Pathology & Oncology Research

Upregulation of RUNX1 Suppresses Proliferation and Migration through Repressing VEGFA Expression in Hepatocellular Carcinoma Abstract Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, and occurs in people with chronic liver diseases. Current treatment methods include surgery, transplant, and chemotherapy. Our study demonstrates runt-related transcription factor 1 (RUNX1) as a novel molecule in the initiation and development of HCC, and the role of its interaction with vascular endothelial growth factor A (VEGFA) in HCC. We showed the suppressive role of RUNX1 in the proliferation and migration of hepatocytes. In addition, the repressor RUNX1 functioned as a transcription factor on the promoter of VEGFA to inhibit the expression of VEGFA. Study in the HCC cells demonstrated that the suppression of HCC proliferation and migration was masked in the presence of overexpressed VEGFA. Introduction of RUNX1 into HCC mice model significantly limited the tumor growth. In summary, our study demonstrated that RUNX1 functions as a repressor in the HCC and this suppressive function was dependent on its effect on VEGFA.

Molecular Network-Based Identification of Circular RNA-Associated ceRNA Network in Papillary Thyroid Cancer Abstract Circular RNAs (circRNAs) have displayed dysregulated expression in several types of cancer. Nevertheless, their function and underlying mechanisms in papillary thyroid cancer (PTC) remains largely unknown. This study aimed to describe the regulatory mechanisms in PTC. The expression profile of circRNA was download from the Gene Expression Omnibus (GEO) database. The mRNA and miRNA data of PTC was downloaded from The Cancer Genome Atlas (TCGA) database. The circRNA-miRNA-mRNA network by Cytoscape. The interactions between proteins were analyzed using the STRING database and hubgenes were identified using MCODE plugin. Then, we conducted a circRNA-miRNA-hubgenes regulatory module. Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genomes (KEGG) pathway analysis were conducted using R packages “Clusterprofile”. We identified 14 differential expression circRNAs (DEcircRNA), 3106 differential expression mRNAs (DEmRNA), 142 differential expression miRNAs (DEmiRNA) and in PTC. Twelve circRNAs, 33 miRNAs, and 356 mRNAs were identified to construct the ceRNA network of PTC. PPI network and module analysis identified 5 hubgenes. Then, a circRNA-miRNA-hubgene subnetwork was constructed based on the 2 DEcircRNAs, 3 DEmiRNAs, and 4 DEmRNAs. GO and KEGG pathway analysis indicated DEmRNAs might be associated with PTC onset and progression. These ceRNAs are critical in the pathogenesis of PTC and may serve as future therapeutic biomarkers.

A Novel Genes Signature Associated with the Progression of Polycystic Ovary Syndrome Abstract To identify genes involving in the pathogenesis of polycystic ovary syndrome (PCOS). In this study, the comprehensive analysis of GSE8157 was downloaded. Overlapping genes of differentially expressed genes (DEGs) were identified, and enrichment analysis for these genes was performed. A modular network of differentially expressed genes was constructed by weighted gene co-expression network analyses (WGCNA), and a total of 322 differentially expressed genes in 5 stable modules were screened. The correlations of genes of the stable modules in BioGRID 3.4, STRING 10.5, HPRD9 databases were screened, and the interaction network of 104 DEGs was constructed. In addition, some genes and the key words were searched in CTD. A total of 596 differentially expressed genes were screened, including 379 genes that were up-regulated in case group and down-regulated in control group and treat group, and 217 genes that were down-regulated in case group and up-regulated in control group and treat group. The differentially expressed genes were enriched in PPAR signaling pathway, Neuroactive ligand-receptor interaction, cAMP signaling pathway, of which pathways were involved in the cancer development. Finally, 7 important target genes were identified, such as APOC3 was interacted with pioglitazone, ADCY2 involved in cAMP signaling pathway, and the genes (C3AR1, HRH2, GRIA1, MLNR and TAAR2) involved in neuroactive ligand-receptor interaction. In addition, the important target genes were significantly differential expression. These results implied that the 7 important target genes were played an important role in the development and progression of PCOS. Our study implied that genes had played a key role in the development and progression of PCOS, the results showed that microarray can be use as a method for the discovery of new biomarkers and therapeutic targets for PCOS.

