Cross-kingdom inhibition of breast cancer growth by plant miR159

Abstract

MicroRNAs (miRNAs) are critical regulators of gene expression, and exert extensive impacts on development, physiology, and disease of eukaryotes. A high degree of parallelism is found in the molecular basis of miRNA biogenesis and action in plants and animals. Recent studies interestingly suggest a potential cross-kingdom action of plant-derived miRNAs, through dietary intake, in regulating mammalian gene expression. Although the source and scope of plant miRNAs detected in mammalian specimens remain controversial, these initial studies inspired us to determine whether plant miRNAs can be detected in Western human sera and whether these plant miRNAs are able to influence gene expression and cellular processes related to human diseases such as cancer. Here we found that Western donor sera contained the plant miRNA miR159, whose abundance in the serum was inversely correlated with breast cancer incidence and progression in patients. In human sera, miR159 was predominantly detected in the extracellular vesicles, and was resistant to sodium periodate oxidation suggesting the plant-originated 2'-O-methylation on the 3′ terminal ribose. In breast cancer cells but not non-cancerous mammary epithelial cells, a synthetic mimic of miR159 was capable of inhibiting proliferation by targeting TCF7 that encodes a Wnt signaling transcription factor, leading to a decrease in MYC protein levels. Oral administration of miR159 mimic significantly suppressed the growth of xenograft breast tumors in mice. These results demonstrate for the first time that a plant miRNA can inhibit cancer growth in mammals.

Literature review of baseline information to support the risk assessment of RNAi‐based GM plants

“…A synthetic mimic of MIR159 was capable of inhibiting cell proliferation in breast cancer cells but not non-cancerous mammary epithelial cells (Chin et al, 2016). Authors claim, "These results demonstrate for the first time that a plant miRNA can inhibit cancer growth in mammals.…”

Small RNA Modifications: Integral to Function and Disease

“…This conserved mechanism provides a rationale in translational research for promoting the stability of small RNA therapeutic agents, with the potential for more efficient RNAi therapy [22]. 2′- O -methylation in plant miRNAs also provides a potential mechanism for prolonging their functional half-life in the human body when ingested, supporting the intriguing – and still controversial – idea that small RNAs derived from plant-based diets can modulate human physiology [23–28]. …”

Toward the promise of microRNAs – Enhancing reproducibility and rigor in microRNA research

“…According to the hypothesis, microRNAs from food first survive processing, then pass through the harsh environment of the digestive tract intact, cross the intestinal barrier, enter the blood circulation, and finally, act systemically at zeptomolar to femtomolar concentrations to cause demonstrable phenotypes (see, for example, the concentrations in [85]). The premise of the function of such xenomiRs may come from studies of C. elegans, which takes up dsRNA from its environment and incorporates it effectively into the RNAi pathway.…”