RT Journal Article
SR Electronic
T1 Targeted Eicosanoid Profiling Reveals MicroRNA-155 Shifts PGE2/PGD2 Balance Towards Oncogenic State
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.04.08.032136
DO 10.1101/2020.04.08.032136
A1 Sinae Kim
A1 Eun Sung Lee
A1 Eun ji Lee
A1 Jae Yun Jung
A1 Sae Byul Lee
A1 Hee Jin Lee
A1 Jisun Kim
A1 Hee Jung Kim
A1 Jong Won Lee
A1 Byung Ho Son
A1 Gyungyub Gong
A1 Sei Hyun Ahn
A1 Suhwan Chang
YR 2020
UL http://biorxiv.org/content/early/2020/04/09/2020.04.08.032136.abstract
AB 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.