AF1q Expression Associates with CD44 and STAT3 and Impairs Overall Survival in Adenoid Cystic Carcinoma of the Head and Neck Abstract Salivary gland malignancies of the head and neck form a heterogeneous group. Adenoid cystic carcinomas are an aggressive entity of salivary gland malignancies characterized by frequent distant metastases and poor response to radio- and chemotherapy. AF1Q is a MLL fusion partner, which can activate Wnt and STAT3 signaling. Recently, overexpression of AF1q has been identified as a poor prognosticator in patients of different malignancies. A total of 46 patients with adenoid cystic carcinoma were immunohistochemically evaluated for expression of AF1q and clinical outcome was analyzed in this context. Additionally, STAT3 and the Wnt downstream target CD44 were investigated and correlated with AF1q. AF1q was overexpressed in 52.2%. Overexpression of AF1q was associated with poorer overall survival (p = 0.03). Additionally, lymph node metastases and solid tumor parts were more frequently observed in AF1qhigh patients (p = 0.07 and 0.05, respectively). AF1q did not influence the occurrence of distant metastases. Expression of AF1q was associated with higher levels of STAT3 and CD44 (p = 0.003 and 0.006, respectively). AF1q is a novel prognostic marker for poor overall survival in adenoid cystic carcinoma patients. The deleterious effects on survival may be a result of promotion of the STAT3 and Wnt pathway.

Peptidyl Arginine Deiminase, Type II (PADI2) Is Involved in Urothelial Bladder Cancer Abstract Peptidyl arginine deiminase, type II (PADI2) expression has been shown to potentiate multiple different carcinogenesis pathway including breast carcinoma and spontaneous skin neoplasia. The objective of this study was to examine the role of PADI2 in urothelial bladder cancer which has not been evaluated previously. Analysis of mutation and genome amplification of bladder cancer within The Cancer Genome Atlas (TCGA) showed that PADI2 is both mutated and amplified in a cohort of bladder cancer patients, with the largest number of mutations detected in urothelial bladder cancer. Even though PADI2 expression was not significantly correlated to survival in bladder cancer patients, it was significantly overexpressed at the mRNA and protein levels, as revealed by TCGA data and immunohistochemistry analysis, respectively. PADI2 showed wide expression pattern in bladder cancer tissues but was hardly detected in tumor adjacent normal tissue. RNAi mediated silencing of PADI2 in the bladder cancer cell line T24 did not result in a change of proliferation. Interestingly knockdown of PADI2 expression did not affect Snail1 protein, which is associated with metastatic progression, in these cells. However, PADI2 silencing remarkably attenuated both in vitro migration and invasion- in T24 cells indicating a Snail1-independent effect of PADI2 on invasive potential of urothelial bladder cancer. This was further corroborated by in vivo xenograft assays where PADI2 shRNA harboring T24 cells did not have detectable tumors by week 4 as compared to robust tumors in the control Luciferase shRNA harboring cells. PADI2 silencing did not affect proliferation rates and hence this would suggest that PADI2 knockdown is perhaps causing increased apoptosis as well as transition through the cell cycle, which needs to be confirmed in future studies. Our results reveal a yet undefined role of PADI2 as an oncogene in urothelial bladder cancer.

