scholarly journals A Truncated NRIP1 Mutant Amplifies Microsatellite Instability of Colorectal Cancer by Regulating MSH2/MSH6 Expression, and Is a Prognostic Marker of Stage III Tumors

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4449
Author(s):  
Pascale Palassin ◽  
Marion Lapierre ◽  
Samuel Pyrdziak ◽  
Antoine Wagner ◽  
Régine Stehle ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Prognostic Marker ◽  
Dominant Negative ◽  
Interacting Protein ◽  
Chemotherapy Drugs ◽  
Protein Levels ◽  
Msh6 Gene ◽  
Dominant Negative Activity

Microsatellite instability (MSI) is related to the alteration of mismatch repair (MMR) genes and plays a key role in colorectal cancer (CRC) pathogenesis. We previously reported that the transcription factor Nuclear Receptor Interacting Protein 1 (NRIP1) is involved in sporadic intestinal tumorigenesis. The aim of this study was to decipher its role in MSI CRC. By using different mouse models and engineered cell lines, we demonstrated that NRIP1 increased MSH2 and MSH6 MMR gene transcription and mRNA/protein levels. In human CRC cells, NRIP1 expression was associated with decreased MSI and the hypermutator phenotype, and with resistance to chemotherapy drugs. Using a cohort of 194 CRC patients, we detected in 22% of the cases a MSI-induced frameshift mutation in the NRIP1 coding sequence. This genetic alteration generates a truncated protein with a dominant negative activity that increased human CRC cell proliferation and impaired the regulation of MSH2 and MSH6 gene expression. Moreover, the NRIP1 mutant correlated with a decreased overall survival of patients with advanced CRC, especially when MLH1-deficient. By decreasing the expression of MSH2 and MSH6 gene expression, the NRIP1 variant may amplify MLH1-dependent CRC progression and behave as a new prognostic marker of advanced MSI CRC.

scholarly journals The Effect of Compound Sophora on Fluorouracil and Oxaliplatin Resistance in Colorectal Cancer Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
WeiHua Yin ◽  
GuPing Zhong ◽  
HuiZhen Fan ◽  
HongMei Xia
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Cell Lines ◽  
Sw480 Cell ◽  
Gastric Cancer Cells ◽  
Glycoprotein P ◽  
Chemotherapy Drugs ◽  
Protein Levels ◽  
Enhanced Expression

Fluorouracil (5-FU) and oxaliplatin (L-OHP) are the most commonly used chemotherapy drugs for colorectal cancer, though resistance is common. Compound Sophora injection is a traditional Chinese medicine that can protect the liver against oxidation, improve immunity, and enhance sensitivity to chemotherapy; it may have an effect of reversing resistance in 5-FU- and L-OHP-resistant gastric cancer cells (5-FU/SW480 and L-OHP/SW480, respectively). A concentration gradient experiment was performed to identify a nontoxic dose of compound Sophora injection. 5-FU/SW480 and L-OHP/SW480 cells were treated with the nontoxic dose of compound radix Sophorae injection for 48 h, and changes in drug resistance to 5-FU and L-OHP were detected. Alterations in apoptosis and the cell cycle were assessed, as were the mRNA and protein levels of permeability glycoprotein (P-gp), annexin A1 (ANXA1), and ATP-binding cassette superfamily G member 2 (ABCG2). Flow cytometry showed a reduction in the number of cells in the G1 phase and an increase of cells in the S phase (P<0.05). mRNA and protein expression of P-gp and ABCG2 was significantly higher in 5-FU/SW480 and L-OHP/SW480 cell lines, and ANXA1 expression decreased significantly (P<0.05). Compound Sophora injection can reverse the drug resistance of 5-FU/SW480 and L-OHP/SW480 cell lines to 5-FU and L-OHP, respectively, possibly through a mechanism involving reduced expression of P-gp and ABCG2 but enhanced expression of ANXA1, which is the basis for the identification of clinical drug resistance in colorectal cancer.

scholarly journals Cross-platform Data Analysis Reveals a Generic Gene Expression Signature for Microsatellite Instability in Colorectal Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Anna Pačínková ◽  
Vlad Popovici
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Colon Cancer ◽  
Microsatellite Instability ◽  
Gene Expression Signature ◽  
Data Sets ◽  
Rna Seq ◽  
Cancer Data ◽  
Expression Signature ◽  
Endometrial Cancers

