Gliomas account for the highest cases of primary brain malignancies. Whereas previous studies have demonstrated the roles of CDC28 Protein Kinase Regulatory Subunit 2 (CKS2) in various cancer types, its functions in lower grade gliomas (LGGs) remain elusive. This study aimed to profile the expression and functions of CKS2 in LGG. Multiple online databases such as The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), Gene Expression Profiling Interactive Analysis 2nd edition (GEPIA2), Tumor Immune Estimation Resource 2nd edition (TIMER2.0) as well as Gene Expression Omnibus (GEO) were used in this study. Immunohistochemistry (IHC) was performed to evaluate CKS2 protein expression. Our data demonstrated upregulation of CKS2 in LGG tissues at both mRNA and protein level, especially in grade III gliomas. Similarly, there was increased expression of CKS2 in isocitrate dehydrogenase 1 (IDH1) wildtype gliomas. In addition, increased DNA copy number and DNA hypomethylation might be associated with the upregulation of the CKS2 in LGG. Using the Kaplan–Meier survival analysis and the Cox regression analysis, CKS2 was shown to be independently associated with poor prognosis of LGG patients. Receiver operating characteristic (ROC) analysis revealed that CKS2 could effectively predict the 1-, 3- and 5-year survival rates of LGG patients. Enrichment analyses revealed that CKS2 was mainly involved in the regulation of the cell cycle in LGG. Taken together, our study demonstrated that CKS2 might be a candidate prognostic biomarker for LGG and could predict the survival rates of LGG patients. Abbreviations: LGG: lower grade glioma; CKS2: CDC28 protein kinase regulatory subunit 2; TCGA: The Cancer Genome Atlas; CGGA: the Chinese Glioma Genome Atlas; GEO: Gene Expression Omnibus; GEPIA: Gene Expression Profiling Interactive Analysis; TIMER: Tumor Immune Estimation Resource; IHC: immunohistochemistry; qRT-PCR: quantitative real-time polymerase chain reaction; PBS: phosphate buffered saline; DAB: diaminobenzidine tetrachloride; OS: overall survival; CAN: copy number alteration; IDH: Isocitrate dehydrogenase; GSEA: Gene Set Enrichment Analysis; DEG: differentially expressed gene; KEGG: Kyoto encyclopedia of genes and genomes; GO: Gene ontology; BP: biological process; CC: cellular component; MF: molecular function; NES: normalized enrichment score; NOM: nominal; FDR: false discovery rate
Objective
To investigate the expression of gastric and intestinal phenotypic markers in Siewert typeⅡand Ⅲ early gastroesophageal junction(GEJ) cancer, and to explore its correlation with clinic-pathological features.
Methods
From April 2010 to July 2015, 53 cases diagnosed as early GEJ cancer were enrolled. The gastric and intestinal phenotypic markers such as mucin5AC(MUC5AC), mucin6(MUC6), mucin2(MUC2), caudal related homeodomain transcription 2(CDX2) and cluster of differentiation 10(CD10) were detected, and then the patients were divided into gastric type, gastrointestinal type, intestinal type and non-classified type according to the results of immunohistochemical staining. Combined with Siewert classification the clinicopathological features were analyzed. Chi square test or Fisher′s exact test was performed for statistical analysis.
