MicroRNA Dysregulation in Colon Cancer Microenvironment Interactions: The Importance of Small Things in Metastases

Abstract

The influence of the microenvironment through the various steps of cancer progression is signed by different cytokines and growth factors, that could directly affect cell proliferation and survival, either in cancer and stromal cells. In colon cancer progression, the cooperation between hypoxia, IL-6 and VEGF-A165 could regulate the DNA repair capacity of the cell, whose impairment is the first step of colon cancer development. This cooperation redirects the activity of proteins involved in the metabolic shift and cell death, affecting the cell fate. The pathways triggered by micro environmental factors could modulate cancer-related gene transcription, affecting also small non coding mRNA, microRNAs. MicroRNAs have emerged as key post-transcriptional regulators of gene expression, directly involved in human cancers. The present review will focus first on the intertwined connection between cancer microenvironment and aberrant expression of microRNAs which contribute to carcinogenesis. In particular, the epigenetic mechanisms triggered by tissue microenvironment will be discussed, in view of the recent identification of miRNAs able to directly or indirectly modulate the epigenetic machinery (epi-miRNAs) and that are involved in the epithelial to mesenchimal transition and metastases development.

Fig. 1

Cancer- stroma interactions in colon cancer progression and spreading. In colon cancer the synergistic action of IL-6, and VEGF-A165a promotes the acquisition of aggressiveness regulating the DNA repair capacity of the cell, whose impairment is the first step of colon cancer development. The cooperative action of these soluble mediators could modulate cancer-related gene transcription (sClusterin, TIMP1), and affect the expression of small non coding mRNA (microRNAs), able to modulate the epigenetic machinery (epi-miRNAs; miR-449) and to induce the epithelial to mesenchimal transition (EMT induction; miR-200 family)