Co-regulatory Network of Oncosuppressor miRNAs and Transcription Factors for Pathology of Human Hepatic Cancer Stem Cells (HCSC)

Rania Hassan Mohamed,Wael Zakaria,Ahmed M. H. Abdelfattah,Mahmoud ElHefnawi,Nourhan Abu-Shahba,Marwa Mahmoud

doi:10.1038/s41598-019-41978-5

Rania Hassan Mohamed, Wael Zakaria + Show 4 more

Open Access

https://doi.org/10.1038/s41598-019-41978-5

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Abstract

Hepatic cancer stem cells (HCSCs) are considered as main players for the hepatocellular carcinoma (HCC) initiation, metastasis, drug resistance and recurrence. There is a growing evidence supporting the down-regulated miRNAs in HCSCs as key suppressors for the stemness traits, but still more details are vague about how these miRNAs modulate the HCC development. To uncover some of these miRNA regulatory aspects in HCSC, we compiled 15 down-regulated miRNA and their validated and predicted up-regulated targets in HCSC. The targets were enriched for several cancer cell stemness hallmarks and CSC pre-metastatic niche, which support these miRNAs role in suppression of HCSCs neoplastic transformation. Further, we constructed miRNA-Transcription factor (TF) regulatory networks, which provided new insights on the role of the proposed miRNA-TF co-regulation in the cancer stemness axis and its cross talk with the surrounding microenvironment. Our analysis revealed HCSC important hubs as candidate regulators for targeting hepatic cancer stemness such as, miR-148a, miR-214, E2F family, MYC and SLC7A5. Finally, we proposed a possible model for miRNA and TF co-regulation of HCSC signaling pathways. Our study identified an HCSC signature and set bridges between the reported results to give guide for future validation of HCC therapeutic strategies avoiding drug resistance.

Highlights

Www.nature.com/scientificreports understanding of the molecular properties of this crucial cell population can potentially improve hepatocellular carcinoma (HCC) patient outcomes and survival
We found 10 of our 15 selected micro RNAs (miRNAs)- the rest are not identified in the miROB intractome database- are predicted to block/inhibit the expression of high number of genes (85% target genes) involved in the biological processes and pathways of the hepatic cancer stemness and chemoresistance (Fig. 1)
That was a first step to proceed forward in our aim and to suggest the role of these miRNAs as hepatic cancer stemness suppressors. We compiled both the validated and predicted targets that are common between our selected bioinformatics target prediction tools and compared them to the significantly up-regulated genes expressed in Hepatic cancer stem cells (HCSCs) and chemoresistant hepatic cancer cells in the literature and Gene Expression Omnibus (GEO) database to pick the possible targets to our selected miRNA (Supplementary Table S1)

Summary

Introduction

Www.nature.com/scientificreports understanding of the molecular (at genetic and epigenetic levels) properties of this crucial cell population can potentially improve HCC patient outcomes and survival. Transcription factors (TF) are indispensable players to regulate the cancer stemness pathways Among these TFs and pathways are Oct[4], Sox[2], Klf[4], and c-Myc, Wnt/β-catenin, IL-6/STAT3, BMI-1, TGF-β, RAS/RAF/ MAPK, PI3K/AKT/mTOR, Notch and Hedgehog. Tumor suppressor miRNAs, which have been reported to be significantly down-regulated in the HCSC play a key role to inhibit stemness and drug resistance features Of these miRNAs, miR-145 and miR-148b suppress hepatic cancer stemness via inhibiting Oct[4] and neuropilin-1, respectively[14,15]. We constructed novel miRNA-TF-gene co-regulatory networks, identified hub elements and proposed a model to link and present a systematic understanding of the molecular mechanisms underlying development of HCSCs and drug resistance. We aim to open new therapeutic strategies to be validated in the future against hepatic cancer stemness and chemoresistance

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