Targeted Eicosanoid Profiling Reveals MicroRNA-155 Shifts PGE2/PGD2 Balance Towards Oncogenic State

Kim, S.; Lee, E. S.; Lee, E. J.; Jung, J. Y.; Lee, S. B.; Lee, H. J.; Kim, J.; Kim, H. J.; Lee, J. W.; Son, B. H.; Gong, G.-Y.; Ahn, S.-H.; Chang, S.

doi:10.1101/2020.04.08.032136

bioRxiv · 10.1101/2020.04.08.032136

Targeted Eicosanoid Profiling Reveals MicroRNA-155 Shifts PGE2/PGD2 Balance Towards Oncogenic State

Kim, S.·Lee, E. S.·Lee, E. J.·Jung, J. Y.·Lee, S. B.·Lee, H. J.·Kim, J.·Kim, H. J.·Lee, J. W.·Son, B. H.·Gong, G.-Y.·Ahn, S.-H.·Chang, S.

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Abstract

microRNA-155 is a strong oncogenic microRNAs with multiple functions. To reveal its novel function in cancer metabolism, we performed a targeted metabolomic analysis of icosanoids, the key metabolites of inflammation-related carcinogenesis. We found miR-155-depleted cells expressed unbalanced prostaglandins, especially in PGE2 and PGD2. Subsequent analysis of primary cancer cells and 20 TNBC specimen indicated a positive correlation between miR-155 and PGE2/PGD2 ratio. Mechanistically, miR-155 controls the prostaglandin shift by up-regulating PGE2-producing enzymes PTGES/PTGES2 and down-regulating PGD2-producing enzyme PTGDS. Further analysis showed that the up-regulation of PTGES2 is driven by miR-155-cMYC axis whereas PTGES is transactivated by miR-155-KLF4 axis, indicating a dual-regulatory mode for the metabolic enzyme expression drives a shift in PGE2/PGD2 balance. Lastly, we show the miR-155-driven cellular proliferation is significantly restored by the siRNA of PTGES1/2, of which expression also correlates with patients survival. Taken altogether, our study reveals an unprecedented oncogenic function of miR-155 on prostaglandin regulation.

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Kim, S., Lee, E. S., Lee, E. J., Jung, J. Y., Lee, S. B., Lee, H. J., Kim, J., Kim, H. J., Lee, J. W., Son, B. H., Gong, G.-Y., Ahn, S.-H., Chang, S.. 2020-04-09. Targeted Eicosanoid Profiling Reveals MicroRNA-155 Shifts PGE2/PGD2 Balance Towards Oncogenic State. https://doi.org/10.1101/2020.04.08.032136

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