Invasion and metastasis of carcinomas is promoted by the activation of the embryonic 'epithelial to mesenchymal transition' (EMT) program, which triggers cellular mobility and subsequent dissemination of tumour cells. We recently showed that the EMT-activator ZEB1 (zinc finger E-box binding homeobox 1) is a crucial promoter of metastasis and demonstrated that ZEB1 inhibits expression of the microRNA-200 (miR-200) family, whose members are strong inducers of epithelial differentiation. Here, we report that ZEB1 not only promotes tumour cell dissemination, but is also necessary for the tumour-initiating capacity of pancreatic and colorectal cancer cells. We show that ZEB1 represses expression of stemness-inhibiting miR-203 and that candidate targets of miR-200 family members are also stem cell factors, such as Sox2 and Klf4. Moreover, miR-200c, miR-203 and miR-183 cooperate to suppress expression of stem cell factors in cancer cells and mouse embryonic stem (ES) cells, as demonstrated for the polycomb repressor Bmi1. We propose that ZEB1 links EMT-activation and stemness-maintenance by suppressing stemness-inhibiting microRNAs (miRNAs) and thereby is a promoter of mobile, migrating cancer stem cells. Thus, targeting the ZEB1-miR-200 feedback loop might form the basis of a promising treatment for fatal tumours, such as pancreatic cancer.

The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs

MicroRNAs (miRNAs) are a class of posttranscriptional regulators that have recently introduced an additional level of intricacy to our understanding of gene regulation. There are currently over 10,000 miRNAs that have been identified in a range of species including metazoa, mycetozoa, viridiplantae, and viruses, of which 940, to date, are found in humans. It is estimated that more than 60% of human protein-coding genes harbor miRNA target sites in their 3′ untranslated region and, thus, are potentially regulated by these molecules in health and disease. This review will first briefly describe the discovery, structure, and mode of function of miRNAs in mammalian cells, before elaborating on their roles and significance during development and pathogenesis in the various mammalian organs, while attempting to reconcile their functions with our existing knowledge of their targets. Finally, we will summarize some of the advances made in utilizing miRNAs in therapeutics.

/pdf/micrornas-in-development-and-disease-472gt45lvo.pdf

MicroRNAs in development and disease.

An extensive microRNA-mediated network of RNA-RNA interactions regulates established oncogenic pathways in glioblastoma.

Polycomb group proteins: multi-faceted regulators of somatic stem cells and cancer

MicroRNAs (miRNAs) comprise species of short noncoding RNA that regulate gene expression post-transcriptionally. Recent studies have demonstrated that epigenetic mechanisms, including DNA methylation and histone modification, not only regulate the expression of protein-encoding genes, but also miRNAs, such as let-7a, miR-9, miR-34a, miR-124, miR-137, miR-148 and miR-203. Conversely, another subset of miRNAs controls the expression of important epigenetic regulators, including DNA methyltransferases, histone deacetylases and polycomb group genes. This complicated network of feedback between miRNAs and epigenetic pathways appears to form an epigenetics-miRNA regulatory circuit, and to organize the whole gene expression profile. When this regulatory circuit is disrupted, normal physiological functions are interfered with, contributing to various disease processes. The present minireview details recent discoveries involving the epigenetics-miRNA regulatory circuit, suggesting possible biological insights into gene-regulatory mechanisms that may underlie a variety of diseases.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1742-4658.2011.08089.x

MicroRNAs and epigenetics.

MicroRNAs (miR) show characteristic expression signatures in various cancers and can profoundly affect cancer cell behavior. We carried out miR expression profiling of human glioblastoma specimens versus adjacent brain devoid of tumor. This revealed several significant alterations, including a pronounced reduction of miR-128 in tumor samples. miR-128 expression significantly reduced glioma cell proliferation in vitro and glioma xenograft growth in vivo. miR-128 caused a striking decrease in expression of the Bmi-1 oncogene, by direct regulation of the Bmi-1 mRNA 3'-untranslated region, through a single miR-128 binding site. In a panel of patient glioblastoma specimens, Bmi-1 expression was significantly up-regulated and miR-128 was down-regulated compared with normal brain. Bmi-1 functions in epigenetic silencing of certain genes through epigenetic chromatin modification. We found that miR-128 expression caused a decrease in histone methylation (H3K27me(3)) and Akt phosphorylation, and up-regulation of p21(CIP1) levels, consistent with Bmi-1 down-regulation. Bmi-1 has also been shown to promote stem cell self-renewal; therefore, we investigated the effects of miR-128 overexpression in human glioma neurosphere cultures, possessing features of glioma "stem-like" cells. This showed that miR-128 specifically blocked glioma self-renewal consistent with Bmi-1 down-regulation. This is the first example of specific regulation by a miR of a neural stem cell self-renewal factor, implicating miRs that may normally regulate brain development as important biological and therapeutic targets against the "stem cell-like" characteristics of glioma.

https://cancerres.aacrjournals.org/content/canres/68/22/9125.full.pdf

Targeting of the Bmi-1 Oncogene/Stem Cell Renewal Factor by MicroRNA-128 Inhibits Glioma Proliferation and Self-Renewal

Histone deacetylase inhibitors augment antitumor efficacy of herpes-based oncolytic viruses.

http://health120years.com/cn/pdf/hd_cancer-killing-viruses-stimulate-tumor-blood-vessel-growth.pdf

Oncolytic HSV-1 infection of tumors induces angiogenesis and upregulates CYR61.

Oncolytic viral (OV) therapy, which uses genetically engineered tumor-targeting viruses, is being increasingly used in cancer clinical trials due to the direct cytolytic effects of this treatment that appear to provoke a robust immune response against the tumor. As OVs enter tumor cells, intrinsic host defenses have the potential to hinder viral replication and spread within the tumor mass. In this report, we show that histone deacetylase 6 (HDAC6) in tumor cells appears to alter the trafficking of post-entry OVs from the nucleus toward lysosomes. In glioma cell lines and glioma-stem-like cells, HDAC6 inhibition (HDAC6i) by either pharmacologic or genetic means substantially increased replication of oncolytic herpes simplex virus type 1 (oHSV). Moreover, HDAC6i increased shuttling of post-entry oHSV to the nucleus. In addition, electron microscopic analysis revealed that post-entry oHSVs are preferentially taken up into glioma cells through the endosomal pathway rather than via fusion at the cell surface. Together, these findings illustrate a mechanism of glioma cell defense against an incoming infection by oHSV and identify possible approaches to enhance oHSV replication and subsequent lysis of tumor cells.

/pdf/histone-deacetylase-6-inhibition-enhances-oncolytic-viral-52x9a3w6gw.pdf

Akihiro Otsuki

Papers

Targeting of the Bmi-1 Oncogene/Stem Cell Renewal Factor by MicroRNA-128 Inhibits Glioma Proliferation and Self-Renewal

Histone deacetylase inhibitors augment antitumor efficacy of herpes-based oncolytic viruses.

Oncolytic HSV-1 infection of tumors induces angiogenesis and upregulates CYR61.

Histone deacetylase 6 inhibition enhances oncolytic viral replication in glioma