Polymorphisms in Genes Related to Cervical Cancer in A Brazilian Population: A Case-Control Study

LncRNA EGOT Promotes Tumorigenesis Via Hedgehog Pathway in Gastric Cancer Abstract Gastric cancer (GC) is one of the mostly terminal malignancies with poor prognosis. Long noncoding RNA EGOT (EGOT) acts as a crucial regulator in the breast cancer. However, the function of EGOT in GC remains unknown. This work was to explore the clinical value and biological significance of EGOT in GC. EGOT levels in GC tissue and cell were analyzed by qRT–PCR. After knockdown of EGOT, GC cell growth and cycle progression were detected. The expression of EGOT was observably elevated in GC. Upregulation of EGOT was related with lymphatic metastasis and TNM stage. In addition, knockdown of EGOT by siRNA could significantly inhibit GC cell proliferation and arrest cycle progression in G1 phase. Moreover, EGOT mediated cyclin D1 expression in GC cells which was regulated by Hedgehog pathway. Further, loss of EGOT downregulated Hedgehog signaling pathway in GC cells. EGOT functions as an oncogene in GC, and may be useful as a conceivable diagnostic and prognostic biomarker for GC tumorigenesis.

Tumor Associated Tissue Eosinophilia in Ameloblastoma

Recent advances of Blood telomere length (BTL) shortening: A potential biomarker for development of cancer Abstract Telomeres, the specific DNA–protein structures remains at both ends of each chromosome and are crucial in the maintenance of chromosome integrity and genomic stability with protection of the chromosome from damage and degradation.. Increasing evidences suggest the correlation between telomere length and the development of cancers, but the findings remain obscure. Generally, the average length of telomere repeats at the ends of chromosomes that gives a clue in providing indirect information about their mitotic history. It plays immense role in preventing genome from nucleolytic degradation, unnecessary recombination, repair, and interchromosomal fusion. It has major role in storing the information in the genome. Telomere attrition during successive cell divisions induces chromosomal instability and contributes significantly to genomic rearrangements that can result in tumorigenesis. Convincing evidence documented that a meagre portion of telomeric DNA is expelled out during mitotic stage of cell division. But accelerated shortening telomere length at critical level triggers senescence and/or apoptosis. Various harmful agents with bad lifestyles are responsible in inducing shortening of telomere length with damage of DNA resulting to occurrence of disease with shortening of lifespan. Besides, telomerases, the specialized polymerase that synthesizes new telomere repeats and is strongly associated with cancer facilitating malignant transformation. Therefore, in the study, it is highlighted that the telomeres may play diverse roles in different cancers whereas shortening of telomere length may be risk factors for the development of tumors.

IDH Mutation Analysis in Glioma Patients by CADMA Compared with SNaPshot Assay and two Immunohistochemical Methods Abstract Mutations in IDH1/2 genes are a marker of good prognosis for glioma patients, associated with low grade gliomas and secondary glioblastomas. Immunohistochemistry and Sanger sequencing are current standards for IDH1/2genotyping while many other methods exist. The aim of this study was to validate Competitive amplification of differentially melting amplicons (CADMA) PCR for IDH genotyping by comparison with SNaPshot assay and two immunohistochemical methods. In our study, 87 glioma patients (46 from Olomouc and 41 from Ostrava) were analyzed. IDH1/2 mutations in native bioptical samples were analyzed at DNA level by CADMA and SNaPshot while IDH1 mutations in FFPE samples were analyzed at protein level by two IHC methods. CADMA PCR sensitivity for IDH1 was 96.4% and specificity 100% for 86 concluded samples. SNaPshot assay sensitivity was 92.9% and specificity of 100% for 85 concluded samples. IHC in the laboratory no. 2 reached sensitivity 85.7% and specificity 100% for 86 concluded samples. IHC in the laboratory no. 4 reached sensitivity of 96.4% and specificity of 79.7% in 74 concluded samples. Only one IDH2 mutation was found by SNaPshot while CADMA yielded false negative result. In conclusion, CADMA is a valid method for IDH1 p.(R132H) testing with higher sensitivity than SNaPshot assay. Also, molecular genetic methods of IDH1 testing from native samples were more robust than IHC from FFPE.