluate the glioma development risks to screen the above RTEL1 tagging SNPs and haplotypes. VIRTUAL SLIDES The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1993021136961998.
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Affiliation(s)
- Gang Li
- Department of Neurosurgery, Tangdu hospital, the Fourth Military Medical University, Xi’an, 710038, China
| | - Tianbo Jin
- National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi’an, 710069, China
| | - Hongjuan Liang
- Department of Neurosurgery, Tangdu hospital, the Fourth Military Medical University, Xi’an, 710038, China
| | - Zhiguo Zhang
- Department of Neurosurgery, Tangdu hospital, the Fourth Military Medical University, Xi’an, 710038, China
| | - Shiming He
- Department of Neurosurgery, Tangdu hospital, the Fourth Military Medical University, Xi’an, 710038, China
| | - Yanyang Tu
- Department of Clinical Experimental Surgery, Tangdu hospital, the Fourth Military Medical University, Xi’an, 710038, China
| | - Haixia Yang
- Department of Neurosurgery, Tangdu hospital, the Fourth Military Medical University, Xi’an, 710038, China
| | | | - Guangbin Cui
- Department of Radiology, Tangdu hospital, the Fourth Military Medical University, Xi’an, 710038, China
| | - Chao Chen
- National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi’an, 710069, China
| | - Guodong Gao
- Department of Neurosurgery, Tangdu hospital, the Fourth Military Medical University, Xi’an, 710038, China
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Riezzo I, Zamparese R, Neri M, De Stefano F, Parente R, Pomara C, Turillazzi E, Ventura F, Fineschi V. Sudden, unexpected death due to glioblastoma: report of three fatal cases and review of the literature. Diagn Pathol 2013; 8:73. [PMID: 23638625 PMCID: PMC3652782 DOI: 10.1186/1746-1596-8-73] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2013] [Accepted: 04/21/2013] [Indexed: 11/10/2022] Open
Abstract
UNLABELLED Sudden death from an undiagnosed primary intracranial neoplasm is an exceptionally rare event, with reported frequencies in the range of 0.02% to 2.1% in medico-legal autopsy series and only 12% of all cases of sudden, unexpected death due to primary intracranial tumors are due to glioblastomas. We present three cases of sudden, unexpected death due to glioblastoma, with different brain localization and expression. A complete methodological forensic approach by means of autopsy, histological and immunohistochemical examinations let us to conclude for an acute central dysregulation caused by glioblastoma and relative complication with rapid increase of intracranial pressure as cause of death. Although modern diagnostic imaging techniques have revolutionized the diagnosis of brain tumors, the autopsy and the careful gross examination and section of the fixed brain (with coronal section) is still the final word in determining exact location, topography, mass effects and histology and secondary damage of brain tumor and contributed the elucidation of the cause of death. Immunohistochemistry and proteomic analysis are mandatory in such cases. VIRTUAL SLIDES The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1218574899466985.
