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Journal of Experimental & Clinical Cancer Research

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01-12-2021 | Breast Cancer | Research

Targeted eicosanoids profiling reveals a prostaglandin reprogramming in breast Cancer by microRNA-155

Authors: Sinae Kim, Eun Sung Lee, Eun ji Lee, Jae Yun Jung, Sae Byul Lee, Hee Jin Lee, Jisun Kim, Hee Jeong Kim, Jong Won Lee, Byung Ho Son, Gyungyub Gong, Sei-Hyun Ahn, Suhwan Chang

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

Abstract

Background

Prostaglandin is one of the key metabolites for inflammation-related carcinogenesis. Despite the microRNA-155 is implicated in various types of cancers, it’s function in prostaglandin metabolism is largely unknown.

Methods

A targeted profiling of eicosanoids including prostaglandin, leukotriene and thromboxanes was performed in miR-155 deficient breast tumors and cancer cells. The molecular mechanism of miR-155-mediated prostaglandin reprogramming was investigated in primary and cancer cell lines, by analyzing key enzymes responsible for the prostaglandin production.

Results

We found miR-155-deficient breast tumors, plasma of tumor-bearing mouse and cancer cells show altered prostaglandin level, especially for the prostaglandin E2 (PGE2) and prostaglandin D2 (PGD2). Subsequent analysis in primary cancer cells, 20 triple-negative breast cancer (TNBC) specimens and breast cancer cell lines with miR-155 knockdown consistently showed a positive correlation between miR-155 level and PGE2/PGD2 ratio. Mechanistically, we reveal the miR-155 reprograms the prostaglandin metabolism by up-regulating PGE2-producing enzymes PTGES/PTGES2 while down-regulating PGD2-producing enzyme PTGDS. Further, we show the up-regulation of PTGES2 is driven by miR-155-cMYC axis, whereas PTGES is transactivated by miR-155-KLF4. Thus, miR-155 hires dual-regulatory mode for the metabolic enzyme expression to reprogram the PGE2/PGD2 balance. Lastly, we show the miR-155-driven cellular proliferation is restored by the siRNA of PTGES1/2, of which expression also significantly correlates with breast cancer patients’ survival.

Conclusions

Considering clinical trials targeting PGE2 production largely have focused on the inhibition of Cox1 or Cox2 that showed cardiac toxicity, our data suggest an alternative way for suppressing PGE2 production via the inhibition of miR-155. As the antagomiR of miR-155 (MRG-106) underwent a phase-1 clinical trial, its effect should be considered and analyzed in prostaglandin metabolism in tumor.

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Title: Targeted eicosanoids profiling reveals a prostaglandin reprogramming in breast Cancer by microRNA-155
Authors: Sinae Kim
Eun Sung Lee
Eun ji Lee
Jae Yun Jung
Sae Byul Lee
Hee Jin Lee
Jisun Kim
Hee Jeong Kim
Jong Won Lee
Byung Ho Son
Gyungyub Gong
Sei-Hyun Ahn
Suhwan Chang
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Breast Cancer
Breast Cancer
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-021-01839-4

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Abstract

Background

Methods

Results

Conclusions

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