Clinicopathologic Significance of CXCL12 and CXCR4 Expressions in Patients with Colorectal Cancer

Background. Colorectal cancer (CRC) is both a global and national burden, being the third most common malignancy in men and the second in women, worldwide. The prognosis of CRC is affected by various factors like the histological grade, angiolymphatic invasion, and distant metastases. Metastasis is an intricate process; one of the possible mechanisms is through the interaction of the chemokines CXCL12 and CXCR4. This study aims to reveal the expression patterns of CXCL12 and CXCR4 in CRC. Methods. The quantitative expressions of CXCL12 and CXCR4 messenger RNA (mRNA) were evaluated in 32 patients with adenocarcinoma-type CRC. Real-time polymerase chain reaction (qRT-PCR) was performed on formalin-fixed tissues. CXCL12 and CXCR4’s expressions, clinicopathologic features, and the treatment response to the CRC were analysed. Results. All tumour tissues showed higher levels of both chemokines compared to normal colonic tissue. The expression of CXCL12 mRNA was higher in rectal location (p=0.04) with a tendency to be higher in later stages (p=0.15), while the expression of CXCR4 was lower in tumours with a lymphatic invasion (p=0.02), compared to their counterparts. There was no difference in the expression of CXCL12 and CXCR4 according to the patients’ ages, gender, tumour differentiation, or response to chemotherapy. Conclusion. Our study demonstrated that the mRNA expression of CXCL12 was significantly correlated with rectal location. CXCR4 mRNA expression was inversely correlated in tumours with a lymphatic invasion.

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RNAScope in situ Hybridization as a Novel Technique for the Assessment of c-KIT mRNA Expression in Canine Mast Cell Tumor

Frontiers in Veterinary Science ◽

10.3389/fvets.2021.591961 ◽

2021 ◽

Vol 8 ◽

Author(s):

Davide De Biase ◽

Francesco Prisco ◽

Giuseppe Piegari ◽

Arianna Ilsami ◽

Ilaria d'Aquino ◽

...

Keyword(s):

Mast Cell ◽

Mrna Expression ◽

Messenger Rna ◽

Histological Grade ◽

Expression Patterns ◽

Cell Tumor ◽

Specific Method ◽

Mast Cell Tumor ◽

Canine Mast Cell Tumor

RNA is considered as an indicator of the dynamic genetic expression changes in a cell. RNAScope is a commercially available in situ hybridization assay for the detection of RNA in formalin-fixed paraffin-embedded tissue. In this work, we describe the use of RNAScope as a sensitive and specific method for the evaluation of c-KIT messenger RNA (mRNA) in canine mast cell tumor. We investigated the expression of c-KIT mRNA with RNAscope in 60 canine mast cell tumors (MCTs), comparing it with the histological grade and KIT immunohistochemical expression patterns. Our results showed an overall good expression of c-KIT mRNA in neoplastic cells if compared with control probes. We also observed a statistically significant correlation between histological grade and c-KIT mRNA expression. No correlations were found between KIT protein immunohistochemical distribution pattern and c-KIT mRNA expression or histological grade. Our results provide a reference basis to better understand c-KIT mRNA expression in canine MCTs and strongly encourage further studies that may provide useful information about its potential and significant role as a prognostic and predictive biological marker for canine MCTs clinical outcome.

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A Systems Biology Approach to Characterize Biomarkers for Blood Stasis Syndrome of Unstable Angina Patients by Integrating MicroRNA and Messenger RNA Expression Profiling

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/510208 ◽

2013 ◽

Vol 2013 ◽

pp. 1-21 ◽

Cited By ~ 5

Author(s):

Jie Wang ◽

Gui Yu

Keyword(s):

