Some characteristics of cancer-testis gene expression regulation in colorectal cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14233-e14233
Author(s):  
Kristina I. Soldatova ◽  
Oleg Ivanovich Kit ◽  
Roman E. Tolmakh ◽  
Denis S. Kutilin
Keyword(s):  
Colorectal Cancer ◽  
Cluster Analysis ◽  
Copy Number ◽  
Dna Methyltransferase ◽  
Gene Expression Regulation ◽  
Strong Positive Correlation ◽  
Aberrant Expression ◽  
Normal Tissues ◽  
Tumor Tissues ◽  
Cancer Testis

e14233 Background: Cancer-testis antigens (CTA) can be used in immunotherapy and for early detection of cancer. Despite numerous studies of the CTA expression in different tumors, their transcriptional activity and its regulation in colorectal cancer (CRC) remain poorly understood. The purpose of the study was to analyze the expression of cancer-testis genes (CT-genes) and mechanisms of its regulation in CRC. Methods: Tumor and intact tissues of the colon were studied in 60 patients. RNAs were isolated using the method described by Chomczynski and Sacchi (2006). The REVERTA-L reagent kit was used for the cDNA synthesis. Expression of 16 CT-genes (MAGE-A1, -A2, -A3, -A4, MAGE-B1, -B2, GAGE-1, -3, -4, MAGEC1, BAGE, XAGE3, NYESO1, SSX2, SCP1, PRAME1) and expression and copy number of 3 DNA methyltransferase genes (DNMT1, DNMT3A, DNMT3B) were determined by Real-Time qPCR (GAPDH and GUSB - reference genes). For the cluster analysis, we used our R scripts. Differences were assessed by the Mann-Whitney test, and correlations – by the Spearman's rank correlation coefficient (r). Results: The expression of 2 CT genes, SSX2 and PRAME1, was increased (p < 0.05) by 1.8 and 2.9 times, respectively, and the BAGE expression was decreased by 2.4 times in tumor tissues, compared to the normal tissues. The expression and copy number of DNMT3A in tumor tissues was 1.5 and 2 times higher (p < 0.05), and that of DNMT3B – 2 times lower (p < 0.005), compared to normal tissues. The copy number and expression of the DNMT1 gene did not change. A strong positive correlation (r = 0.996) between the expression and copy number of DNA methyltransferase genes was observed. Using cluster analysis (Hierarchical Clustering, Euclidean distance), we detected two clusters of CRC samples different in the expression of CT-genes and methyltransferases. Cluster 1 showed increased expression of DNMT1, DNMT3A and DNMT3B and decreased expression of BAGE, SSX2 and PRAME1; cluster 2 – decreased expression of DNMT1, DNMT3A and DNMT3B and increased expression of BAGE, SSX2 and PRAME1. Conclusions: The detected aberrant expression of the CT-genes BAGE, SSX2, PRAME1 in CRC depends on the expression of DNMT1, DNMT3A, DNMT3B, which in its turn depends on the copy number of the corresponding DNA methyltransferase genes.

Copy number variation and expression of CT-genes in patients with colorectal cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16104-e16104
Author(s):  
Yuriy A. Gevorkyan ◽  
Denis S. Kutilin ◽  
Oleg I. Kit ◽  
Natalya V. Soldatkina ◽  
Dmitry A. Kharagezov ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Copy Number ◽  
Tumor Tissue ◽  
Malignant Tumors ◽  
Regulation Of Gene Expression ◽  
Rank Correlation ◽  
Normal Colon ◽  
Aberrant Expression ◽  
Spearman’S Rank Correlation

