Combined analysis of chromosomal instabilities and gene expression for colon cancer progression inference

Background Genetic and epigenetic alterations in colorectal cancer are numerous. However, it is difficult to judge whether such changes are primary or secondary to the appearance and progression of tumors. Therefore, the aim of the present study was to identify altered DNA regions with significant covariation to transcription alterations along colon cancer progression. Methods Tumor and normal colon tissue were obtained at primary operations from 24 patients selected by chance. DNA, RNA and microRNAs were extracted from the same biopsy material in all individuals and analyzed by oligo-nucleotide array-based comparative genomic hybridization (CGH), mRNA- and microRNA oligo-arrays. Statistical analyses were performed to assess statistical interactions (correlations, co-variations) between DNA copy number changes and significant alterations in gene and microRNA expression using appropriate parametric and non-parametric statistics. Results Main DNA alterations were located on chromosome 7, 8, 13 and 20. Tumor DNA copy number gain increased with tumor progression, significantly related to increased gene expression. Copy number loss was not observed in Dukes A tumors. There was no significant relationship between expressed genes and tumor progression across Dukes A–D tumors; and no relationship between tumor stage and the number of microRNAs with significantly altered expression. Interaction analyses identified overall 41 genes, which discriminated early Dukes A plus B tumors from late Dukes C plus D tumor; 28 of these genes remained with correlations between genomic and transcriptomic alterations in Dukes C plus D tumors and 17 in Dukes D. One microRNA (microR-663) showed interactions with DNA alterations in all Dukes A-D tumors. Conclusions Our modeling confirms that colon cancer progression is related to genomic instability and altered gene expression. However, early invasive tumor growth seemed rather related to transcriptomic alterations, where changes in microRNA may be an early phenomenon, and less to DNA copy number changes.

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Peroxireduxin-4 is Over-Expressed in Colon Cancer and its Down-Regulation Leads to Apoptosis

Cancer Growth and Metastasis ◽

10.4137/cgm.s6584 ◽

2011 ◽

Vol 4 ◽

pp. CGM.S6584 ◽

Cited By ~ 1

Author(s):

Sandra M. Leydold ◽

Michael Seewald ◽

Christian Stratowa ◽

Klaus Kaserer ◽

Wolfgang Sommergruber ◽

...

Keyword(s):

Gene Expression ◽

Colon Cancer ◽

Cancer Progression ◽

Expression Patterns ◽

Morphological Characteristics ◽

Normal Colon ◽

Primary Tumors ◽

Colon Cancer Progression ◽

Primary Colon ◽

Insight Into

The objective of this study was to gain insight into the biological basis of colon cancer progression by characterizing gene expression differences between normal colon epithelium, corresponding colorectal primary tumors and metastases. We found a close similarity in gene expression patterns between primary tumors and metastases, indicating a correlation between gene expression and morphological characteristics. PRDX4 was identified as highly expressed both in primary colon tumors and metastases, and selected for further characterization. Our study revealed that “Prdx4” (PrxIV, AOE372) shows functional similarities to other Prx family members by negatively affecting apoptosis induction in tumor cells. In addition, our study links Prdx4 with Hif-1α, a key regulatory factor of angiogenesis. Targeting Prdx4 may be an attractive approach in cancer therapy, as its inhibition is expected to lead to induction of apoptosis and blockage of Hif-1α-mediated tumor angiogenesis.

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RBMS1 suppresses colon cancer metastasis through targeted stabilization of its mRNA regulon

10.1101/2020.01.22.916205 ◽

2020 ◽

Author(s):

Johnny Yu ◽

Bruce Culbertson ◽

Hosseinali Asgharian ◽

Albertas Navickas ◽

Lisa Fish ◽

...

Keyword(s):

Gene Expression ◽

Colon Cancer ◽

Cancer Progression ◽

Cancer Metastasis ◽

Rna Binding ◽

Rna Stability ◽

Transcriptional Regulator ◽

Clinical Samples ◽

Colon Cancer Metastasis ◽

Colon Cancer Progression

AbstractBroad dysregulation of gene expression control is a hallmark of cancer progression. Identifying the underlying master regulators that drive pathological gene expression is a key challenge in precision oncology. Here, we have developed a network analytical framework, named PRADA, that identifies oncogenic RNA-binding proteins through the systematic detection of coordinated changes in their target regulons. Application of this approach to data collected from clinical samples, patient-derived xenografts, and cell line models of colon cancer metastasis revealed the RNA-binding protein RBMS1 as a suppressor of colon cancer progression. We observed that silencing RBMS1 results in increased metastatic capacity in xenograft mouse models, and that restoring its expression blunts metastatic liver colonization. We have found that RBMS1 functions as a post-transcriptional regulator of RNA stability by directly binding and stabilizing ~80 target mRNAs. Measurements in more than 180 clinical samples as well as survival analyses in publicly available datasets, have shown that RBMS1 silencing and the subsequent downregulation of its targets are strongly associated with disease progression and poor survival in colon cancer patients. Together, our findings establish a role for RBMS1 as a previously unknown regulator of RNA stability and as a suppressor of colon cancer metastasis with clinical utility for risk stratification of patients.SignificanceBy applying a new analytical approach to transcriptomic data from clinical samples and models of colon cancer progression, we have uncovered RBMS1 as a suppressor of metastasis and as a post-transcriptional regulator of RNA stability. Notably, RBMS1 silencing and downregulation of its targets are negatively associated with patient survival.

