The aspirin-induced long non-coding RNA OLA1P2 blocks phosphorylated STAT3 homodimer formation.

Abstract

BACKGROUND:

Although the chemopreventive effects of aspirin have been extensively investigated, the roles of many cell components, such as long non-coding RNAs, in these effects are still not completely understood.

RESULTS:

We identify an aspirin-induced upregulated lncRNA, OLA1P2, in human colorectal cancer. Aspirin induces demethylation of the FOXD3 promoter and promotes expression of the FOXD3 gene. Subsequently, upregulated FOXD3 protein transcriptionally activates lncRNA OLA1P2 expression. OLA1P2 upregulation markedly affects STAT3 signaling pathway activity by inhibiting the nuclear import of phosphorylated STAT3. The phosphorylation of tyrosine-705 of STAT3 is the first step in OLA1P2 binding, and the formation of phosphorylated STAT3 homodimers is subsequently blocked. OLA1P2 interacts directly with STAT3 due to OLA1P2 sharing the same conservative STAT3 transcription response element as STAT3 targets. Regular use of aspirin dramatically decreases the number of metastatic nodules of cancer cells in immunodeficient mouse lungs, and OLA1P2 silencing markedly weakens the anti-metastatic activity of aspirin in the lungs. Additionally, low OLA1P2 levels are associated with malignant transformation and lower overall survival in cancers.

CONCLUSIONS:

The present study finds that the aspirin-FOXD3-OLA1P2-STAT3 axis exhibits exciting anticancer effects and provides new insights into the chemopreventive mechanisms underlying aspirin use.

• Authors: Haiyan Guo, Jun Liu, Qiwen Ben, Yuehong Qu, Man Li, Ying Wang, Wantao Chen, Jianjun Zhang
• Journal: Genome biology (Genome Biol) Vol. 17 Pg. 24 (Feb 22 2016) ISSN: 1474-760X [Electronic] England
• PMID: 26898989 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• FOXD3 protein, human
• Forkhead Transcription Factors
• RNA, Long Noncoding
• STAT3 Transcription Factor
• STAT3 protein, human
• Aspirin

Topics

• Animals
• Apoptosis (drug effects)
• Aspirin (administration & dosage)
• Cell Line, Tumor
• Cell Transformation, Neoplastic (drug effects)
• Colorectal Neoplasms (drug therapy, genetics, pathology)
• Forkhead Transcription Factors (biosynthesis, genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Mice
• Phosphorylation
• Protein Multimerization (drug effects)
• RNA, Long Noncoding (genetics)
• STAT3 Transcription Factor (chemistry, genetics, metabolism)
• Signal Transduction (drug effects)