e16104 Background: Cancer-testis antigens (CTAs) can be used for immunotherapeutic approaches and early detection of malignant tumors. Despite numerous studies of CTA expression in various tumors, including colon tumors, the mechanisms of transcriptional activity regulation in colorectal cancer (CRC) remain poorly studied. One of the possible mechanisms of regulation of gene expression is a change in their copy number (CNV). The aim of the study was to analyze the changes in the copy number and expression of CT-genes in patients with CRC. Methods: Tumor and normal colon tissues of 81 patients were used in the study. DNA was isolated by phenol-chloroform extraction. RNA was isolated by the Chomczynski&Sacchi method (2006). The REVERTA-L reagent kit was used for the cDNA synthesis. Determination of expression and copy number of 16 CT genes ( MAGE-A1, -A2, -A3, -A4, MAGE-B1, -B2, GAGE-1, -3, -4, MAGEC1, BAGE, XAGE3, NYESO1, SSX2, SCP1, PRAME1) was performed using the Real-Time qPCR method (reference genes - GAPDH and GUSB). Differences were evaluated using the Mann-Whitney test, correlation analysis - using Spearman's rank correlation coefficient (r). Results: An analysis of CT-gene expression and CNV in tumor and normal colon tissues (n = 81) revealed a statistically significant (p < 0.05) difference between these parameters in tumor tissue relative to normal one: for MAGEB1 an increase of 2.0 and 2.7 times, GAGE3 an increase of 2.0 and 2.5 times, GAGE4 decreased by 5.0 and 6.8 times, BAGE decreased by 2.4 and 1.7 times, SSX2 increased by 1.8 and 2.1 times, SCP1 increased copy number by 4.4 times and PRAME1 increased expression and copy number by 2.9 and 2.3 times, respectively. When comparing CNV and expression of 16 CT genes, a positive correlation was observed (r = 0.875). Conclusions: Thus, the aberrant expression of MAGEB1, GAGE3, GAGE4, BAGE, SSX2 and PRAME1 found in the tumor tissue of CRC patients depends on the copy number of these CT-genes.

scholarly journals ANRIL promotes chemoresistance via disturbing expression of ABCC1 by regulating the expression of Let-7a in colorectal cancer

2018 ◽  
Vol 38 (6) ◽  
Author(s):  
Zhen Zhang ◽  
Lifeng Feng ◽  
Pengfei Liu ◽  
Wei Duan
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Clinical Prognosis ◽  
Normal Tissues ◽  
Kaplan Meier ◽  
Non Coding Rna ◽  
Tumor Tissues ◽  
Oncogenic Gene ◽  
Poor Clinical Prognosis

Increasing evidence indicates that long non-coding RNAs (lncRNAs) antisense non-coding RNA in the INK4 locus (ANRIL) has been involved in various diseases and promotes tumorigenesis and cancer progression as an oncogenic gene. However, the effect of ANRIL on chemoresistance remains still unknown in colorectal cancer (CRC). Here, we investigated ANRIL expression in 63 cases of colorectal cancer specimens and matched normal tissues. Results revealed that ANRIL was up-regulated in tumor tissues samples from patients with CRC and CRC cell lines. Increased ANRIL expression in CRC was associated with poor clinical prognosis. Kaplan–Meier analysis showed that ANRIL was associated with overall survival of patients with colorectal cancer, and patients with high ANRIL expression tended to have unfavorable outcome. In vitro experiments revealed that ANRIL knockdown significantly inhibited CRC cell proliferation, improved the sensitivity of chemotherapy and promoted apoptosis. Further functional assays indicated that ANRIL overexpression significantly promoted cell chemoresistance by regulating ATP-binding cassette subfamily C member 1 through binding Let-7a. Taken together, our study demonstrates that ANRIL could act as a functional oncogene in CRC, as well as a potential therapeutic target to inhibit CRC chemoresistance.

scholarly journals Comprehensive Analysis of the Expression Profiles of Long Non-Coding RNAs with Associated ceRNA Network Involved in the Colon Cancer Staging and Progression

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Meini Wu ◽  
Wenliang Li ◽  
Fengchang Huang ◽  
Jing Sun ◽  
Kang ping Li ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Expression Profiles ◽  
Comprehensive Analysis ◽  
Differentially Expressed ◽  
Stage Iii ◽  
Aberrant Expression ◽  
Normal Tissues ◽  
Cerna Network ◽  
Tumor Tissues ◽  
Non Coding Rnas