Results
In the cancer tissues of 47 patients with Siewert type Ⅱand Ⅲ early GEJ cancer, the case numbers of positive expression of MUC5AC, MUC6, MUC2, CDX2 and CD10 were 21(44.7%), 19(40.4%), 31(66.0%), 27(57.4%) and 17(36.2%), respectively; the case numbers of gastric type, gastrointestinal type, intestinal type and non-classified type were 11(23.4%), 14(29.8%), 21(44.7%) and one(2.1%), respectively. The positive expression rates of MUC5AC and MUC6 in Siewert typeⅡwere 55.9%(19/34) and 50.0%(17/34), which were higher than those of Siewert typeⅢ(2/13), and the positive expression rate of MUC2 was 55.9%(19/34), which was lower than that of Siewert typeⅢ(12/13), and the differences were statistically significant (χ2=6.240, 4.679 and 4.053; all P<0.05). In Siewert typeⅡ, the proportion of intestinal type was 32.4%(11/34), which was lower than that of Siewert typeⅢ(10/13), and the differences were statistically significant (χ2=7.142, P=0.010). In patients with Siewert typeⅡand Ⅲ early cancer, males predominated in intestinal type which were mostly well differentiated type with less submucosal carcinoma. The maximum diameter of tumor was less than those of gastric type and gastrointestinal type. In paracancerous mucosal tissues, the incidences of intestinal metaplasia in gastrointestinal type and intestinal type were 11/14 and 81.0%(17/21), which were higher than that of gastric type (3/11); the incidences of atrophy in gastrointestinal type and intestinal type were 12/14 and 85.7%(18/21), which were higher than that of gastric type (4/11), and the differences were statistically significant (Fisher′s exact test, all P<0.05).
Conclusions
Siewert typeⅡand Ⅲ early GEJ cancer can directly originated not only from gastric mucosa, but also from gastrointestinal and intestinal mucosa. Atrophy and intestinal metaplasia could exist before cancer genesis.
Key words:
Early gastroesophageal junctional cancer; Siewert classification; Gastric and intestinal phenotypic markers
Abstract Background Although an association between the cytochrome P4502D6 (CYP2D6) *10 (100C>T) polymorphism and hepatocellular carcinoma (HCC) is known, the mechanism remains unclear. Here we aimed to explore mechanisms of CYP2D6*10 (100C>T) polymorphism conferring to HCC, and screen markers for HCC. Methods Label-free global proteome profiling with 34 normal livers and peritumor tissue from 61 HCC patients was performed, and angiopoietin-like protein-6 (ANGPTL6) was evaluated in 2 liver samples validation cohorts and 2 blood specimens validation cohorts. Results We found a significantly decreased frequency of TT in HCC patients which reduced HCC susceptibility by 69.2% and was accompanied by lowered enzymatic activity for CYP2D6. Proteomic analysis revealed 1342 differentially expressed proteins (DEPs) that were associated with HCC and 88 DEPs were identified as 100 TT-related proteins, likely underlying the susceptibility to HCC. Twenty-two upregulated DEPs and 66 downregulated DEPs were mainly related to lipid metabolism and the extracellular matrix, respectively. High ANGPTL6 was associated with a higher risk to HCC and worse prognosis. ANGPTL6 was both an independent risk factor and an independent prognostic factor for HCC and exhibited strong potential for predicting HCC occurrence, with comparable AUC values and higher sensitivity compared with alpha-fetoprotein. Conclusions The TT genotype-associated decreased risk of HCC appears to be related to lowered CYP2D6 activity and altered protein expression in the tumor microenvironment, and ANGPTL6 is a promising new diagnostic and prognostic biomarker for HCC. Our findings reveal new mechanistic insights for polymorphisms related to HCC risk and provide avenues for screening for HCC.
Glioblastoma (GBM) is a devastating inflammation-related cancer for which novel therapeutic targets are urgently required. Previous studies of the authors indicate Cytochrome P450 2E1 (CYP2E1) as a novel inflammatory target and develop a specific inhibitor Q11. Here it is demonstrated that CYP2E1 overexpression is closely related to higher malignancy in GBM patients. CYP2E1 activity is positively correlated with tumor weight in GBM rats. Significantly higher CYP2E1 expression accompanied by increased inflammation is detected in a mouse GBM model. Q11, 1-(4-methyl-5-thialzolyl) ethenone, a newly developed specific inhibitor of CYP2E1 here remarkably attenuates tumor growth and prolongs survival in vivo. Q11 does not directly affect tumor cells but blocks the tumor-promoting effect of microglia/macrophage (M/Mφ) in the tumor microenvironment through PPARγ-mediated activation of the STAT-1 and NF-κB pathways and inhibition of the STAT-3 and STAT-6 pathways. The effectiveness and safety of targeting CYP2E1 in GBM are further supported by studies with Cyp2e1 knockout rodents. In conclusion, a pro-GBM mechanism in which CYP2E1-PPARγ-STAT-1/NF-κB/STAT-3/STAT-6 axis fueled tumorigenesis by reprogramming M/Mφ and Q11 as a promising anti-inflammatory agent for GBM treatment is uncovered.