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Affiliation(s)
- Irene Riezzo
- Department of Forensic Pathology, University of Foggia, Ospedale “C. D’Avanzo”, viale degli Aviatori, 1, Foggia 71100, Italy
| | - Rosanna Zamparese
- Department of Forensic Pathology, University of Foggia, Ospedale “C. D’Avanzo”, viale degli Aviatori, 1, Foggia 71100, Italy
| | - Margherita Neri
- Department of Forensic Pathology, University of Foggia, Ospedale “C. D’Avanzo”, viale degli Aviatori, 1, Foggia 71100, Italy
| | - Francesco De Stefano
- Department of Legal Medicine, University of Genova, via de’ Toni 12, Genova 16132, Italy
| | - Ruggero Parente
- Department of Forensic Pathology, University of Foggia, Ospedale “C. D’Avanzo”, viale degli Aviatori, 1, Foggia 71100, Italy
| | - Cristoforo Pomara
- Department of Forensic Pathology, University of Foggia, Ospedale “C. D’Avanzo”, viale degli Aviatori, 1, Foggia 71100, Italy
| | - Emanuela Turillazzi
- Department of Forensic Pathology, University of Foggia, Ospedale “C. D’Avanzo”, viale degli Aviatori, 1, Foggia 71100, Italy
| | - Francesco Ventura
- Department of Legal Medicine, University of Genova, via de’ Toni 12, Genova 16132, Italy
| | - Vittorio Fineschi
- Department of Forensic Pathology, University of Foggia, Ospedale “C. D’Avanzo”, viale degli Aviatori, 1, Foggia 71100, Italy
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Abstract
Background Epigenetic silencing of tumor suppressor genes plays important role in gliomagenesis. Recently, GATA4 and DcR1 were suggested to be a tumor suppressor genes involved in tumorigenesis in various types of human cancers. However, up to now the methylation frequency of GATA4 and DcR1 genes has not been determined in glioblastoma. In this study, we investigated methylation of GATA4 and DcR1 promoters and their association with patient prognosis in glioblastoma. Methods Methylation status of GATA4 and DcR1 promoters was investigated by methylation specific PCR in 99 glioblastoma patients. Statistical analyses were conducted to investigate the association between clinical variables and overall survival time. Results GATA4 and DcR1 were aberrantly methylated in 23.2% and 27.6% of glioblastoma tumors, but not in normal brain. GATA4 promoter hypermethylation showed significant association with patients age (p = 0.027). Relationship between genes promoter methylation and glioblastoma patient survival was not determined. Conclusions The present work demonstrated that GATA4 and DcR1 promoter hypermethylation is tumor specific event in glioblastoma but they promoter methylation cannot be considered as a prognostic marker of glioblastoma survival. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1381170351801852
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Li G, Zhang Z, Tu Y, Jin T, Liang H, Cui G, He S, Gao G. Correlation of microRNA-372 upregulation with poor prognosis in human glioma. Diagn Pathol 2013; 8:1. [PMID: 23298385 PMCID: PMC3551676 DOI: 10.1186/1746-1596-8-1] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2012] [Accepted: 01/02/2013] [Indexed: 12/27/2022] Open
Abstract
UNLABELLED MicroRNA-372 (miR-372) acts as either an oncogenic miRNA or an anti-oncomiR in various human malignancies. However, its roles in gliomas have not been elucidated. To address this problem, we here detected miR-372 expression in human gliomas and non-neoplastic brain tissues by real-time quantitative RT-PCR assay. The association of miR-372 expression with clinicopathological factors or prognosis of glioma patients was also statistically analyzed. As the results, miR-372 expression levels were significantly upregulated in glioma tissues compared to the corresponding non-neoplastic brain tissues (P<0.001). In addition, the high miR-372 expression was significantly associated with the advanced pathological grade (P=0.008) and the low Karnofsky performance score (KPS) of glioma patients (P=0.01). Moreover, the overall survival of patients with high miR-372 expression was dramatically shorter than those with low miR-372 expression (P<0.001). Furthermore, multivariate Cox regression analysis indicated that miR-372 expression was an independent prognostic factor for glioma patients (P=0.008). More importantly, subgroup analyses according to tumor pathological grade revealed that the cumulative overall survival of glioma patients with advanced pathological grades was significantly worse for high miR-372 expression group than for low miR-372 expression group (P<0.001), but no significant difference was found for patients with low pathological grades (P=0.08). Taken together, these data offer the convincing evidence for the first time that miR-372 may act as an oncogenic miRNA in gliomas and represent a potential regulator of aggressive development and a candidate prognostic marker for this malignancy, especially for advanced tumors with high pathological grades. VIRTUAL SLIDES The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1707761328850011.
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Affiliation(s)
- Gang Li
- Department of Neurosurgery, Tangdu hospital, the Fourth Military Medical University, No. 569, Xinsi Road, Xi'an 710038, China
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