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

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Abstract
BackgroundProstaglandin 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.MethodsA 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.ResultsWe 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.ConclusionsConsidering 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.
Author(s)
김시내이은성이은지정재윤이새별이희진김지선김희정이종원손병호공경엽안세현장수환
Issued Date
2021
Type
Article
Keyword
KLF4Microrna-155MycPTGES1PTGES2Prostaglandin D2Prostaglandin E2TNBC.
DOI
10.1186/s13046-021-01839-4
URI
https://oak.ulsan.ac.kr/handle/2021.oak/7529
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_doaj_primary_oai_doaj_org_article_2731acedd910428daab5d405955437d3&context=PC&vid=ULSAN&lang=ko_KR&search_scope=default_scope&adaptor=primo_central_multiple_fe&tab=default_tab&query=any,contains,Targeted%20eicosanoids%20profiling%20reveals%20a%20prostaglandin%20reprogramming%20in%20breast%20Cancer%20by%20microRNA-155&offset=0&pcAvailability=true
Publisher
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
Location
미국
Language
영어
ISSN
1756-9966
Citation Volume
40
Citation Number
1
Citation Start Page
43
Citation End Page
53
Appears in Collections:
Medicine > Medicine
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