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Ubiquitin Hybrid Protein Gene Expression During Human Colon Cancer Progression

Archives of Surgery ◽

10.1001/archsurg.1991.01410280064009 ◽

1991 ◽

Vol 126 (4) ◽

pp. 462 ◽

Cited By ~ 7

Author(s):

Ken-ichi Mafune

Keyword(s):

Gene Expression ◽

Colon Cancer ◽

Cancer Progression ◽

Protein Gene ◽

Human Colon ◽

Hybrid Protein ◽

Human Colon Cancer ◽

Colon Cancer Progression

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Role of MicroRNAs in Colon Cancer Progression and Metastasis

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320666200825184924 ◽

2020 ◽

Vol 20 ◽

Author(s):

Shruthi Sanjitha Sampath ◽

Sivaramakrishnan Venkatabalsubramanian ◽

Satish Ramalingam

Keyword(s):

Colon Cancer ◽

Cancer Progression ◽

Target Genes ◽

Tumour Progression ◽

Intestinal Barrier ◽

Colon Cancer Progression ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Novel Therapeutic Strategies

: MicroRNAs regulate gene expression at the posttranscriptional level by binding to the mRNA of their target genes. The dysfunction of miRNAs is strongly associated with the inflammation of the colon. Besides, some microRNAs are shown to suppress tumours while others promote tumour progression and metastasis. Inflammatory bowel diseases include Crohn’s disease and Ulcerative colitis which increase the risk factor for inflammation-associated colon cancer. MicroRNAs are shown to be involved in gastrointestinal pathologies, by targeting the transcripts encoding proteins of the intestinal barrier and their regulators that are associated with inflammation and colon cancer. Detection of these microRNAs in the blood, serum, tissues, faecal matter, etc will enable us to use these microRNAs as biomarkers for early detection of the associated malignancies and design novel therapeutic strategies to overcome the same. Information on MicroRNAs can be applied for the development of targeted therapies against inflammation-mediated colon cancer.

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Computational Analysis of miRNA and their Gene Targets Significantly Involved in Colorectal Cancer Progression

MicroRNA ◽

10.2174/2211536607666180803100246 ◽

2018 ◽

Vol 8 (1) ◽

pp. 68-75 ◽

Cited By ~ 1

Author(s):

Jeyalakshmi Kandhavelu ◽

Kumar Subramanian ◽

Amber Khan ◽

Aadilah Omar ◽

Paul Ruff ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Cancer Progression ◽

Target Prediction ◽

Computational Prediction ◽

Initial Step ◽

Kegg Pathways ◽

Candidate Mirnas ◽

Common Cancer ◽

Colon Cancer Progression

Background:Globally, colorectal cancer (CRC) is the third most common cancer in women and the fourth most common cancer in men. Dysregulation of small non-coding miRNAs have been correlated with colon cancer progression. Since there are increasing reports of candidate miRNAs as potential biomarkers for CRC, this makes it important to explore common miRNA biomarkers for colon cancer. As computational prediction of miRNA targets is a critical initial step in identifying miRNA: mRNA target interactions for validation, we aim here to construct a potential miRNA network and its gene targets for colon cancer from previously reported candidate miRNAs, inclusive of 10 up- and 9 down-regulated miRNAs from tissues; and 10 circulatory miRNAs. </P><P> Methods: The gene targets were predicted using DIANA-microT-CDS and TarBaseV7.0 databases. Each miRNA and its targets were analyzed further for colon cancer hotspot genes, whereupon DAVID analysis and mirPath were used for KEGG pathway analysis.Results:We have predicted 874 and 157 gene targets for tissue and serum specific miRNA candidates, respectively. The enrichment of miRNA revealed that particularly hsa-miR-424-5p, hsa-miR-96-5p, hsa-miR-1290, hsa-miR-224, hsa-miR-133a and has-miR-363-3p present possible targets for colon cancer hallmark genes, including BRAF, KRAS, EGFR, APC, amongst others. DAVID analysis of miRNA and associated gene targets revealed the KEGG pathways most related to cancer and colon cancer. Similar results were observed in mirPath analysis. A new insight gained in the colon cancer network pathway was the association of hsa-mir-133a and hsa-mir-96-5p with the PI3K-AKT signaling pathway. In the present study, target prediction shows that while hsa-mir-424-5p has an association with mostly 10 colon cancer hallmark genes, only their associations with MAP2 and CCND1 have been experimentally validated.These miRNAs and their targets require further evaluation for a better understanding of their associations, ultimately with the potential to develop novel therapeutic targets.

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