Published OnlineFirst June 20, 2016; DOI: 10.1158/0008-5472.CAN-16-0359

Cancer Review Research

OncomiR or Tumor Suppressor? The Duplicity of in Alexander A. Svoronos1, Donald M. Engelman1, and Frank J. Slack2

Abstract

MicroRNAs (miRNA) are short, noncoding whose competing oncogenic and tumor suppressive effects by sup- dysregulation has been implicated in most, if not all, . pressing both tumor suppressive mRNAs and oncogenic They regulate expression by suppressing mRNA transla- mRNAs, respectively. In addition, miRNAs can modulate tion and reducing mRNA stability. To this end, there is a tumor-modifying extrinsic factors, such as cancer-immune great deal of interest in modifying miRNA expression levels system interactions, stromal cell interactions, oncoviruses, and for the treatment of cancer. However, the literature is fraught sensitivity to therapy. Ultimately, it is the balance between with inconsistent accounts as to whether various miRNAs are these processes that determines whether a specificmiRNA oncogenic or tumor suppressive. In this review, we directly produces a net oncogenic or net tumor suppressive effect. examine these inconsistencies and propose several mechan- A solid understanding of this phenomenon will likely prove isms to explain them. These mechanisms include the valuable in evaluating miRNA targets for cancer therapy. Cancer possibility that specific miRNAs can simultaneously produce Res; 76(13); 3666–70. Ó2016 AACR.

Introduction with conflicting reports as to whether specific miRNAs are onco- genic or tumor suppressive. Repeatedly, certain miRNAs have MicroRNAs (miRNA) are short, 18–25 nucleotide-long, been shown to be oncogenic in one scenario, but tumor suppres- noncoding RNA molecules that regulate by sive in another. Diversity of effects is not a surprise given the large suppressing mRNA and reducing mRNA stability, number of influenced by a particular miRNA. It hence usually through imperfect complementary base pairing to the follows that the classification of a miRNA as oncogenic or tumor 30-untranslated region. Since their 1993 discovery in C. elegans, suppressive may represent an oversimplification that must be it has become ever more apparent that miRNAs are dysregu- carefully scrutinized in all cancer miRNA studies. To date, this lated in most, if not all, cancers. Many of these miRNAs either issue has received little consideration, and few studies have contribute to or repress the cancer phenotype by inhibiting the directly examined its potential causes. expression of tumor suppressors or , respectively. Here, we highlight several examples in which a specific miRNA Generally, oncogenic miRNAs (oncomiRs) are overexpressed can act either as a tumor suppressor or an , depending on in cancers while tumor-suppressive miRNAs are underex- the context. We attempt to explain the phenomenon via exam- pressed. When these oncomiRs or tumor-suppressor miRNAs ination of the affected cellular and molecular mechanisms, and are inhibited or stimulated, respectively, cancer cell prolifer- we propose multiple factors that can influence whether a miRNA ation, , and/or survival may be significantly reduced, has a net oncogenic or net tumor suppressive effect. Finally, we depending on the type of cancer and the specific miRNA being argue for a holistic approach in examining the effects of miRNAs affected. It is even possible for cancers to become completely in cancer that incorporates the interactions of the miRNA's mul- reliant