Pan-cancer EMT-signature identifies RBM47 down-regulation during colorectal cancer progression

abstract: ...Epithelial-mesenchymal transition ( EMT) plays an important role in tumor invasion and metastasis. A comprehensive, bioinformatics analysis of CCLE and TCGA datasets of seven tumor types allowed us to identify a novel pan-cancer EMT-associated gene expression signature consisting of 16 epithelial and 4 mesenchymal state-associated mRNAs. Among the identified epithelial cell state-associated factors, down-regulation of the RBM47 (RNA binding motif protein 47) mRNA displayed the most significant association with metastasis and poor survival in multiple cohorts of colorectal cancer (CRC) patients. Moreover, decreased RBM47 protein expression was associated with metastasis in a cohort of primary CRCs. RBM47 was directly suppressed during EMT induced by IL6-activated STAT3 or ectopic SNAIL and SLUG expression via conserved binding motifs of these factors within the RBM47 promoter. Moreover, RNAi-mediated down-regulation of RBM47 in CRC lines resulted in increased cell migration, invasion and metastases formation. As demonstrated by the example of RBM47, the EMT-associated signature characterized here allows to identify biomarkers for predicting clinical outcome of CRC and presumably other cancer entities. In addition, our functional analysis of RBM47 shows that the down-regulation of RBM47 during CRC progression may promote EMT and metastasis.

...Sci Rep Sci Rep Scientific Reports 2045-2322 Nature Publishing Group UK London 28680090 5498532 4234 10.1038/s41598-017-04234-2 Article Pan-cancer EMT-signature identifies RBM47 down-regulation during colorectal cancer progression Rokavec Matjaz 1 Kaller Markus 1 Horst David 2 3 4 Hermeking Heiko heiko.hermeking@med.uni-muenchen.de 1 3 4 1 0000 0004 1936 973X grid.5252.0 Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-Universitt Mnchen, Munich, Germany 2 0000

...-associated mRNAs. Among the identified epithelial cell state-associated factors, down-regulation of the RBM47 (RNA binding motif protein 47) mRNA displayed the most significant association with metastasis and poor survival in multiple cohorts of colorectal cancer (CRC) patients. Moreover, decreased RBM47 protein expression was associated with metastasis in a cohort of primary CRCs. RBM47 was directly suppressed during EMT induced by IL6-activated STAT3 or ectopic SNAIL and SLUG expression via conserved binding motifs of these factors within the RBM47 promoter. Moreover, RNAi-mediated down-regulation of RBM47 in CRC lines resulted in increased cell migration, invasion and metastases formation. As demonstrated by the example of RBM47, the EMT-associated signature characterized here allows to identify biomarkers for predicting clinical outcome of CRC and presumably other cancer entities. In addition, our functional analysis of RBM47 shows that the down-regulation of RBM47 during CRC progression may

... cells 21 23 . Because of the problematic nature of mesenchymal tumor markers we focused on the analysis of epithelial markers. We performed an exemplary validation of the RNA binding motif protein 47 (RBM47) as an epithelial state-associated factor and found that it is required for the maintenance of an epithelial state and the suppression of migration, invasion, and metastasis. Moreover, analysis of patient samples showed that down-regulation of RBM47 protein expression represents a potential

... functionally relevant regulators of EMT. Next, we analyzed whether the identified EMT-associated mRNAs associate with nodal status and distal metastasis in the TCGA COAD cohort (Table 2 ). The most significant association with these clinical parameters was observed for the RBM47 mRNA, encoding the RNA binding motif 47. Notably, decreased expression of the RBM47 mRNA was also significantly associated with presence of distal metastases and increased nodal status in the TCGA COAD cohort (Fig. 3a ). Moreover, low RBM47 expression was significantly associated with poor overall and relapse free survival in TCGA COAD and five additional CRC patient cohorts (Fig. 3bg ), Decreased expression of RBM47 was also significantly associated with poor overall and relapse free survival in the TCGA pan-cancer dataset, which encompasses expression profiles of more than 8400 cancer patients from 30 different entities (Supplemental Fig. S3 ). Finally, the expression of RBM47 was lowest in the mesenchymal CMS4 subtype in

... 1.03 EPCAM 1.02 1.05 VIM 1.41* 1.33* ESRP1 1.02 1.02 ESRP2 1.04 1.00 FA2H 0.93 1.02 HOOK1 0.94 0.91 * LNX1 1.00 1.06 MAP7 1.01 0.94 MAPK13 1.03 1.06 MARVELD2 1.03 0.99 MARVELD3 0.88 * 1.00 MYO5B 0.90 * 0.92 * MYO5C 0.83 ** 0.85 *** RBM47 0.84 *** 0.89 *** Fold change: average expression of indicated mRNAs in primary tumors from patients without distant metastases (M0) or negative nodal status (N0) divided by average expression of indicated mRNAs in primary tumors

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Gene: RBM47 - RNA binding motif protein 47 - (NCBI)

Protein : 2dis

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