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Establishment of optimal regulatory network of colorectal cancer based on p42.3 protein.

ABSTRACT: Objective: to establish regulatory network of colorectal cancer involving p42.3 protein and to provide theoretical evidence for deep functional exploration of p42.3 protein in the onset and development of colorectal cancer. Methods: with protein similarity algorithm, reference protein set of p42.3 cell apoptosis was built according to structural features of p42.3. GO and KEGG databases were used to establish regulatory network of tumor cell apoptosis involving p42.3; meanwhile, the largest possible working pathway that involves p42.3 protein was screened out based on Bayesian network theory. Besides, GO and KEGG were used to build regulatory network on early diagnosis gene markers for colorectal cancer including WWOX, K-ras, COX-2, p53, APC, DCC and PTEN, at the same time, a regulatory network of colorectal cancer cell apoptosis which involves p42.3 was established. Results: cell apoptotic regulatory network that p42.3 participates in primarily consists of Bcl-2 family genes and the largest possible pathway is p42.3???FKBP???Bcl-2 centered as FKBP protein. Combined with colorectal cancer regulatory network that involves early diagnosis gene markers, it can be predicted that p42.3 is most likely to regulate the colorectal cancer cell apoptosis through FKBP???Bcl-2???Bax???caspase-9???caspase-3 pathway. Conclusion: the colorectal cancer apoptosis network based on p42.3 established in the study provides theoretical evidence for deep exploration of p42.3 regulatory mechanism and molecular targeting treatment of colorectal cancer.

SUBMITTER: Hao Y

PROVIDER: S-EPMC5851908 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Establishment of optimal regulatory network of colorectal cancer based on p42.3 protein.

Hao Yibin Y Zhang Jianhua J Shan Guoyong G Zhang Ning N Jin Wenwen W Nan Kejun K

Saudi journal of biological sciences 20171109 8

<i>Objective:</i> to establish regulatory network of colorectal cancer involving p42.3 protein and to provide theoretical evidence for deep functional exploration of p42.3 protein in the onset and development of colorectal cancer. <i>Methods:</i> with protein similarity algorithm, reference protein set of p42.3 cell apoptosis was built according to structural features of p42.3. GO and KEGG databases were used to establish regulatory network of tumor cell apoptosis involving p42.3; meanwhile, the ...[more]

PMID: 29551923

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Project description:ObjectivesThe high morbidity and mortality of colorectal cancer (CRC) have posed great threats to human health. Circular RNA (circRNA) and microRNA (miRNA), acting as competing endogenous RNAs (ceRNAs), have been found to play vital roles in carcinogenesis. This paper aims to construct a circRNA/miRNA/mRNA regulatory network so as to explore the molecular mechanism of CRC.MethodsThe sequencing data of circRNA from CRC were obtained from Gene Expression Omnibus (GEO). The differential circRNA was screened and its structure was identified by Cancer-specific CircRNA Database (CSCD); the sequencing data of miRNA and messenger RNA (mRNAs) were downloaded from The Cancer Genome Atlas (TCGA) database and the differentially expressed genes were screened; the corresponding miRNA of differential circRNAs were predicted by CircInteractome database; DIANA, Miranda, PicTar, and TargetScan databases were used to predict the target genes of different miRNAs; the target genes from Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were enriched by R language; String database combined with Cytoscape 3.7.2 software was used to construct protein-protein interaction (PPI) network and hub genes were screened; the expressions of mRNAs in the Top10 hub genes were verified in CRC. The network diagrams of circRNAs/miRNAs/mRNAs and circRNAs/miRNAs/Top10 hub mRNAs were constructed by Cytoscape3.7.2. Real-time PCR was used to examine the expression levels of hsa_circRNA_0065173, hsa-mir-450b, hsa-mir-582, adenylate cyclase 5 (ADCY5), muscarinic acetylcholine receptor M2 (CHRM2), cannabinoid receptor 1 (CNR1), and lysophosphatidic acid receptor 1 (LPAR1) in the CRC tissues and the adjacent normal tissues.ResultsA total of 14 differential circRNAs were identified, and 8 were found in CSCD; 34 miRNAs targeted by circRNAs were obtained. The PPI network was constructed, and the Top10 hub genes were identified, which were CHRM2, melanin concentrating hormone receptor 2 (MCHR2), G-protein gamma 3 subunit (GNG3), neuropeptide Y receptor Y1 (NPY1R), CNR1, LPAR1, ADCY5, adenylate cyclase 2 (ADCY2), gamma 7 (GNG7) and chemokine 12 (CXCL12), respectively. The expressions of Top 10 hub genes were also verified, and the results showed that the Top 10 hub genes were down-regulated in CRC; the constructed network diagram showed that hsa_circRNA_0065173 may regulate ADCY5, CHRM2, and Hsa-mir-450b by modulating hsa-mir-450b and hsa-mir-582. CNR1 and LPAR1 genes might serve as potentially relevant targets for the treatment of CRC. Real-time PCR results showed that the expression levels of hsa_circRNA_0065173, ADCY5, CHRM2, CNR1 and LPAR1 in the CRC tissues were significantly reduced compared with the adjacent normal tissues (all P<0.05); the expression levels of hsa-mir-450b and hsa-miR-582 were significantly increased (both P<0.05).ConclusionsIn this study, a potential circRNAs/miRNAs/mRNAs network is successfully constructed, which provides a new insight for CRC development mechanism through ceRNA mediated by circRNAs.

Project description:BackgroundColon cancer occurrence is increasing worldwide, making it the third most frequent cancer. Although many therapeutic options are available and quite efficient at the early stages, survival is strongly decreased when the disease has spread to other organs. The identification of molecular markers of colon cancer is likely to help understanding its course and, eventually, to uncover novel genes to be targeted by drugs. In this study, we compared gene expression in a set of 95 human colon cancer samples to that in 19 normal colon mucosae, focusing on 401 genes from 5 selected pathways (Apoptosis, Cancer, Cholesterol metabolism and lipoprotein signaling, Drug metabolism, Wnt/beta-catenin). Deregulation of mRNA levels largely matched that of proteins, leading us to build in silico protein networks, starting from mRNA levels, to identify key proteins central to network activity.ResultsAmong the analyzed genes, 10.5% (42) had no reported link with colon cancer, including the SFRP1, IGF1 and ADH1B (down), and MYC and IL8 (up), whose encoded proteins were most interacting with other proteins from the same or even distinct networks. Analyzing all pathways globally led us to uncover novel functional links between a priori unrelated or rather remotely connected pathways, such as the Drug metabolism and the Cancer pathways or, even more strikingly, between the Cholesterol metabolism and lipoprotein signaling and the Cancer pathways. In addition, we analyzed the responsiveness of some of the deregulated genes essential to network activities, to chemotherapeutic agents used alone or in presence of Lovastatin, a lipid-lowering drug. Some of these treatments could oppose the deregulations occurring in cancer samples, including those of the CHECK2, CYP51A1, HMGCS1, ITGA2, NME1 or VEGFA genes.ConclusionsOur network-based approach allowed discovering genes not previously known to play regulatory roles in colon cancer. Our results also showed that selected drug treatments might revert the cancer-specific deregulation of genes playing prominent roles within the networks operating to maintain colon homeostasis. Among those genes, some could constitute novel testable targets to eliminate colon cancer cells, either directly or, potentially, through the use of lipid-lowering drugs such as statins, in association with selected anticancer drugs.

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Establishment of optimal regulatory network of colorectal cancer based on p42.3 protein.

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Establishment of optimal regulatory network of colorectal cancer based on p42.3 protein.

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