AbstractLong non-coding RNAs (lncRNAs) act as competing endogenous RNAs (ceRNAs) to compete with microRNAs (miRNAs) in cancer occurrence and development. However, the differential expression of RNAs and their ceRNA network during the development of colon cancer (CC) remains unclear. This study was aimed at comprehensive analysis of the lncRNAs and their ceRNA networks associated with CC. Whole transcriptome sequencing was performed on colorectal and adjacent normal tissues at different pathological stages. Forty-nine lncRNAs were differently expressed between the CC tissues and their adjacent normal tissues at all stages. Aberrant expression of lncRNA CDKN2B-AS1 and lncRNA MIR4435-2HG was confirmed by TCGA database. Moreover, 14 lncRNAs were differentially expressed between early and advance stages of the tumor tissues, and 117 miRNAs were specifically expressed in stage III & IV. Weighted gene co-expression network analysis of 17105 differently expressed mRNAs revealed that the mRNAs shown in module pink, midnight blue, black, and light cyan were related to TNM and pathological stage, and that these mRNAs were enriched in cancer related functions and pathways. As DElncRNA showed a trend of change similar to that of the DEmRNA and opposite to that of DEmiRNA, ceRNA network was constructed with 3 DEmiRNAs, 5 DElncRNAs, and 130 DEmRNAs. Real time PCR revealed that expression of MEG3 was decreased in the tumor tissues belonging to stage III and IV as compared to that in stage I. Moreover, hsa-miR-324-5p was upregulated, while FGFR3, PLCB4, and IKBKB were downregulated in the tumor tissues as compared to that in the adjacent normal tissues. Thus, this study revealed differentially expressed lncRNA between different stages of CC as well as suggested that lncRNA CDKN2B-AS1, MIR4435-2HG, and MEG3 may act as diagnostic biomarkers for the development of CC.

scholarly journals TRIM39 deficiency inhibits tumor progression and autophagic flux in colorectal cancer via suppressing the activity of Rab7

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Jia Hu ◽  
Xueliang Ding ◽  
Shaobo Tian ◽  
Yanan Chu ◽  
Zhibo Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Autophagic Flux ◽  
Dependent Manner ◽  
Functional Studies ◽  
Normal Tissues ◽  
Tumor Tissues ◽  
Autophagic Degradation ◽  
Activity Dependent

AbstractThe biological function of TRIM39, a member of TRIM family, remains largely unexplored in cancer, especially in colorectal cancer (CRC). In this study, we show that TRIM39 is upregulated in tumor tissues compared to adjacent normal tissues and associated with poor prognosis in CRC. Functional studies demonstrate that TRIM39 deficiency restrains CRC progression in vitro and in vivo. Our results further find that TRIM39 is a positive regulator of autophagosome–lysosome fusion. Mechanistically, TRIM39 interacts with Rab7 and promotes its activity via inhibiting its ubiquitination at lysine 191 residue. Depletion of TRIM39 inhibits CRC progression and autophagic flux in a Rab7 activity-dependent manner. Moreover, TRIM39 deficiency suppresses CRC progression through inhibiting autophagic degradation of p53. Thus, our findings uncover the roles as well as the relevant mechanisms of TRIM39 in CRC and establish a functional relationship between autophagy and CRC progression, which may provide promising approaches for the treatment of CRC.

scholarly journals Analysis of changes in microbiome compositions related to the prognosis of colorectal cancer patients based on tissue-derived 16S rRNA sequences

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Sukjung Choi ◽  
Jongsuk Chung ◽  
Mi-La Cho ◽  
Donghyun Park ◽  
Sun Shim Choi
Keyword(s):  
Colorectal Cancer ◽  
16S Rrna ◽  
Pathogenic Bacteria ◽  
Fusobacterium Nucleatum ◽  
Amplicon Sequencing ◽  
Normal Tissues ◽  
16S Rrna Amplicon Sequencing ◽  
Tumor Tissues ◽  
Colorectal Cancer Patients ◽  
Host Genes