Objective: To analyse the clinicopathologic features of gastric plexiform fibromyxoma (PF) including diagnosis, differential diagnosis, immunohistochemistry and molecular pathology. Methods: Eight cases of PF were collected from June 2006 to June 2017 at the Second Affiliated Hospital of Zhengzhou University and the First Affiliated Hospital of Zhengzhou University. The clinicopathologic findings of eight cases of PF were retrospectively analyzed, and immunohistochemistry (EnVision method) and molecular detection of glioma-associated oncogene homologue 1 (GLI1) gene translocation were performed. All cases were histologically reviewed with immunohistochemical staining for smooth muscle actin (SMA), CD10, CD117, DOG1, CD34, ER, PR, ALK and S-100. Fluorescence in situ hybridization (FISH) was used to detect the GLI1 gene translocation, and mutation of CKIT exons 9, 11, 13 and 17; and PDGFRA exons 12, 14 and 18 were identified by Sanger sequencing in four cases. Relevant literature was reviewed. Results: The study included four men and four women, age ranged from 26 to 72 years (mean 51 years). Histologically, the tumors were rich in small thin-walled blood vessels and myxoid matrix, and exhibited multiple nodular growth pattern in the gastric wall. The tumor cells were bland, spindled or oval. Immunohistochemically, all cases strongly expressed vimentin and SMA, and some expressed CD10 (4/8), desmin (3/8), H-caldesmon (5/8) and PR (5/8), but were negative for CD34, S-100, ER, ALK, CD117 and DOG1. The GLI1 gene translocation detection was performed in eight cases by FISH with three positive cases and five negative cases. Mutation analyses for exons 9, 11, 13, and 17 of CKIT genes and exons 12, 14, and 18 of the PDGFRA genes were performed and the tumors all of four tested cases were wild-type. Seven patients were followed up (ranged from 24 to 95 months, mean 50 months) after diagnosis and none of the patients had recurrence or metastasis. Conclusions: PF is a rare novel mesenchymal tumor of the stomach. Its distinct clinicopathologic features and immunohistochemical positivity for SMA, CD10 and PR can help differentiating this entity from other gastrointestinal mesenchymal tumors. FISH detection of GLI1 gene translocation offers an additional molecular diagnostic marker for the diagnosis.目的： 探讨胃丛状纤维黏液瘤(plexiform fibromyxoma，PF)的临床病理学待征、诊断及鉴别诊断。 方法： 收集郑州大学第二附属医院及郑州大学第一附属医院2006年6月至2017年6月期间8例手术病例胃PF的临床病理资料及随访资料，光镜下观察HE切片、免疫组织化学染色(EnVision法)、荧光原位杂交(FISH)方法检测GLI1基因易位情况，Sanger测序法检测CKIT基因(第9、11、13和17号外显子)及PDGFRA基因(第12、14和18号外显子)的突变状态，并结合文献进行分析。 结果： 男性4例，女性4例；年龄26～72岁(平均年龄51岁)；胃窦6例，胃底2例；肿瘤最大径1.2～7.0 cm，平均3.1 cm；肉眼观肿瘤边界较清，切面灰黄色或灰白色，质韧。低倍镜下肿瘤呈丛状或多结节状，浸润性生长；间质富含薄壁小血管及黏液样基质。高倍镜下肿瘤呈束状、席纹状及编织状排列，瘤细胞梭形或卵圆形，未见肿瘤性坏死，核分裂象(0～2)/50 HPF。免疫组织化学显示，波形蛋白(8/8)、平滑肌肌动蛋白(SMA，8/8)均阳性，CD10(4/8)、结蛋白(3/8)、H－caldesmon(5/8)、孕激素受体(PR，5/8)部分阳性，CD117、DOG1、CD34、间变性淋巴瘤激酶、雌激素受体及S－100蛋白均阴性。分子检测结果：3例检测到GLI1基因易位(3/8)，4例行CKIT及PDGFRA基因突变检测均为野生型。7例获得随访资料，随访时间24～95个月(平均50个月)，均无瘤生存。 结论： 胃PF是一种伴有肌样分化的间叶源性肿瘤，主要发生于胃窦部，目前的随访证据表明其生物学行为呈惰性临床经过，诊断时需与胃肠道间质瘤等多种间叶源性肿瘤鉴别。综合考虑肿瘤的丛状生长方式及免疫组织化学染色表达SMA、PR及CD10对胃PF的诊断与鉴别诊断有较大价值，GLI1基因易位检测亦可作为重要的辅助诊断手段。.
