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Plant miR171 modulates mTOR pathway in HEK293 cells by targeting GNA12

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Abstract

Plant microRNAs have shown the capacity to regulate mammalian systems. The potential bioactivity of miR171vr, an isoform of the plant miR171, on human embryonic kidney 293 (HEK293) cells was investigated. Bioinformatics simulations revealed that human G protein subunit alpha 12 (GNA12) transcript could represent an excellent target for miR171vr. To confirm this prediction, in vitro experiments were performed using a synthetic microRNA designed on miR171vr sequence. MiR-treated cells showed a significant decrease of GNA12 mRNA and protein levels, confirming the putative cross-kingdom interaction. In addition, miR171vr determined the modulation of GNA12 downstream signaling factors, including mTOR, as expected. Finally, the effect of the plant miRNA on HEK293 cell growth and its stability in presence of several stressors, such as those miming digestive processes and procedures for preparing food, were evaluated. All this preliminary evidence would suggest that miR171vr, introduced by diet or as supplement in gene therapies, could potentially influence human gene expression, especially for treating disorders where GNA12 is over-expressed (i.e. oral cancer, breast and prostate adenocarcinoma) or mTOR kinase is down-regulated (e.g. obesity, type 2 diabetes, neurodegeneration).

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Abbreviations

miRNAs, miRs:

MicroRNAs

RISC:

RNA-induced silencing complex

AGOs:

Argonaute proteins

miR171:

MiRNA171

HEK293:

Human embryonic kidney 293 cells

miR171v:

MiR171 variant

UPE:

Max target accessibility-maximum energy to unpair the target site

HSP:

Length for complementarity scoring

GNA12:

Homo sapiens G protein subunit alpha 12

DMEM:

Dulbecco’s modified Eagle Medium

STR:

Starvation

MTT:

3-(4,5-Dimethyl-thiazol- 2-yl)-2,5-diphenyltetrazolium bromide

CNT:

Control

CNT SCR:

Different concentrations of synthetic miR171vr (1, 10 and 100 nM), or scrambled miRNA

PI3K:

P80-phosphatidylinositol 3-kinase

Akt:

Protein kinase B, both total and phosphorylated form

mTOR:

Mammalian target of rapamycin, both total and phosphorylated form

S6K:

P70-ribisomal protein S6 kinase, directly activated by mTOR

PP242:

ATP‑competitive inhibitor of mTOR

RASA2:

Ras GTPase-activating protein 2

HRas:

Harvey Ras

mTORC1 and mTORC2:

MTOR complexes

RhoGEF:

Ras homolog gene family guanine nucleotide exchange factor 12

RhoA:

Ras homolog gene family member A

ROCK:

Rho-associated coiled-coil containing protein kinase

PTEN:

Phosphatase and tensin homolog protein

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Authors and Affiliations

  1. Department of Biology, University of Rome “Tor Vergata”, via della Ricerca Scientifica 1, 00133, Rome, Italy

    Angelo Gismondi, Valentina Nanni, Valentina Monteleone, Claudia Colao, Gabriele Di Marco & Antonella Canini

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  1. Angelo Gismondi
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  2. Valentina Nanni
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  3. Valentina Monteleone
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Conceptualization: AG, VN, AC; Data curation: AG; Formal analysis: VN, VM, CC, GDM; Funding acquisition: AG, AC; Supervision: AG; Writing—original draft: AG; Writing—review & editing: all authors.

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Correspondence to Angelo Gismondi or Antonella Canini.

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Gismondi, A., Nanni, V., Monteleone, V. et al. Plant miR171 modulates mTOR pathway in HEK293 cells by targeting GNA12. Mol Biol Rep 48, 435–449 (2021). https://doi.org/10.1007/s11033-020-06070-6

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