Dataset Information

Prostaglandin E₂ Induces miR675-5p to Promote Colorectal Tumor Metastasis via Modulation of p53 Expression.

ABSTRACT:

Background & aims

Prostaglandin E₂ (PGE₂) promotes colorectal tumor formation and progression by unknown mechanisms. We sought to identify microRNAs (miRNAs) that might mediate the effects of PGE₂ on colorectal cancer (CRC) development.

Methods

We incubated LS174T colorectal cancer cells with PGE₂ or without (control) and used miRNA-sequencing technology to compare expression patterns of miRNAs. We knocked down levels of specific miRNAs or proteins in cells using small interfering RNAs or genome editing. Cells were analyzed by immunoblot, quantitative polymerase chain reaction, chromosome immunoprecipitation, cell invasion, and luciferase reporter assays; we measured gene expression, binding activity, cell migration and invasion, and transcriptional activity of transcription factors. NOD-scidIL-2Rg^-/- mice were given injections of LS174T cells, and growth of primary tumors and numbers of liver and lung metastases were quantified and analyzed by histology. We used public databases to identify correlations in gene expression pattern with patient outcomes.

Results

We identified miRNA 675-5p (miR675-5p) as the miRNA most highly up-regulated by incubation of colorectal cancer cells with PGE₂. PGE₂ increased expression of miR675-5p by activating expression of Myc, via activation of protein kinase B, also known as (AKT), nuclear factor ?B, and ?-catenin. PGE₂ increased the invasive activities of cultured CRC cells. LS174T cells incubated with PGE₂ formed more liver and lung metastases in mice than control LS174T cells. We identified a 3' untranslated region in the TP53 messenger RNA that bound miR675-5p; binding resulted in loss of the p53 protein. Expression of miR675-5p or its precursor RNA, H19, correlated with expression of cyclooxygenase-1 and cyclooxygenase-2 and shorter survival times of patients with CRC.

Conclusions

We found that treatment of mice with PGE₂ increased CRC cells invasive activity and ability to form liver and lung metastases. PGE₂ down-regulates expression of p53 by increasing expression of miR675-5p, which binds to and prevents translation of TP53 messenger RNA. These findings provide insight into the mechanisms by which PGE₂ promotes tumor development and progression. Strategies to target PGE₂ might be developed for treatment of CRC.

SUBMITTER: Cen B

PROVIDER: S-EPMC7062589 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Publications

Prostaglandin E<sub>2</sub> Induces miR675-5p to Promote Colorectal Tumor Metastasis via Modulation of p53 Expression.

Cen Bo B Lang Jessica D JD Du Yuchen Y Wei Jie J Xiong Ying Y Bradley Norma N Wang Dingzhi D DuBois Raymond N RN

Gastroenterology 20191114 4

<h4>Background & aims</h4>Prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) promotes colorectal tumor formation and progression by unknown mechanisms. We sought to identify microRNAs (miRNAs) that might mediate the effects of PGE<sub>2</sub> on colorectal cancer (CRC) development.<h4>Methods</h4>We incubated LS174T colorectal cancer cells with PGE<sub>2</sub> or without (control) and used miRNA-sequencing technology to compare expression patterns of miRNAs. We knocked down levels of specific miRNAs ...[more]

PMID: 31734182

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Project description:BackgroundThe low expression of miR93/25 (members of miR-106b~25 cluster) promoted the invasion and metastasis of colon cancer cells, which predicted poor survival. However, the role of miR-106b-5p, the member of miR-106b~25 cluster, in colorectal cancer (CRC) remains unclear.MethodsBioinformatics methods were used to predict the potential pairs of lncRNA-miRNA-mRNA. In situ hybridization and qPCR were used to evaluate the expression of MALAT1 and miR-106b-5p in the paraffin-embedded normal and CRC tissues. Kaplan-Meier analysis with the log-rank test was used for survival analyses. Immunohistochemistry staining was applied to investigate the expression of SLAIN2. Fluorescence recovery after photobleaching assay was applied to observe the microtubule (MT) mobility. In vitro and in vivo invasion and metastasis assays were used to explore the function of MALAT1/miR-106b-5p/SLAIN2 in the progression of CRC.FindingsmiR-106b-5p was identified as a suppressor in CRC. Functionally, ectopic or silencing the expression of miR-106b-5p inhibited or promoted the invasion and metastasis of CRC cells in vitro and in vivo. The long non-coding RNA MALAT1 regulated the miR-106b-5p expression and further mediated the mobility of SLAIN2-related MTs by functioning as a competing endogenous RNA in vitro and in vivo, which resulted in the progression of CRC. Clinically, low miR-106b-5p expression predicted poor survival of CRC patients, especially in combination with high MALAT1/ SLAIN2 expression.InterpretationmiR-106b-5p served as a suppressor in combination with MALAT1/miR-106b-5p/SLAIN2, which might be a group of potential prognostic biomarkers in the prognosis of CRC. FUND: This work was supported by National Program Project for Precision Medicine in National Research and Development Plan of China (2016YFC0905300), National Natural Science Foundation of China (81572930), National Key Research and Development Program of the Ministry of Science and Technology of China (2016YFC0905303, 2016YFC1303200), Beijing Science and Technology Program (D17110002617004), Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2018PT32012), CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-001), Incentive Fund for Academic Leaders of Oncology Hospital, Chinese Academy of Medical Sciences (RC2016003), and Beijing Hope Run Special Fund from Cancer Foundation of China (LC2017A19). The project of Shanghai Jiaotong Univversity (YG2017QN30).

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Dataset Information

Prostaglandin E₂ Induces miR675-5p to Promote Colorectal Tumor Metastasis via Modulation of p53 Expression.

Background & aims

Methods

Results

Conclusions

Publications

Prostaglandin E<sub>2</sub> Induces miR675-5p to Promote Colorectal Tumor Metastasis via Modulation of p53 Expression.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Prostaglandin E2 Induces miR675-5p to Promote Colorectal Tumor Metastasis via Modulation of p53 Expression.

Background & aims

Methods

Results

Conclusions

Publications

Prostaglandin E<sub>2</sub> Induces miR675-5p to Promote Colorectal Tumor Metastasis via Modulation of p53 Expression.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Prostaglandin E₂ Induces miR675-5p to Promote Colorectal Tumor Metastasis via Modulation of p53 Expression.