Systems Biology ◽

Unstable Angina ◽

Mrna Expression ◽

Messenger Rna ◽

Expression Patterns ◽

Blood Stasis ◽

Differentially Expressed ◽

Blood Stasis Syndrome ◽

Major Type ◽

Healthy Controls

Blood stasis syndrome (BSS) has been considered to be the major type of syndromes in unstable angina (UA) patients. The aim of this study was to find the systems biology-based microRNA (miRNA) and mRNA expression biomarkers for BSS of UA. We identified 1081 mRNAs and 25 miRNAs differentially expressed between BSS of UA patients and healthy controls by microarrays. We used DAVID, miRTrail, and the protein-protein interactions method to explore the related pathways and networks of differentially expressed miRNAs and mRNAs. By combining the results of pathways and networks, we found that the upregulation of miR-146b-5p may induce the downregulation of CALR to attenuate inflammation and the upregulation of miR-199a-5p may induce the downregulation of TP53 to inhibit apoptosis in BSS of UA patients. The expression patterns of miR-146b-5p, miR-199a-5p, CALR, and TP53 were confirmed by qRT-PCR in an independent validation cohort including BBS of UA patients, non-BBS of UA patients, and healthy controls. miR-146b-5p, miR-199a-5p, CALR, and TP53 could be significant biomarkers of BSS of UA patients. The systems biology-based miRNA and mRNA expression biomarkers for the BSS of UA may be helpful for the further stratification of UA patients when deciding on interventions or clinical trials.

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Correlation of messenger RNA expression patterns of ERCC1, TS, EGFR, and VEGFR2 with KRAS and BRAF mutational status in advanced colorectal cancer: Implications for targeted therapies.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.383 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 383-383

Author(s):

Martin K. H. Maus ◽

Craig Stephens ◽

Stephanie H. Astrow ◽

Peter Philipp Grimminger ◽

Dongyun Yang ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Mrna Expression ◽

Advanced Colorectal Cancer ◽

Expression Patterns ◽

Mrna Levels ◽

Expression Levels ◽

Mutational Status ◽

Mrna Expression Levels ◽

Gene Expression Levels

383 Background: Gene expression levels of ERCC1, TS, EGFR and VEGFR2 may have predictive value for the personalized use of standard chemotherapeutics as well as agents targeting the EGFR and VEGF pathways and the efficacy of EGFR directed monoclonal antibodies like panitumumab and cetuximab has been confirmed to be dependent on wt KRAS and wt BRAF in patients with advanced colorectal cancer. We investigated the correlations between KRAS/BRAF mutational status and the mRNA expression levels of these genes. Methods: Formalin-fixed paraffin-embedded tumor specimens from 600 patients with advanced colorectal adenocarcinoma were microdissected and DNA and RNA was extracted. Specifically designed primers and probes were used to detect 7 different base substitutions in codon 12 and 13 of KRAS, V600E mutations in BRAF and the expression levels of ERCC1, TS, EGFR and VEGFR2 by RT-PCR. Results: Mt KRAS tumors had significantly lower TS and EGFR gene expression levels compared with wt KRAS (p<0,001), whereas mt BRAF tumors showed significantly increased TS and EGFR mRNA levels compared to wt BRAF (p<0,001). Mt BRAF tumors showed significantly higher mRNA levels than mt KRAS tumors (p<0,001). ERCC1 and VEGFR2 mRNA levels were significantly down-regulated in mt KRAS specimen (p<0,001), but showed no significant correlation with BRAF mutational status. Conclusions: KRAS and BRAF mutations are associated with opposite mRNA expression levels for TS and EGFR. Recently, resistance to BRAF inhibition in mt BRAF colorectal tumors has been shown in preclinical models to be associated with up-regulation of EGFR. Our data suggests that BRAF mutants are associated with high EGFR levels at the time of diagnosis, and not necessarily part of an acquired mechanism of resistance. Significantly lower mRNA expression levels of VEGFR2 in mt KRAS tumors may explain lower response to angiogenesis inhibition seen in the TML study.