Abstract Background Comparing the microbiome compositions obtained under different physiological conditions has frequently been attempted in recent years to understand the functional influence of microbiomes in the occurrence of various human diseases. Methods In the present work, we analyzed 102 microbiome datasets containing tumor- and normal tissue-derived microbiomes obtained from a total of 51 Korean colorectal cancer (CRC) patients using 16S rRNA amplicon sequencing. Two types of comparisons were used: ‘normal versus (vs.) tumor’ comparison and ‘recurrent vs. nonrecurrent’ comparison, for which the prognosis of patients was retrospectively determined. Results As a result, we observed that in the ‘normal vs. tumor’ comparison, three phyla, Firmicutes, Actinobacteria, and Bacteroidetes, were more abundant in normal tissues, whereas some pathogenic bacteria, including Fusobacterium nucleatum and Bacteroides fragilis, were more abundant in tumor tissues. We also found that bacteria with metabolic pathways related to the production of bacterial motility proteins or bile acid secretion were more enriched in tumor tissues. In addition, the amount of these two pathogenic bacteria was positively correlated with the expression levels of host genes involved in the cell cycle and cell proliferation, confirming the association of microbiomes with tumorigenic pathway genes in the host. Surprisingly, in the ‘recurrent vs. nonrecurrent’ comparison, we observed that these two pathogenic bacteria were more abundant in the patients without recurrence than in the patients with recurrence. The same conclusion was drawn in the analysis of both normal and tumor-derived microbiomes. Conclusions Taken together, it seems that understanding the composition of tissue microbiomes is useful for predicting the prognosis of CRC patients.

scholarly journals Cytotoxic T-Cell Trafficking Chemokine Profiles Correlate With Defined Mucosal Microbial Communities in Colorectal Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiali Zhang ◽  
Ji Tao ◽  
Ruo-Nan Gao ◽  
Zhi-Yuan Wei ◽  
Yu-Shan He ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Gut Microbiota ◽  
Oral Bacteria ◽  
Cytotoxic T Cell ◽  
Cell Trafficking ◽  
Gut Microbes ◽  
T Cell Trafficking ◽  
Normal Tissues ◽  
Tumor Tissues

The involvement of gut microbiota in T-cell trafficking into tumor tissue of colorectal cancer (CRC) remains to be further elucidated. The current study aimed to evaluate the expression of major cytotoxic T-cell trafficking chemokines (CTTCs) and chemokine-associated microbiota profiles in both tumor and adjacent normal tissues during CRC progression. We analyzed the expression of chemokine C-X-C motif ligands 9, 10, and 11 (CXCL9, CXCL10, and CXCL11), and C-C motif ligand 5 (CCL5), characterized gut mucosa-associated microbiota (MAM), and investigated their correlations in CRC patients. Our results showed that the expression of CXCL9, CXCL10, and CXCL11 was significantly higher in tumor than in adjacent normal tissues in 136 CRC patients. Notably, the high expression of CXCL9 in tumor tissues was associated with enhanced CD8+ T-cell infiltration and improved survival. Moreover, the MAM in tumor tissues showed reduction of microbial diversity and increase of oral bacteria. Microbial network analysis identified differences in microbial composition and structure between tumor and adjacent normal tissues. In addition, stronger associations between oral bacteria and other gut microbes were observed. Furthermore, the correlation analysis between the defined MAM and individual CTTCs showed that the CTTCs’ correlated operational taxonomic units (OTUs) in tumor and adjacent normal tissues rarely overlap with each other. Notably, all the enriched OTUs were positively correlated with the CTTCs in either tumor or adjacent normal tissues. Our findings demonstrated stronger interactions between oral bacteria and gut microbes, and a shifted correlation pattern between MAM and major CTTCs in tumor tissues, underlining possible mechanisms of gut microbiota–host interaction in CRC.

