MicroRNA–mRNA interactions underlying colorectal cancer molecular subtypes

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Abstract

Colorectal cancer (CRC) transcriptional subtypes have been recently identified by gene expression profiling. Here we describe an analytical pipeline, microRNA master regulator analysis (MMRA), developed to search for microRNAs potentially driving CRC subtypes. Starting from a microRNA–mRNA tumour expression data set, MMRA identifies candidate regulator microRNAs by assessing their subtype-specific expression, target enrichment in subtype mRNA signatures and network analysis-based contribution to subtype gene expression. When applied to a CRC data set of 450 samples, assigned to subtypes by 3 different transcriptional classifiers, MMRA identifies 24 candidate microRNAs, in most cases downregulated in the stem/serrated/mesenchymal (SSM) poor prognosis subtype. Functional validation in CRC cell lines confirms downregulation of the SSM subtype by miR-194, miR-200b, miR-203 and miR-429, which share target genes and pathways mediating this effect. These results show that, by combining statistical tests, target prediction and network analysis, MMRA effectively identifies microRNAs functionally associated to cancer subtypes.

Abstract

Colorectal cancer subtypes can be distinguished by their different biological and molecular properties. Here the authors present microRNA Master Regulator Analysis, a tool to identify microRNAs driving subtype-specific gene expression and cancer variation.

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The transcriptional network for mesenchymal transformation of brain tumors

Maria Stella Carro, Wei Lim, Mariano Alvarez … (2009)

Inference of transcriptional networks that regulate transitions into physiologic or pathologic cellular states remains a central challenge in systems biology. A mesenchymal phenotype is the hallmark of tumor aggressiveness in human malignant glioma but the regulatory programs responsible for implementing the associated molecular signature are largely unknown. Here, we show that reverse-engineering and unbiased interrogation of a glioma-specific regulatory network reveal the transcriptional module that activates expression of mesenchymal genes in malignant glioma. Two transcription factors (C/EBPβ and Stat3) emerge as synergistic initiators and master regulators of mesenchymal transformation. Ectopic co-expression of C/EBPβ and Stat3 reprograms neural stem cells along the aberrant mesenchymal lineage whereas elimination of the two factors in glioma cells leads to collapse of the mesenchymal signature and reduces tumor aggressiveness. In human glioma, expression of C/EBPβ and Stat3 correlates with mesenchymal differentiation and predicts poor clinical outcome. These results reveal that activation of a small regulatory module is necessary and sufficient to initiate and maintain an aberrant phenotypic state in cancer cells.

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Activation of NF-kappaB by Akt upregulates Snail expression and induces epithelium mesenchyme transition.

S Julien, I. Puig, E Caretti … (2007)

Carcinoma progression is associated with the loss of epithelial features, and the acquisition of mesenchymal characteristics and invasive properties by tumour cells. The loss of cell-cell contacts may be the first step of the epithelium mesenchyme transition (EMT) and involves the functional inactivation of the cell-cell adhesion molecule E-cadherin. Repression of E-cadherin expression by the transcription factor Snail is a central event during the loss of epithelial phenotype. Akt kinase activation is frequent in human carcinomas, and Akt regulates various cellular mechanisms including EMT. Here, we show that Snail activation and consequent repression of E-cadherin may depend on AKT-mediated nuclear factor-kappaB (NF-kappaB) activation, and that NF-kappaB induces Snail expression. Expression of the NF-kappaB subunit p65 is sufficient for EMT induction, validating this signalling module during EMT. NF-kappaB pathway activation is associated with tumour progression and metastasis of several human tumour types; E-cadherin acts as a metastasis suppressor protein. Thus, this signalling and transcriptional network linking AKT, NF-kappaB, Snail and E-cadherin during EMT is a potential target for antimetastatic therapeutics.

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Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer

Eva Budinska, Vlad Popovici, Sabine Tejpar … (2013)

The recognition that colorectal cancer (CRC) is a heterogeneous disease in terms of clinical behaviour and response to therapy translates into an urgent need for robust molecular disease subclassifiers that can explain this heterogeneity beyond current parameters (MSI, KRAS, BRAF). Attempts to fill this gap are emerging. The Cancer Genome Atlas (TGCA) reported two main CRC groups, based on the incidence and spectrum of mutated genes, and another paper reported an EMT expression signature defined subgroup. We performed a prior free analysis of CRC heterogeneity on 1113 CRC gene expression profiles and confronted our findings to established molecular determinants and clinical, histopathological and survival data. Unsupervised clustering based on gene modules allowed us to distinguish at least five different gene expression CRC subtypes, which we call surface crypt-like, lower crypt-like, CIMP-H-like, mesenchymal and mixed. A gene set enrichment analysis combined with literature search of gene module members identified distinct biological motifs in different subtypes. The subtypes, which were not derived based on outcome, nonetheless showed differences in prognosis. Known gene copy number variations and mutations in key cancer-associated genes differed between subtypes, but the subtypes provided molecular information beyond that contained in these variables. Morphological features significantly differed between subtypes. The objective existence of the subtypes and their clinical and molecular characteristics were validated in an independent set of 720 CRC expression profiles. Our subtypes provide a novel perspective on the heterogeneity of CRC. The proposed subtypes should be further explored retrospectively on existing clinical trial datasets and, when sufficiently robust, be prospectively assessed for clinical relevance in terms of prognosis and treatment response predictive capacity. Original microarray data were uploaded to the ArrayExpress database (http://www.ebi.ac.uk/arrayexpress/) under Accession Nos E-MTAB-990 and E-MTAB-1026.

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Author and article information

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Pub. Group

ISSN (Electronic): 2041-1723

Publication date (Electronic): 17 November 2015

Publication date Collection: 2015

Volume: 6

Electronic Location Identifier: 8878

Affiliations

[1 ]Department of Oncology, Università degli Studi di Torino , S.P. 142, km 3, 95—10060 Candiolo, Italy

[2 ]Department of Control and Computer Engineering, Politecnico di Torino , Cso Duca degli Abruzzi 24, 10129 Torino, Italy

[3 ]Istituto Nazionale Biostrutture e Biosistemi—Consorzio Interuniversitario , Viale delle Medaglie d'Oro, 305—00136 Roma, Italy

[4 ]Candiolo Cancer Institute, FPO IRCCS , S.P. 142, km 3, 95—10060 Candiolo, Italy

[5 ]Department of Physics and INFN, Università degli Studi di Torino , via P.Giuria 1, I-10125 Turin, Italy

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[a ] enzo.medico@ 123456unito.it

Article

Publisher Item ID: ncomms9878

DOI: 10.1038/ncomms9878

PMC ID: 4660217

PubMed ID: 27305450

SO-VID: a5b0d00a-6135-4c6b-980e-e0bff71d8a04

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This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

History

Date received : 11 June 2015

Date accepted : 12 October 2015

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MicroRNA–mRNA interactions underlying colorectal cancer molecular subtypes

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Most cited references 30

The transcriptional network for mesenchymal transformation of brain tumors

Activation of NF-kappaB by Akt upregulates Snail expression and induces epithelium mesenchyme transition.

Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer

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