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An Assessment of Database-Validated microRNA Target Genes in Normal Colonic Mucosa: Implications for Pathway Analysis

Cancer Informatics ◽

10.1177/1176935117716405 ◽

2017 ◽

Vol 16 ◽

pp. 117693511771640 ◽

Cited By ~ 7

Author(s):

Martha L Slattery ◽

Jennifer S Herrick ◽

John R Stevens ◽

Roger K Wolff ◽

Lila E Mullany

Keyword(s):

Colorectal Cancer ◽

Mrna Expression ◽

Messenger Rna ◽

Colonic Mucosa ◽

Target Gene ◽

Target Genes ◽

Multiple Comparisons ◽

Normal Colonic Mucosa ◽

Seed Region ◽

Discovery Phase

Background: Determination of functional pathways regulated by microRNAs (miRNAs), while an essential step in developing therapeutics, is challenging. Some miRNAs have been studied extensively; others have limited information. In this study, we focus on 254 miRNAs previously identified as being associated with colorectal cancer and their database-identified validated target genes. Methods: We use RNA-Seq data to evaluate messenger RNA (mRNA) expression for 157 subjects who also had miRNA expression data. In the replication phase of the study, we replicated associations between 254 miRNAs associated with colorectal cancer and mRNA expression of database-identified target genes in normal colonic mucosa. In the discovery phase of the study, we evaluated expression of 18 miRNAs (those with 20 or fewer database-identified target genes along with miR-21-5p, miR-215-5p, and miR-124-3p which have more than 500 database-identified target genes) with expression of 17 434 mRNAs to identify new targets in colon tissue. Seed region matches between miRNA and newly identified targeted mRNA were used to help determine direct miRNA-mRNA associations. Results: From the replication of the 121 miRNAs that had at least 1 database-identified target gene using mRNA expression methods, 97.9% were expressed in normal colonic mucosa. Of the 8622 target miRNA-mRNA associations identified in the database, 2658 (30.2%) were associated with gene expression in normal colonic mucosa after adjusting for multiple comparisons. Of the 133 miRNAs with database-identified target genes by non-mRNA expression methods, 97.2% were expressed in normal colonic mucosa. After adjustment for multiple comparisons, 2416 miRNA-mRNA associations remained significant (19.8%). Results from the discovery phase based on detailed examination of 18 miRNAs identified more than 80 000 miRNA-mRNA associations that had not previously linked to the miRNA. Of these miRNA-mRNA associations, 15.6% and 14.8% had seed matches for CRCh38 and CRCh37, respectively. Conclusions: Our data suggest that miRNA target gene databases are incomplete; pathways derived from these databases have similar deficiencies. Although we know a lot about several miRNAs, little is known about other miRNAs in terms of their targeted genes. We encourage others to use their data to continue to further identify and validate miRNA-targeted genes.

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Expression of MMP28 in bladder cancer tissue microarray and its clinical significance

10.21203/rs.2.12805/v1 ◽

2019 ◽

Author(s):

Wang Heng ◽

Wu Junxiu ◽

Chen Xinpeng ◽

Zhang Qi ◽

Zhao Tingxiao ◽

...

Keyword(s):

Bladder Cancer ◽

Disease Progression ◽

Clinical Significance ◽

Histological Grade ◽

Expression Patterns ◽

Lymphatic Invasion ◽

Cancer Tissue ◽

Cancer Specific Survival ◽

Stage Disease ◽

Bladder Cancer Tissue

Abstract Background: The aim of this study was to explore the expression pattern and prognostic value of MMP-28 for bladder cancer and analyze its relationship with the clinicopathological features of human bladder cancer. Methods: Immunohistochemical staining for MMP28 was performed in 491 archived radical bladder cancer resection and 80 normal specimens. The immunoreactivity of these proteins was correlated to evaluate their clinical significance as prognostic factors. Results: Protein level of MMP-28 was up-regulated in bladder cancer compared with adjacent non-tumor tissues. The increased expression of MMP-28 was significantly associated with high histological grade, lymph node metastasis, lymphatic invasion and distant metastasis (P<0.05). High expression of MMP-28 was also associated with greater risk of disease progression and decreased chance of cancer-specific survival. Further analysis suggested that MMP-28 was related with decreased overall survival. Conclusions: MMP-28 could be used as an effective marker for tumor diagnosis and predict tumor progression in bladder cancer. The expression patterns of MMP-28 interaction correlated well with the pathological stage, disease progression and tumor-specific survival. The finding may help identify more biologically aggressive carcinomas which could aid in patients who benefit from more intensive adjuvant therapy.

