Alternative mechanisms of miR-34a regulation in cancer

Abstract

MicroRNA miR-34a is recognized as a master regulator of tumor suppression. The strategy of miR-34a replacement has been investigated in clinical trials as the first attempt of miRNA application in cancer treatment. However, emerging outcomes promote the re-evaluation of existing knowledge and urge the need for better understanding the complex biological role of miR-34a. The targets of miR-34a encompass numerous regulators of cancer cell proliferation, survival and resistance to therapy. MiR-34a expression is transcriptionally controlled by p53, a crucial tumor suppressor pathway, often disrupted in cancer. Moreover, miR-34a abundance is fine-tuned by context-dependent feedback loops. The function and effects of exogenously delivered or re-expressed miR-34a on the background of defective p53 therefore remain prominent issues in miR-34a based therapy. In this work, we review p53-independent mechanisms regulating the expression of miR-34a. Aside from molecules directly interacting with MIR34A promoter, processes affecting epigenetic regulation and miRNA maturation are discussed. Multiple mechanisms operate in the context of cancer-associated phenomena, such as aberrant oncogene signaling, EMT or inflammation. Since p53-dependent tumor-suppressive mechanisms are disturbed in a substantial proportion of malignancies, we summarize the effects of miR-34a modulation in cell and animal models in the clinically relevant context of disrupted or insufficient p53 function.

6mer Seed Toxicity Determines Strand Selection in miRNAs

“…Traditionally, scientists have attempted to explain tumor-promoting or tumor-suppressive activities of miRNAs by identifying targets that are either tumor-suppressive or oncogenic, respectively (Esquela-Kerscher & Slack, 2006). Examples of targets of tumor-suppressive miRNAs are the oncogenes Bcl-2 for miR-15/16 (Balatti, Pekarky, Rizzotto, & Croce, 2013) and miR-34a or c-Myc for miR-34a (Slabakova, Culig, Remsik, & Soucek, 2017). However, particularly for miR-34a, the major oncogenic targets have never been identified.…”

“…However, particularly for miR-34a, the major oncogenic targets have never been identified. Intense studies have resulted in a bewildering list of potential targets (summarized in (Slabakova et al, 2017)). Over 700 targets implicated in cancer cell proliferation, survival, and resistance to therapy have been described (Slabakova et al, 2017).…”

“…Intense studies have resulted in a bewildering list of potential targets (summarized in (Slabakova et al, 2017)). Over 700 targets implicated in cancer cell proliferation, survival, and resistance to therapy have been described (Slabakova et al, 2017). Our data now suggest that certain tumor-suppressive miRNAs such as miR-34a use 6mer seed toxicity to target hundreds of housekeeping genes.…”

“…The study was recently terminated and reported immune-related adverse effects in several individuals. It was suggested that these adverse effects may have been caused by either a reaction to the liposome-based carrier or the use of double-stranded RNA (Slabakova et al, 2017). In addition, they may be due to an undesired gene modulation by miR-34a itself.…”

MicroRNA 34a promotes ionizing radiation–induced DNA damage repair in murine hematopoietic stem cells

“…miRNA 34a (miR-34a) is a well-known tumor suppressor in many types of cancers (14,15). Previous studies have focused on the role of miR-34a in the tumor suppressor p53 regulatory network and validated that its upregulation induces apoptosis and cell cycle arrest in cancer cells (14,16).…”