Multifaceted enrichment analysis of RNA–RNA crosstalk reveals cooperating micro-societies in human colorectal cancer

Mazza, Tommaso; Mazzoccoli, Gianluigi; Fusilli, Caterina; Capocefalo, Daniele; Panza, Anna; Biagini, Tommaso; Castellana, Stefano; Gentile, Annamaria; Cata, Angelo De; Palumbo, Orazio; Stallone, Raffaella; Rubino, Rosa; Carella, Massimo; Piepoli, Ada

doi:10.1093/nar/gkw245

Cited by 15 publications

(12 citation statements)

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“…Mazza et al evaluated of the miRNAome and transcriptome of matched pairs of tumour and adjacent non-tumorous mucosa samples of CRC. He found concurrent downregulation of KRAS and the miR-143/145 cluster in CRC tissue [16]. This result was interpreted in terms of a feed-forward mechanism in which the miR-143/145 polycistronic cluster targets the RAS-responsive element-binding protein RREB1 and KRAS, which, in turn, induce downregulation of the cluster [14].…”

Section: Discussionmentioning

confidence: 96%

“…The KRAS oncogene is an important upstream mediator of the MAPK pathway, and its overexpression can lead to increased activation of the RAF/MEK/MAPK pathway, thereby promoting tumorigenesis [14]. KRAS is an important target of miR-143/145, which has been identi ed not only by computational predictions using software such as TargetScan, miRanda, and PicTar, but also by experimental validation [15,16].…”

Section: Introductionmentioning

confidence: 99%

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Association analysis of miRNA-related genetic polymorphisms in miR-143/145 and KRAS with colorectal cancer susceptibility and survival

Wang

Liu

Ren

et al. 2019

Preprint

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Background MicroRNAs have important roles in tumorigenesis. There is accumulating evidence of aberrant expression of miR-143 and miR-145 and their target gene KRAS has been described in colorectal cancer (CRC). We hypothesize that single nucleotide polymorphisms (SNPs) within or near mRNA-miRNA binding sites may affect miRNA/target gene interaction, resulting in differential mRNA/protein expression and promoting the development and progression of CRC.Methods We conducted a case-control study of 507 CRC cases recruited from a tertiary hospital and 497 population-based controls to assess the association of genetic polymorphisms in miR-143/145 and the KRAS 3′ untranslated region (3′ UTR) with CRC susceptibility and survival. Deaths and causes of death among the CRC cases were identified using the Hangzhou Cancer Registration System and Death Surveillance System. Genetic variations of genomic regions located from 500 bp upstream to 500 bp downstream of the miR-143/miR-145 gene and the 3′ UTR of KRAS were selected using the Haploview and HaploReg software. Results Using publicly available expression profiling data, we found that miR-143/145 and KRAS expression were all reduced in rectal cancer tissue compared with adjacent normal mucosa. The Rs74693964 C/T variant located 65 bp downstream of miR-145 genomic regions was observed to be associated with CRC susceptibility (adjusted odds ratio 2.414, 95% CI: 1.385–4.206). Among non-smokers, the miR-143 rs41291957 GA genotype and miR-145 rs74693964 CT genotype were borderline significantly associated with an increased risk of rectal cancer. However, there was no interaction effect between selected SNPs and smoking status. Cumulative effects of miR-143 and miR-145 on CRC risk were observed (Ptrend=0.03). CRC cases carrying variant genotype TT of KRAS rs712 had poorer survival (log-rank P=0.044, adjusted hazard ratio 4.328, 95% CI: 1.236–15.147). Conclusions Our results indicate that miRNA-related polymorphisms in miR-143/145 and KRAS are likely to be deleterious and represent potential biomarkers for CRC susceptibility and survival.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Association analysis of miRNA-related genetic polymorphisms in miR-143/145 and KRAS with colorectal cancer susceptibility and survival

Wang

Liu

Ren

et al. 2019

Preprint

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“…This, in turn, may help in discovering biological pathways deregulated in tumorigenesis and their possible roles in cancer onset and progression [28]. This method of analysis takes advantage of network-based models and, in the present study, was conducted pinpointing core clock genes and their targeting miRNAs.…”

