Expression of HTRA Genes and Its Association with Microsatellite Instability and Survival of Patients with Colorectal Cancer

HtrA proteases regulate cellular homeostasis and cell death. Their dysfunctions have been correlated with oncogenesis and response to therapeutic treatment. We investigated the relation between HtrA1-3 expression and clinicopathological, and survival data, as well as the microsatellite status of tumors. Sixty-five colorectal cancer patients were included in the study. The expression of HTRA1-3 was estimated at the mRNA and protein levels by quantitative PCR and immunoblotting. Microsatellite status was determined by high-resolution-melting PCR. We found that the HTRA1 mRNA level was higher in colorectal cancer tissue as compared to the unchanged mucosa, specifically in primary lesions of metastasizing cancer. The levels of HtrA1 and HtrA2 proteins were reduced in tumor tissue when compared to unchanged mucosa, specifically in primary lesions of metastasizing disease. Moreover, a decrease in HTRA1 and HTRA2 transcripts’ levels in cancers with a high level of microsatellite instability compared to microsatellite stable ones has been observed. A low level of HtrA1 or/and HtrA2 in cancer tissue correlated with poorer patient survival. The expression of HTRA1 and HTRA2 changes during colorectal carcinogenesis and microsatellite instability may be, at least partially, associated with these changes. The alterations in the HTRA1/2 genes’ expression are connected with metastatic potential of colorectal cancer and may affect patient survival.

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Abstract 4026: Assessment of microsatellite instability (MSI) status in colorectal cancer tissue using a next-generation sequencing-based tumor profiling assay

10.1158/1538-7445.sabcs18-4026 ◽

2019 ◽

Author(s):

Kevin Z. Qu ◽

Suzzette Arnal ◽

Sirisha Sunkara ◽

Mohammad R. Sheikholeslami ◽

Zhong J. Zhang ◽

...

Keyword(s):

Colorectal Cancer ◽

Next Generation Sequencing ◽

Microsatellite Instability ◽

Cancer Tissue ◽

Next Generation ◽

Colorectal Cancer Tissue ◽

Generation Sequencing ◽

Tumor Profiling

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Methylation in p14ARF is Frequently Observed in Colorectal Cancer with Low-level Microsatellite Instability

Journal of International Medical Research ◽

10.1177/147323000903700408 ◽

2009 ◽

Vol 37 (4) ◽

pp. 1038-1045 ◽

Cited By ~ 8

Author(s):

K Kominami ◽

T Nagasaka ◽

HM Cullings ◽

N Hoshizima ◽

H Sasamoto ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Promoter Methylation ◽

Dna Methyltransferase ◽

Methylation Status ◽

Gene Promoters ◽

Braf Mutations ◽

Low Level ◽

Methylguanine Dna Methyltransferase ◽

High Level

Colorectal cancer (CRC) can be classified as high-level microsatellite instability (MSI-H), low-level MSI (MSI-L) and microsatellite stable (MSS) depending on levels of MSI. MSI-H CRC relies on a distinct molecular pathway due to the mismatch repair (MMR) deficiency and shows methylation in multiple gene promoters. The genetic pathway leading to MSI-L is unknown, although higher levels of promoter methylation are observed in this group compared with MSS CRCs. This study explored how promoter methylation affects MSI phenotype, by analysing the methylation status of eight CRC-related promoters, MSI phenotype and KRAS/BRAF mutations in a series of 234 CRCs. Promoter methylation of p14ARF was significantly related to MSI-L CRC with KRAS mutation. The MSI-H phenotype was related to methylation of MLH1 as expected, while the MSS phenotype was related to methylation of p16INK4a and O6-methylguanine-DNA methyltransferase, although this was not statistically significant. Thus, promoter methylation of p14ARF could be a significant alteration leading to CRC with MSI-L.