Treatment of Chronic Lymphocytic Leukemia with a Hypomethylating Agent Induces Expression of NXF2, An Immunogenic Cancer Testis Antigen

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4207-4207
Author(s):  
Jason A Dubovsky ◽  
Douglas G McNeel ◽  
John J. Powers ◽  
Eduardo M. Sotomayor ◽  
Javier Pinilla
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Antigen Presentation ◽  
Lymphocytic Leukemia ◽  
Active Immunotherapy ◽  
Aberrant Expression ◽  
Normal Tissues ◽  
Cancer Testis Antigens ◽  
Solid Malignancies ◽  
Specific Proteins ◽  
Cancer Testis

Abstract Critical to success of active immunotherapy against cancer is the identification of immunologically recognized cancer-specific proteins with low tolerogenic potential. Cancer testis antigens (CTAs) in particular, fulfill this requirement as a result of their aberrant expression restricted to cancer cells and lack of expression in normal tissues bypassing tolerogenic mechanisms against self. Although CTAs have been extensively studied in solid malignancies little is known regarding their expression in chronic lymphocytic leukemia (CLL). Using a two-pronged approach we evaluated the immunogenicity of 29 CTAs in 22 patients with CLL and correlated these results to RTPCR data from CLL cell lines and patient cells. We identified IgG specific antibodies for one antigen, NXF2 and confirmed this response by ELISA and Western blot. We found that treatment of CLL with 5-aza-2′-deoxycytidine can induce expression of NXF2 that lasted for several weeks after treatment. Treatment also increased levels of MHC and costimulatory molecules (CD80, CD86, and CD40) necessary for antigen presentation. In addition, we identified other promising antigens such as NY-ESO-1 and MAGE which may have potential immunotherapeutic application. Our findings suggest that NXF2 could be further pursued as an immunotherapeutic target in CLL, and that treatment with demethylating agents could be exploited to specifically modulate CTA expression and effective antigen presentation in malignant B-cells.

scholarly journals Clinical value and potential association of Rab1A and FoxM1 aberrant expression in colorectal cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Menglin Xu ◽  
Xinyu Shao ◽  
Haoran Li ◽  
Zhengrong Zhang ◽  
Chunli Zhou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Metastasis ◽  
Clinical Value ◽  
Aberrant Expression ◽  
Normal Tissues ◽  
Clinical Biomarkers ◽  
Potential Association ◽  
Foxm1 Expression ◽  
Colorectal Cancer Metastasis ◽  
Worse Prognosis

AbstractColorectal carcinoma (CRC) is one of the most common malignancies with a dismal 5-year survival rate. Our recent study indicated that Rab1A expression was closely related to GLI1 expression. A previous study shows that aberrant overexpression of GLI1 promotes colorectal cancer metastasis via FoxM1 overexpression. However, the potential correlation between Rab1A and FoxM1 in CRC remains elusive. Immunohistochemistry was performed to investigate the association of the expression of Rab1A and FoxM1 and to determine the prognosis in 135 CRC tissue and adjacent normal tissues. Using Oncomine datasets, we found that Rab1A and FoxM1 mRNA were obviously upregulated in CRC tissues compared to normal tissues. Additionally, the expression of Rab1A and FoxM1 was significantly higher in CRC tissues than that in normal tissues. Rab1A expression was positively correlated with FoxM1 expression in CRC, especially in TNM stage III. In addition, Rab1A and FoxM1 overexpression was found to be significantly correlated with poor prognosis in CRC patients. Besides, both high expression of Rab1A and FoxM1 led to a worse prognosis than anyone low group, and both low expression of Rab1A and FoxM1 had a better prognosis than the anyone low group. Therefore, Rab1A and FoxM1 play crucial roles and could be used as clinical biomarkers in CRC.

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