H19 Noncoding RNA, an Independent Prognostic Factor, Regulates Essential Rb-E2F and CDK8-β-Catenin Signaling in Colorectal Cancer

Abstract

HighlightsHigh H19 expression in primary tumors is an independent predictor of short overall survival in CRC patients.RB1-E2F and CDK8-β-catenin signaling are essential in mediating the oncogenic activity of H19 in CRC.Combined analysis of H19 and its targets further improved the prediction power on overall survival of CRC patients.Long noncoding RNAs (lncRNAs) are transcripts at least 200 nucleotides long that do not code for proteins. The clinical relevance of lncRNAs in colorectal cancer (CRC) is largely unknown. Here we identified that H19 expression in primary tumors is an independent prognostic predictor of poor prognosis of CRC patients and further proved its oncogenic role. To characterize the mechanisms, we profiled gene expression changes following H19 modulation in CRC cell lines and analyzed gene expression association in clinical datasets. Our data revealed important cancer-signaling pathways, including the RB1-E2F and the CDK8-β-catenin signaling, underlying H19 function.

Biological and Clinical Relevance of H19 in Colorectal Cancer Patients

“…Thus, as a part of the transcription machinery, CDK8 plays a crucial role in regulating gene expression. Accordingly, the findings by Calin and coworkers (Ohtsuka et al, in this issue) show, that apart from the detection of the H19 action on CDK8/β-catenin, as well as on RB1/E2F signaling, H19 may be involved in further regulation networks that control CRC malignancies.…”

“…In this case, the data emphasize that H19 functions are performed by miR-675. However, Calin and coworkers (Ohtsuka et al, in this issue) found a direct interaction of H19, without the involvement of miR-675, with RB1 protein, using RNA immunoprecipitation experiments. This excellent study also showed that H19 silencing dramatically reduced RB1 phosphorylation by reducing both RNA and protein expression of cyclin-dependent kinase (CDK) 4 and cyclin D1 (two essential upstream factors controlling RB1 phosphorylation).…”

“…MiR-675-5p was undetectable in TCGA samples, while miR-675-3p expression correlated with H19 levels, but was no predictor either for overall or disease-free survival. At least in their model system that Calin and coworkers used, H19 effect could hardly be attributed to miR-675 function (Ohtsuka et al, in this issue). …”

“…Moreover, Calin and coworkers also showed that H19 is able to regulate β-catenin activity via modulating CDK8 expression (Ohtsuka et al, in this issue). In CRC, CDK8 is an essential oncogenic driver with multiple functions.…”

“…Compared to previous studies (Raveh et al, 2015), the strength of the study by Calin and coworkers lies in the detailed investigation on the involvement of H19 in RB1/E2F and CDK8/β-catenin signaling pathways using effectively combined bioinformatics (TCGA database) and in vitro experimental models (Ohtsuka et al, in this issue). It is also of note that H19 was reported to affect the Wnt/β-catenin signaling pathway (Wang et al, 2016), and additionally, to be involved in the repression of E-Cadherin (CDH1) (Luo et al, 2013).…”