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Quasimonomorphic Mononucleotide Repeats for High-Level Microsatellite Instability Analysis

Disease Markers ◽

10.1155/2004/159347 ◽

2004 ◽

Vol 20 (4-5) ◽

pp. 251-257 ◽

Cited By ~ 89

Author(s):

Olivier Buhard ◽

Nirosha Suraweera ◽

Aude Lectard ◽

Alex Duval ◽

Richard Hamelin

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Screening Test ◽

Consensus Meeting ◽

Dinucleotide Repeats ◽

Primary Tumors ◽

Low Level ◽

High Level ◽

Msi Analysis ◽

Microsatellite Instability Analysis

Microsatellite instability (MSI) analysis is becoming more and more important to detect sporadic primary tumors of the MSI phenotype as well as in helping to determine Hereditary Non-Polyposis Colorectal Cancer (HNPCC) cases. After some years of conflicting data due to the absence of consensus markers for the MSI phenotype, a meeting held in Bethesda to clarify the situation proposed a set of 5 microsatellites (2 mononucleotide repeats and 3 dinucleotide repeats) to determine MSI tumors. A second Bethesda consensus meeting was held at the end of 2002. It was discussed here that the 1998 microsatellite panel could underestimate high-level MSI tumors and overestimate low-level MSI tumors. Amongst the suggested changes was the exclusive use of mononucleotide repeats in place of dinucleotide repeats. We have already proposed a pentaplex MSI screening test comprising 5 quasimonomorphic mononucleotide repeats. This article compares the advantages of mono or dinucleotide repeats in determining microsatellite instability.

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CEND1 and GJB6 co-expression as a prognostic factor in colorectal cancer

10.21203/rs.3.rs-709485/v1 ◽

2021 ◽

Author(s):

Rui Chen ◽

Zhan Wang ◽

Dong Ma ◽

Yijiang Han ◽

Junsong Liu ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Progression ◽

Perineural Invasion ◽

Patient Survival ◽

Colorectal Cancer Patient ◽

Cell Communication ◽

Tumor Location ◽

Protein Levels ◽

Kaplan Meier ◽

Clinicopathological Findings

Abstract Background: Perineural invasion is an important mechanism of cancer progression that is not well understood at present. The present study explored the relationship between GJB6, CEND1, and cell-cell communication as regulators of colorectal cancer patient survival and clinicopathological findings.Method: Immunohistochemical staining was performed to assess CEND1 and GJB6 expression levels in CRC patient samples, while survival outcomes were assessed using Kaplan-Meier curves and log-rank tests.Results: Elevated CEND1 expression was associated with tumor location, poor differentiation, and perineural invasion, while GJB6 expression was positively correlated with TNM stage, distant metastasis, and perineural invasion. In addition, GJB6 and CEND1 protein levels were correlated with one another in CRC patient tissues, and high expression of both of these proteins was associated with a higher risk of perineural invasion. CEND1+/GJB6+ status was also associated with poorer patient survival, highlighting both of these proteins as prognostic biomarkers in CRC patients.Conclusion: Elevated levels of CEND1 and GJB6 are independent predictors of poorer CRC patient prognosis.

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Downregulation of B3GNT6 Predicts Poor Outcome in Colorectal Cancer Patients

10.21203/rs.3.rs-127044/v1 ◽

2020 ◽

Author(s):

Chen Yang ◽

Changhao Huang ◽

Pengwei Zeng ◽

Heyuan Huang ◽

Zhikang Chen ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Cancer Patients ◽

Prognostic Marker ◽

Protein Level ◽

Mrna Level ◽

The Cancer Genome Atlas ◽

Cancer Tissue ◽

Poor Overall Survival ◽

Colorectal Cancer Patients

Abstract Background: B3GNT6 encodes the core 3 synthase in O-glycan biosynthesis. It is commonly expressed in the GI tract, while its clinical significance in colorectal cancer remains largely unknown.Methods: We gathered mRNA transcriptomic sequencing data from 3 Gene Expression Omnibus (GEO) datasets (GSE37182, GSE39582, GSE103512) and The Cancer Genome Atlas (TCGA) to compare the B3GNT6 mRNA level between colorectal cancer tissues and normal tissues and to evaluate its value as a prognostic marker. We further validated this in protein level using online database Human Protein Atlas and with immunohistochemical staining of B3GNT6 with our own cohort. Results: B3GNT6 expression was downregulated in colorectal cancer tissue compared with that in normal tissue in both mRNA and in protein level. Downregulation of B3GNT6 was associated with poor overall survival of colorectal cancer in GSE39582 and in TCGA database. Low B3GNT6 mRNA level was significantly associated with chromosome stable (CIN negative) and KRAS mutated group colorectal cancer patient. GSEA revealed that low B3GNT6 level in colorectal cancer is associated with upregulated proteasome activity.Conclusions: Downregulated B3GNT6 was correlated with poor overall survival of colorectal cancer patients. B3GNT6 could be used as a good prognostic marker in colorectal cancer.