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Low Serum Interleukin-13 Levels Correlate with Poorer Prognoses for Colorectal Cancer Patients

International Surgery ◽

10.9738/intsurg-d-13-00259.1 ◽

2014 ◽

Vol 99 (3) ◽

pp. 223-229 ◽

Cited By ~ 6

Author(s):

Susumu Saigusa ◽

Koji Tanaka ◽

Yasuhiro Inoue ◽

Yuji Toiyama ◽

Yoshinaga Okugawa ◽

...

Keyword(s):

Colorectal Cancer ◽

Poor Prognosis ◽

Predictive Marker ◽

Distant Metastases ◽

Lymphatic Invasion ◽

Enzyme Linked Immunosorbent Assay ◽

Interleukin 13 ◽

Preoperative Serum ◽

Colorectal Cancer Patients ◽

Low Serum

Abstract Interleukin-13 (IL-13) is an immunosuppressive cytokine produced by several immune cells and cancer cells. The aim of this retrospective study was to determine if serum IL-13 levels have an association with clinical outcome in patients with colorectal cancer. A total of 241 patients with colorectal cancer were enrolled in the present study. Preoperative serum IL-13 concentrations were measured by enzyme-linked immunosorbent assay. We analyzed the association of serum IL-13 levels with clinicopathological variables. Patients with lymph node metastasis, lymphatic invasion, vascular invasion, distant metastases or advanced stage of disease had significantly lower serum IL-13 levels. Low serum IL-13 was significantly associated with both poor recurrence-free and overall survival. Multivariate analysis showed that low IL-13 levels were an independent predictive marker for poor prognosis. In conclusion, our data suggest that low serum IL-13 levels may be a useful predictive marker for poor prognosis in colorectal cancer.

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Altered Expression of MLH1, MSH2, and MSH6 in Predisposition to Hereditary Nonpolyposis Colorectal Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2003.03.181 ◽

2003 ◽

Vol 21 (19) ◽

pp. 3629-3637 ◽

Cited By ~ 65

Author(s):

Elise Renkonen ◽

Yange Zhang ◽

Hannes Lohi ◽

Reijo Salovaara ◽

Wael M. Abdel-Rahman ◽

...

Keyword(s):

Colorectal Cancer ◽

Protein Expression ◽

Mrna Expression ◽

Messenger Rna ◽

Hereditary Nonpolyposis Colorectal Cancer ◽

Population Based ◽

Altered Expression ◽

Dna Mismatch ◽

Mmr Genes ◽

Hereditary Nonpolyposis

Purpose: A considerable fraction (30% to 70%) of families with verified or putative hereditary nonpolyposis colorectal cancer fails to show mutations in DNA mismatch repair (MMR) genes. Our purpose was to address the genetic etiology of such families. Materials and Methods: We scrutinized a population-based cohort of 26 families from Finland that had screened mutation-negative by previous techniques. Blood was tested for allelic messenger RNA (mRNA) expression of MLH1, MSH2, and MSH6 by single nucleotide primer extension (SNuPE), and tumor tissue for MMR protein expression by immunohistochemistry (IHC) as well as for microsatellite instability (MSI). Full-length cDNAs of genes implicated by SNuPE or IHC were cloned and sequenced. Results: Unbalanced mRNA expression of MLH1 alleles was evident in two families. An inherited nonsense mutation was subsequently identified in one family, and complete silencing of the mutated allele was identified in the other family. Extinct protein expression by IHC implicated MLH1 in these two and in four other families, MSH2 in four families, and MSH6 in one family. Although no unequivocal genomic mutations were detected in the latter families, haplotype and other findings provided support for heritable defects. With one exception, all tumors with IHC alterations showed MSI, in contrast to the remaining families, which showed neither IHC changes nor MSI. Conclusion: Our expression-based strategy stratified the present “mutation-negative” cohort into two discrete categories: families linked to the major MMR genes MLH1, MSH2, and MSH6 (11 [42%] of 26) and those likely to be associated with other, as yet unknown susceptibility genes (15 [58%] of 26).

