miR-34: from bench to bedside

Abstract

The mir-34 family was originally cloned and characterized in 2007 as a p53 target gene. Almost immediately it became clear that its major role is as a master regulator of tumor suppression. Indeed, when overexpressed, it directly and indirectly represses several oncogenes, resulting in an increase of cancer cell death (including cancer stem cells), and in an inhibition of metastasis. Moreover, its expression is deregulated in several human cancers. In 2013, a miR-34 mimic has become the first microRNA to reach phase 1 clinical trials. Here we review the miR-34 family and their role in tumor biology, and discuss the potential therapeutic applications of miR-34a mimic.

Figure 1. The miR-34 family regulators and their functions

In the last few years, the miR-34a family has emerged as a pleiotropic microRNA. It was originally identified as a p53 target after DNA damage. The outcome of this upregulation is the induction of apoptosis, cell cycle arrest and senescence. Lately, p53 independent regulation has been observed. For instance, TAp73 is able to drive the expression of miR-34a and in turn, it regulates neuronal differentiation. miR-34a is also regulated by phorbol ester during megakaryocytic differentiation but the detailed molecular mechanisms have not been defined (?).

Figure 2. miR-34a as a regulator of cancer stem cell biology

Cancer stem cells (CSC) have the capacity to self-renew and differentiate as well as the ability to regenerate tumors. miR-34a has been found to be dysregulated in CSC, particularly in pancreatic, prostatic cancer and in glioblastoma. a) In pancreatic CSC, miR-34a is able to regulate the proliferation of CSC, targeting Cyclin D1, CDK4 and CDK6. b) In prostatic CSC, miR-34a inhibits cell migration and invasion through the inhibition of CD44 expression. c) Finally, in glioblastoma, miR-34a regulates CSC self-renewal through the inhibition of Notch signaling and SIRT1.

Figure 3. Survival correlation of miR-34 family in several human cancer datasets

A and B) GEO dataset Title: Global microRNA expression profiling of high-risk ER+ breast cancers from patients receiving adjuvant Tamoxifen mono-therapy: a DBCG study. C) GEO dataset Title: MicroRNA expression profile in human hepatocellular carcinoma. D) GEO dataset Title: MicroRNA profiling of advanced serous ovarian carcinoma.