miR-210: fine-tuning the hypoxic response

Abstract

Hypoxia is a central component of the tumor microenvironment and represents a major source of therapeutic failure in cancer therapy. Recent work has provided a wealth of evidence that noncoding RNAs and, in particular, microRNAs, are significant members of the adaptive response to low oxygen in tumors. All published studies agree that miR-210 specifically is a robust target of hypoxia-inducible factors, and the induction of miR-210 is a consistent characteristic of the hypoxic response in normal and transformed cells. Overexpression of miR-210 is detected in most solid tumors and has been linked to adverse prognosis in patients with soft-tissue sarcoma, breast, head and neck, and pancreatic cancer. A wide variety of miR-210 targets have been identified, pointing to roles in the cell cycle, mitochondrial oxidative metabolism, angiogenesis, DNA damage response, and cell survival. Additional microRNAs seem to be modulated by low oxygen in a more tissue-specific fashion, adding another layer of complexity to the vast array of protein-coding genes regulated by hypoxia.

Fig. 10.1

Schematic view of microRNA (miRNA) biogenesis and action. RNA polymerase II (Pol II) transcribes genes that encode miRNAs into primary miRNAs, which usually have a 5′ cap structure and a 3′ poly(A) tail as protein-coding messenger RNAs (mRNAs). The pri-miRNA is first processed in the nucleus by the microprocessor by two partners, Pasha and Drosha, into precursor miRNAs (pre-miRNAs) that are approximately 70 nucleotides in length and have a stem-loop structure. The pre-miRNA is then exported into cytoplasm and further processed by a type III RNA endonuclease Dicer to generate a mature miRNA duplex (~22 nucleotides in length). The sense strand of the miRNA duplex is then loaded into the RNA-induced silencing complex (RISC), whereas the complementary “star” strand (*) of the miRNA duplex is degraded. The RISC regulates gene expression through the inhibition of RNA translation or degradation of target mRNA by base pairing the “seed region” of an miRNA to the 3′ untranslated region of its target mRNA. This figure is modified from Huang et al. (2010)

Fig. 10.2

Experimentally identified micro RNA target genes implicated in cancer biology. Genes that have been experimentally identified as miR-210 targets can be classified into five major functional categories: mitochondrial metabolism, cell cycle control, angiogenesis, apoptosis, and DNA damage repair, indicating a complex functional network regulated by miR-210 in the hypoxic microenvironment in which tumor cells reside