Section: Discussionmentioning

confidence: 99%

Analysis of clock gene-miRNA correlation networks reveals candidate drivers in colorectal cancer

et al. 2016

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Altered functioning of the biological clock is involved in cancer onset and progression. MicroRNAs (miRNAs) interact with the clock genes modulating the function of genetically encoded molecular clockworks. Collaborative interactions may take place within the coding-noncoding RNA regulatory networks. We aimed to evaluate the cross-talk among miRNAs and clock genes in colorectal cancer (CRC). We performed an integrative analysis of miRNA-miRNA and miRNA-mRNA interactions on high-throughput molecular profiling of matched human CRC tissue and non-tumor mucosa, pinpointing core clock genes and their targeting miRNAs. Data obtained in silico were validated in CRC patients and human colon cancer cell lines. In silico we found severe alterations of clock gene–related coding-noncoding RNA regulatory networks in tumor tissues, which were later corroborated by the analysis of human CRC specimens and experiments performed in vitro. In conclusion, specific miRNAs target and regulate the transcription/translation of clock genes and clock gene-related miRNA-miRNA as well as mRNA-miRNA interactions are altered in colorectal cancer. Exploration of the interplay between specific miRNAs and genes, which are critically involved in the functioning of the biological clock, provides a better understanding of the importance of the miRNA-clock genes axis and its derangement in colorectal cancer.

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“…BMAL1 hinders the G2/M transition activating WEE1 kinase expression, with successive inhibition of C DK1 , and inhibits c-MYC reducing cyclin E expression and cyclin E/Cdk2 activity, hampering the G1/S transition [28,29]. Severe alterations of the biological clock functioning have been reported in the tumour tissue of CRC patients and in colon cancer cells [30,31,32,33,34,35,36,37]. Thus, the aim of our study was to evaluate the putative impact of the interplay between colon cancer cells and stromal cells on the function of the biological clock.…”

Section: Introductionmentioning

confidence: 99%

The Interplay between Colon Cancer Cells and Tumour-Associated Stromal Cells Impacts the Biological Clock and Enhances Malignant Phenotypes

Fuhr

Abreu

Carbone

et al. 2019

Cancers

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Cancer cells interrelate with the bordering host microenvironment that encompasses the extracellular matrix and a nontumour cellular component comprising fibroblasts and immune-competent cells. The tumour microenvironment modulates cancer onset and progression, but the molecular factors managing this interaction are not fully understood. Malignant transformation of a benign tumour is among the first crucial events in colorectal carcinogenesis. The role of tumour stroma fibroblasts is well-described in cancer, but less well-characterized in benign tumours. In the current work we utilized fibroblasts isolated from tubulovillous adenoma, which has high risk for malignant transformation, to study the interaction between benign tumour stroma and the circadian clock machinery. We explored the role of the biological clock in this interplay taking advantage of an experimental model, represented by the co-culture of colon cancer cells with normal fibroblasts or tumour-associated fibroblasts, isolated from human colorectal tumour specimens. When co-cultured with tumour-associated fibroblasts, colon cancer cells showed alterations in their circadian and metabolic parameters, with decreased apoptosis, increased colon cancer cell viability, and increased resistance to chemotherapeutic agents. In conclusion, the interactions among colon cancer cells and tumour-associated fibroblasts affect the molecular clockwork and seem to aggravate malignant cell phenotypes, suggesting a detrimental effect of this interplay on cancer dynamics.

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Multifaceted enrichment analysis of RNA–RNA crosstalk reveals cooperating micro-societies in human colorectal cancer

Cited by 15 publications

References 53 publications

Association analysis of miRNA-related genetic polymorphisms in miR-143/145 and KRAS with colorectal cancer susceptibility and survival

Association analysis of miRNA-related genetic polymorphisms in miR-143/145 and KRAS with colorectal cancer susceptibility and survival

Analysis of clock gene-miRNA correlation networks reveals candidate drivers in colorectal cancer

The Interplay between Colon Cancer Cells and Tumour-Associated Stromal Cells Impacts the Biological Clock and Enhances Malignant Phenotypes

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