Aims: The dysfunction of placenta development is correlated to the defects of pregnancy and fetal growth. The detailed molecular mechanism of placenta development is not identified in human due to the lack of material in vivo. Image-based reconstructions of GRN are still very underdeveloped. Methods and Results: In this study, immunohistochemistry images of different TFs in chorionic villus were obtained by a high-resolution scanner. Next, we used a convolutional neural network and machine learning method to infer gene interaction networks of human placenta from these images based on the transfer learning technique. The experimental results show that deep learning models reveals regulatory roles that have not yet been fully recognized. The spatial expression data reveal new regulatory relationships that traditional experiments have failed to recognize, and has allowed the development of gene regulation networks based on the spatial distribution of gene expression. Conclusions: We demonstrate the effectiveness of this approach in building networks using high-resolution images of the human placenta. Our analysis is of certain significance for further exploration of the development of the placenta and the occurrence of pregnancy-related diseases in the future. The datasets and analysis provide a useful source for the researchers in the field of the maternal-fetal interface and the establishment of pregnancy.
Plexiform fibromyxoma (PF) is a unique mesenchymal tumor of the stomach. The molecular characteristics of these tumors remain unclear. Here, we report 10 cases of PF with clinicopathological features and molecular features in detail. The patients ranged in age from 26 to 72 years (mean, 49 y) and most commonly presented with abdominal pain and distension, black stool, and anemia. Eight tumors were located at the antrum while two in the fundus of stomach. Histologically, tumor cells exhibited a plexiform growth pattern with multiple nodules in the muscularis propria of stomach wall and infiltrative borders. Immunohistochemically, all tumors were strongly positive for vimentin and smooth muscle actin (SMA), some were staining for CD10 (5/10), desmin (5/10), H-caldesmon (6/10) and progesterone receptor (PR, 6/10), however, CD34, S-100, Estrogen Receptor (ER), ALK, CD117 and DOG-1 were all negative in our cases. The glioma-associated oncogene homologue 1 (GLI1) gene translocation was detected in eight cases by FISH with three positive and five negative. Mutation analyses of C-KIT and platelet-derived growth factor receptor alpha (PDGFRA) genes were performed on five cases and all of which were wild-type for mutation. Our follow-up indicated that all of the patients made an uneventful recovery at 24 to 95 months after diagnosis. In summary, the distinctively histological features and immunohistochemical positivity of SMA, CD10 and PR can help differentiate PF from other gastrointestinal mesenchymal tumors. GLI1 gene translocation offers an additional molecular instrument for the diagnosis. The expression of PR and the existence of GLI1 gene translocation in PF highlights of our article.
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