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The Association of Aberrant Expression of FGF1 and mTOR-S6K1 in Colorectal Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.706838 ◽

2021 ◽

Vol 11 ◽

Author(s):

Tinghui Duan ◽

Diyuan Zhou ◽

Yizhou Yao ◽

Xinyu Shao

Keyword(s):

Colorectal Cancer ◽

Malignant Neoplasms ◽

Aberrant Expression ◽

Protein Levels ◽

And Migration ◽

High Level ◽

Proliferation And Migration

Colorectal cancer (CRC) is one of the most frequent malignant neoplasms worldwide, and the effect of treatments is limited. Fibroblast growth factor 1 (FGF1) has been involved in a wide variety of several malignant diseases and takes part in the tumorigenesis of CRC. However, the function and mechanism of FGF1 in CRC remains elusive. In this study, the results indicated that FGF1 is elevated in CRC tissues and linked with poor prognosis (P < 0.001). In subgroup analysis of FGF1 in CRC, regardless of any clinic-factors except gender, high level FGF1 expression was associated with markedly shorter survival (P < 0.05). In addition, the expression of p-S6K1 and FGF1 was not associated in normal tissue (P = 0.781), but their expression was closely related in tumor tissue (P = 0.010). The oncogenic role of FGF1 was determined using in vitro and in vivo functional assays. FGF1 depletion inhibited the proliferation and migration of CRC cells in vitro and vivo. FGF1 was also significantly correlated with mTOR-S6K1 pathway on the gene and protein levels (P < 0.05). In conclusion, FGF1 acts as a tumor activator in CRC, and against FGF1 may provide a new visual field on treating CRC, especially for mTORC1-targeted resistant patients.

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Assessment of Expression of Homeobox A5 in Endometrial Cancer on the mRNA and Protein Level

Current Pharmaceutical Biotechnology ◽

10.2174/1389201021666191227121627 ◽

2020 ◽

Vol 21 (7) ◽

pp. 635-641

Author(s):

Konrad Dziobek ◽

Marcin Oplawski ◽

Nikola Zmarzły ◽

Beniamin O. Gabarek ◽

Robert Kiełbasiński ◽

...

Keyword(s):

Endometrial Cancer ◽

Histopathological Examination ◽

Gynecological Cancer ◽

Mrna Level ◽

Developed Countries ◽

Cancer Tissue ◽

Tissue Samples ◽

Protein Levels ◽

Glandular Cells ◽

The Developed Countries

Background: Endometrial cancer is one of the most common gynecological cancer in the developed countries and occurs mainly in postmenopausal women. Angiogenesis is important for cancer formation as it provides nutrients for growing tumor mass. Most tumors do not show detectable Homeobox A5 (HOXA5 level), suggesting its potential role as a cancer suppressor. It was demonstrated that HOXA5 is involved in the progression of various types of cancer and the loss of its expression correlates with higher pathological grade and poorer outcome. Objective: The aim of the study was to evaluate HOXA5 expression at transcriptome and protein levels. Material and methods: The study enrolled 45 women diagnosed with endometrial cancer and 15 without neoplastic changes. The histopathological examination allowed us to divide cancer tissue samples according to the degree of histological differentiation: G1, 17; G2, 15; G3, 13. The expression of the HOXA5 protein was determined by immunohistochemistry. Microarray and RT-qPCR techniques were used to assess HOXA5 expression at the mRNA level. Results: The reaction to the HOXA5 protein was only visible in glandular cells in G1 endometrial cancer and was lower compared to the control. In grades 2 and 3, reactions were noted at the limit of the method’s sensitivity. In addition, reduced HOXA5 expression was observed at the transcriptome level. Conclusion: HOXA5 may become a potential complementary molecular marker, allowing early detection of neoplastic changes in the endometrium. It also seems that detection of HOXA5 at the mRNA and protein levels may be helpful in improving the accuracy of diagnosis and planning effective oncological therapy.