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Preoperative evaluation of heat shock protein 47 expression to identify patients with colorectal cancer with lymph node metastasis and poor prognosis.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.546 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 546-546

Author(s):

Koichiro Mori ◽

Yuji Toiyama ◽

Yoshinaga Okugawa ◽

Takashi Ichikawa ◽

Yuka Nagano ◽

...

Keyword(s):

Colorectal Cancer ◽

Lymph Node ◽

Heat Shock ◽

Heat Shock Protein ◽

Mrna Expression ◽

Messenger Rna ◽

Poor Prognosis ◽

University Hospital ◽

Heat Shock Protein 47 ◽

Node Metastasis

546 Background: Accumulating evidences reveal that overexpression of Heat shock protein 47 (HSP47) increase cancer progression, and that HSP47 expression in the tumor-associated stroma serve as diagnostic marker in various cancers. In addition, we recently performed immunohistochemistry to evaluate HSP47 expression in surgical colorectal cancer (CRC) specimens, and showed that the count of HSP47 positive spindle cell in cancer stroma was significantly associated with lymph node (LN) metastasis, early recurrence and poor prognosis in CRC patients. Thus, evaluating HSP47 expression in CRCs preoperatively may be valuable for planning the treatment of patients with CRC. In this study, we quantified the messenger RNA(mRNA) expression of HSP47 in CRCs by using preoperative biopsy samples, and analyzed the association between HSP47 mRNA expression and clinico-pathological factors including prognosis in patients with CRC. Methods: A total of 139 CRC samples, which were taken by biopsy before surgery at Mie University Hospital from 2000 to 2005, were enrolled. HSP47 gene expression was determined by quantitative real-time reverse transcription–PCR using Power SYBR Green PCR methods. Results: All CRC patients were classified according to the tumor-node-metastasis (TNM) classification system as follows: stage I (n = 33); stage II (n = 44); stage III (n = 33), and stage IV (n = 29). High HSP47 expression in CRC was significantly associated with higher T stage (p = 0.0163), LN metastasis (p = 0.0186), vessel invasion (p = 0.0328) and higher TNM staging (p = 0.0115). Kaplan-Meier analysis showed that patients with high HSP47 expression had significantly poorer overall survival (OS) than those with low (p = 0.0003). Furthermore, multivariate analyses revealed that HSP47 expression was an independent predictive marker for LN metastasis and poor OS in CRC patients, respectively (LN metastasis; OR; 2.3946, p = 0.0249, OS; HR; 2.7407, p = 0.00224). Conclusions: In conclusion, quantification of HSP47 expression using biopsy samples can identify the CRC patients who may suffer from LN metastasis and poor prognosis, preoperatively.

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Thymidylate synthase and MDR1 mRNA levels predict response to chemotherapy with S-1 in metastatic colorectal cancer

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.13107 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 13107-13107

Author(s):