The dysfunction of the DNA mismatch repair system results in microsatellite instability (MSI). MSI plays a central role in the development of multiple human cancers. In colon cancer, despite being associated with resistance to 5-fluorouracil treatment, MSI is a favourable prognostic marker. In gastric and endometrial cancers, its prognostic value is not so well established. Nevertheless, recognising the MSI tumours may be important for predicting the therapeutic effect of immune checkpoint inhibitors. Several gene expression signatures were trained on microarray data sets to understand the regulatory mechanisms underlying microsatellite instability in colorectal cancer. A wealth of expression data already exists in the form of microarray data sets. However, the RNA-seq has become a routine for transcriptome analysis. A new MSI gene expression signature presented here is the first to be valid across two different platforms, microarrays and RNA-seq. In the case of colon cancer, its estimated performance was (i) AUC = 0.94, 95% CI = (0.90 – 0.97) on RNA-seq and (ii) AUC = 0.95, 95% CI = (0.92 – 0.97) on microarray. The 25-gene expression signature was also validated in two independent microarray colon cancer data sets. Despite being derived from colorectal cancer, the signature maintained good performance on RNA-seq and microarray gastric cancer data sets (AUC = 0.90, 95% CI = (0.85 – 0.94) and AUC = 0.83, 95% CI = (0.69 – 0.97), respectively). Furthermore, this classifier retained high concordance even when classifying RNA-seq endometrial cancers (AUC = 0.71, 95% CI = (0.62 – 0.81). These results indicate that the new signature was able to remove the platform-specific differences while preserving the underlying biological differences between MSI/MSS phenotypes in colon cancer samples.

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

2020 ◽  
Vol 21 (11) ◽  
pp. 3947
Author(s):  
Dorota Zurawa-Janicka ◽  
Jarek Kobiela ◽  
Tomasz Slebioda ◽  
Rafal Peksa ◽  
Marcin Stanislawowski ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Survival Data ◽  
Patient Survival ◽  
Mrna Level ◽  
Metastatic Potential ◽  
Colorectal Carcinogenesis ◽  
Cancer Tissue ◽  
Protein Levels ◽  
High Level

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.

MET overexpression as a hallmark of the epithelial-mesenchymal transition (EMT) phenotype in colorectal cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3529-3529 ◽  
Author(s):  
Kanwal Pratap Singh Raghav ◽  
Hesham M. Amin ◽  
Wenting Wang ◽  
Ganiraju C. Manyam ◽  
Bradley Broom ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Overall Survival ◽  
Protein Expression ◽  
Protein Gene ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Gene Signatures ◽  
Protein Levels ◽  
Emt Markers

3529 Background: Epithelial-mesenchymal transition (EMT) has been identified as a dominant molecular subtype of colorectal cancer (CRC). This EMT phenotype as recognized by complex gene signatures is prognostic and associated with chemoresistance, but a biomarker for EMT suitable for clinical utilization has not yet been validated. The purpose of this study was to compare MET protein expression with protein/gene expression of EMT markers and to evaluate its impact on overall survival (OS). Methods: We performed an exploratory analysis of 139 untreated primary CRC samples using data from The Cancer Genome Atlas. Protein and gene expressions were measured using reverse-phase protein array (RPPA) and RNA-sequencing, respectively. MET high/overexpressed group was defined by protein level in the highest quartile. Mann-Whitney U-test and Spearman rank correlation was used to determine association between MET protein expression and protein/gene expression of EMT markers and EMT gene signature scores. Regression tree method and Kaplan-Meier estimates were used to assess overall survival (OS). Results: The MET protein distribution is right skewed, demonstrating a unique population of MET high expressing tumors (P < 0.01). Colon tumors had higher MET protein levels compared to rectal tumors (P < 0.01). MET overexpression was associated with decreased OS (HR 2.92; 95% CI: 1.45 - 5.92). MET protein expression correlated strongly with protein expressions of SLUG (transcription factor for EMT) (r = 0.6) and ERCC1 (a marker for oxaliplatin chemo-resistance) (r = 0.6) (P < 0.01). Higher MET protein levels were associated with higher gene expression of 28 EMT markers including AXL, VIM, ZEB1, ZEB2, FGF1, TGFB1I1 and MMP11 (P < 0.05). Higher MET protein levels were also associated with higher gene scores derived from three published EMT gene signatures (P < 0.05). MET protein expression did not correlate with MET gene expression (r = 0.16). Conclusions: Increased MET protein expression strongly correlates with a molecular EMT phenotype and poor survival in patients with CRC. MET protein expression may be used as a surrogate biomarker to represent and select for this unique molecular subset of CRC driven by EMT biology.