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Ectopic Expression of Hematopoietic SHIP1 in Human Colorectal Cancer

Biomedicines ◽

10.3390/biomedicines8070215 ◽

2020 ◽

Vol 8 (7) ◽

pp. 215

Author(s):

Matthias Schaks ◽

Kristina Allgoewer ◽

Nina Nelson ◽

Patrick Ehm ◽

Asmus Heumann ◽

...

Keyword(s):

Colorectal Cancer ◽

Dna Repair ◽

Microsatellite Instability ◽

Tissue Microarray ◽

Ectopic Expression ◽

Strong Relationship ◽

Cancer Tissue ◽

Beta Catenin ◽

Dna Repair Genes ◽

Repair Genes

Colorectal cancer (CRC) is a heterogeneous disease that results from the accumulation of mutations in colonic mucosa cells. A subclass of CRC is characterized by microsatellite instability, which is thought to occur mainly through inactivation of the DNA mismatch repair genes MLH1 and MSH2. The inositol 5-phosphatase SHIP1 is expressed predominantly in hematopoietic cells. In this study, the expression of SHIP1 in carcinomas and its putative correlation with clinicopathologic parameters, expression of DNA repair genes and microsatellite instability was investigated. By analyzing a multi-tumor tissue microarray, expression of SHIP1 was detected in 48 out of 72 cancer entities analyzed. The expression of SHIP1 protein of 145 kDa was confirmed by Western blot analysis in 7 out of 14 carcinoma cell lines. Analysis of a large colorectal cancer tissue microarray with 1009 specimens revealed SHIP1 expression in 62% of the samples analyzed. SHIP1 expression was inversely correlated with lymph node metastasis, vascular invasion and tumor grade, and it was positively associated with left-sided tumor localization. Interestingly, a strong relationship between the expression of SHIP1 and nuclear and membranous beta-catenin and the DNA repair genes MLH1 and MSH2 was observed.

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Adenine Inhibits the Invasive Potential of DLD-1 Human Colorectal Cancer Cell via the AMPK/FAK Axis

Pharmaceuticals ◽

10.3390/ph14090860 ◽

2021 ◽

Vol 14 (9) ◽

pp. 860

Author(s):

Chien-Wei Huang ◽

You-Cian Lin ◽

Chia-Hung Hung ◽

Han-Min Chen ◽

Jiun-Tsai Lin ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Potential ◽

Tissue Inhibitor Of Metalloproteinase ◽

Dependent Manner ◽

Protein Levels ◽

Src Signaling ◽

Invasion Potential ◽

Integrin Αv ◽

Human Colorectal Cancer Cell ◽

Mtor Phosphorylation

Tumor metastasis is a major cause of death of patients with colorectal cancer (CRC). Our previous findings show that adenine has antiproliferation activity against tumor cells. However, whether adenine reduces the invasiveness of DLD-1 and SW480 CRC cells has not been thoroughly explored. In this study, we aimed to explore the effects of adenine on the invasion potential of DLD-1 cells. Our findings showed that adenine at concentrations of ≤200 μM did not influence the cell viability of DLD-1 and SW480 CRC cells. By contrast, adenine reduced the migratory potential of the CRC cells. Moreover, it decreased the invasion capacity of the CRC cells in a dose-dependent manner. We further observed that adenine downregulated the protein levels of tissue plasminogen activator, matrix metalloproteinase-9, Snail, TWIST, and vimentin, but upregulated the tissue inhibitor of metalloproteinase-1 expression in DLD-1 cells. Adenine decreased the integrin αV level and reduced the activation of integrin-associated signaling components, including focal adhesion kinase (FAK), paxillin, and Src in DLD-1 cells. Further observations showed that adenine induced AMP-activated protein kinase (AMPK) activation and inhibited mTOR phosphorylation in DLD-1 cells. The knockdown of AMPK restored the reduced integrin αV level and FAK/paxillin/Src signaling inhibited by adenine in DLD-1 cells. Collectively, these findings reveal that adenine reduces the invasion potential of DLD-1 cells through the AMPK/integrin/FAK axis, suggesting that adenine may have anti-metastatic potential in CRC cells.

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