I. Fujita ◽

K. Hayashi ◽

K. Uchida ◽

H. Kuramochi ◽

K. Kudo ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Mrna Expression ◽

Thymidylate Synthase ◽

Response Rate ◽

Expression Level ◽

Response To Chemotherapy ◽

Mdr1 Mrna ◽

Mdr1 Expression

13107 Background: To test the hypotheses of whether the relative mRNA expression of the thymidylate synthase (TS) gene and multidrug resistance 1 (MDR1) gene are associated with response to chemotherapy with S-1 in metastatic colorectal cancer. Methods: Eighteen patients with progressive stage IV CRC were treated with S-1 twice daily (BSA = 1.5 m2, 60 mg/day) for 28 days, followed by a 2-week period rest. cDNA was derived from frozen tumor specimens to determine TS and MDR1 mRNA expression relative to the internal reference gene GAPDH using fluorescence-based, real-time reverse transcriptase polymerase chain reaction (Taqman) system. Results: The median TS gene expression level from 18 CRC tumors was 0.94 × 10(−3) (minimum expression, 0.15 × 10(−3); maximum expression, 8.0 × 10(−3)), and the median MDR1 gene expression level was 7.75 × 10(−3) (minimum, 0.83; maximum, 41.5 × 10(−3)). The gene expression cutoff values for chemotherapy nonresponse were 1.0 x 10(-3) for TS and 10.0 × 10(−3) for MDR1. The response rate for patients with TS < or = 1.0 × 10(−3) (10 of 18 patients) was 60% (6/10), compared with 0% (0/8) for patients with TS greater than 1.0 × 10(−3) (P = 0.013). Patients with MDR1 expression < or = 10.0 × 10(−3) (13 of 18 patients) had a response rate of 46% (6/13), compared with 0% (0/5) for patients with MDR1 expression greater than 10.0 × 10(−3) (P = 0.11). Regarding the combination of TS and MDR1 Expression, low TS and MDR1 expression levels were detected in 8 (44%) of the patients, and 10 patients (56%) had a high TS and/or MDR1 expression level. The response rate was 75% (6/8) for the low TS and MDR1 expressors and 0% (0/10) for the high TS and/or MDR1 expressors (P = 0.001). Conclusions: These data suggest that intratumoral TS and MDR1 mRNA expression levels are independent predictive markers of response to S-1 chemotherapy in metastatic colorectal cancer. No significant financial relationships to disclose.

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An Integrated Bioinformatic Analysis of the S100 Gene Family for the Prognosis of Colorectal Cancer

BioMed Research International ◽

10.1155/2020/4746929 ◽

2020 ◽

Vol 2020 ◽

pp. 1-15

Author(s):

Meng-Lu Zeng ◽

Xian-Jin Zhu ◽

Jin Liu ◽

Peng-Chong Shi ◽

Yan-Li Kang ◽

...

Keyword(s):

Colorectal Cancer ◽

Mrna Expression ◽

Calcium Binding ◽

Expression Patterns ◽

Disease Free Survival ◽

S100 Proteins ◽

S100 Family ◽

Expression Levels ◽

Ppi Networks ◽

Mrna Expression Levels

Background. S100 family genes exclusively encode at least 20 calcium-binding proteins, which possess a wide spectrum of intracellular and extracellular functions in vertebrates. Multiple lines of evidences suggest that dysregulated S100 proteins are associated with human malignancies including colorectal cancer (CRC). However, the diverse expression patterns and prognostic roles of distinct S100 genes in CRC have not been fully elucidated. Methods. In the current study, we analyzed the mRNA expression levels of S100 family genes and proteins and their associations with the survival of CRC patients using the Oncomine analysis and GEPIA databases. Expressions and mutations of S100 family genes were analyzed using the cBioPortal, and protein-protein interaction (PPI) networks of S100 proteins and their mutation-related coexpressed genes were analyzed using STRING and Cytoscape. Results. We observed that the mRNA expression levels of S100A2, S100A3, S100A9, S100A11, and S100P were higher and the level of S100B was lower in CRC tissues than those in normal colon mucosa. A high S100A10 levels was associated with advanced-stage CRC. Results from GEPIA database showed that highly expressed S100A1 was correlated with worse overall survival (OS) and disease-free survival (DFS) and that overexpressions of S100A2 and S100A11 were associated with poor DFS of CRC, indicating that S100A1, S100A2, and S100A11 are potential prognostic markers. Unexpectedly, most of S100 family genes showed no significant prognostic values in CRC. Conclusions. Our findings, though still need to be ascertained, offer novel insights into the prognostic implications of the S100 family in CRC and will inspire more clinical trials to explore potential S100-targeted inhibitors for the treatment of CRC.

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