scholarly journals Tissue-Specific Transgenic Knockdown of Fos-Related Antigen 2 (Fra-2) Expression Mediated by Dominant Negative Fra-2

2001 ◽  
Vol 21 (11) ◽  
pp. 3704-3713 ◽  
Author(s):  
Martin Smith ◽  
Zoe Burke ◽  
Ann Humphries ◽  
Tim Wells ◽  
David Klein ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pineal Gland ◽  
Target Genes ◽  
Second Messengers ◽  
Regulatory Region ◽  
Dominant Negative ◽  
Transgenic Rat ◽  
Iodothyronine Deiodinase ◽  
Protein Levels ◽  
Genes Encoding

ABSTRACT Fos-related antigen 2 (Fra-2) is a member of the Fos family of immediate-early genes, most of which are rapidly induced by second messengers. All members of this family act by binding to AP-1 sites as heterodimeric complexes with other proteins. However, each appears to have a distinct role. The role and biology of Fra-2 are less well understood than those of its relatives c-Fos, Fra-1, and FosB; moreover, Fra-2 target genes remain largely unknown, as does the basis of its selective effects on transcriptional activity. To pursue these issues, we created a transgenic rat line (NATDNF2) in which a dominant negative fra-2 (DNF2) gene is strongly expressed in the pineal gland; tissue selectivity was achieved by putting the DNF2 gene under the control of the rat arylalkylamineN-acetyltransferase (AANAT) regulatory region, which targets gene expression to a very restricted set of tissues (pineal gland ≫ retina). Expression of AANAT is normally turned on after the onset of darkness in the rat; as a result, pineal DNF2 expression occurs only at night. This was associated with marked suppression of the nocturnal increase in fra-2 mRNA and protein levels, indicating that DNF2 expression inhibits downstream effects of Fra-2, including the maintenance of high levels offra-2 gene expression. Analysis of 1,190 genes in the NATDNF2 pineal gland, including the AANAT gene, identified two whose expression is strongly linked to fra-2 expression: the genes encoding type II iodothyronine deiodinase and nectadrin (CD24).

scholarly journals Serum Cathepsin H as a Potential Prognostic Marker in Patients with Colorectal Cancer

2004 ◽  
Vol 19 (4) ◽  
pp. 289-294 ◽  
Author(s):  
A. Schweiger ◽  
I.J. Christensen ◽  
H.J. Nielsen ◽  
S. Sørensen ◽  
N. Brünner ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Marker ◽  
Malignant Disease ◽  
Prognostic Information ◽  
Protein Levels ◽  
Risk Of Death ◽  
Weak Association ◽  
Cathepsin H ◽  
Significant Difference ◽  
Lysosomal Cysteine Protease

Cathepsin H is a lysosomal cysteine protease that may participate in tumor progression. In order to evaluate its potential as a prognostic marker, its protein levels were measured by ELISA in preoperative sera from 324 patients with colorectal cancer. The level of cathepsin H was significantly increased in patient sera, the median level was 8.4 ng/mL versus 2.1 ng/mL in 90 healthy blood donors (p<0.0001). A weak association of cathepsin H levels was found with patient age (p=0.02) but not with Dukes’ stage, sex, or the level of carcinoembryonic antigen (CEA). In survival analysis a significant difference was found between the group of patients with low cathepsin H (first tertile) who had a poor prognosis and the remaining patients (p=0.03). The risk of patients was further stratified when cathepsin H levels were combined with CEA. Patients with high CEA and low cathepsin H had the highest risk of death with a hazard ratio of 2.72 (95% CI 1.73–4.28), p<.0001. Our results show that the prognostic information of cathepsin H differs from that of the related cathepsins B and L and suggest different roles during the progression of malignant disease.

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