The Contribution of Inflammatory Pathway Signaling and Microrna Changes to Colon Cancer Progression

Persistent Link:
http://hdl.handle.net/10150/299126
Title:
The Contribution of Inflammatory Pathway Signaling and Microrna Changes to Colon Cancer Progression
Author:
Onyeagucha, Benjamin Chidi
Issue Date:
2013
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Embargo:
Release after 09-Jul-2015
Abstract:
Inflammation and aberrant microRNAs expressions promote colon cancer growth and progression. However, the molecular mechanisms that link these pathways remain to be determined. In this dissertation, the causal relationship between inflammation and aberrant microRNAs expressions were explored. Elevated expression of prostaglandin E₂ (PGE₂) receptor EP4 has been seen in human colon cancer. However, the mechanism by which EP4 receptor protein is deregulated is not known. Experiments in this dissertation demonstrate, for the first time, that the EP4 receptor is negatively regulated by miR-101.In previous work, we show that S100P is induced by stimulation of the PGE₂/EP4 receptor signaling pathway. S100P is a ligand for Receptor for Advance Glycation End-products (RAGE). However, little is known about the downstream targets of S100P/RAGE signaling. Here, we demonstrated that S100P/RAGE receptor signaling induces expression of miR-155 via the transcription factor AP-1. In addition, we investigated the genes that are downstream of S100P/RAGE/miR-155 pathway. Our microarrays and bioinformatics analyses identified two novel miR-155 targets, WNK1 and ZNF493 that are down-regulated upon activation of the S100P/RAGE/miR-155 pathway. Lastly, we investigated whether inhibition of S100P/RAGE signaling pathway would be beneficial as a cancer therapy using methyl-2-acetamidoacrylate (M2AA). M2AA treatments decreased colon cancer cells viability and also suppressed colon tumor growth and metastasis in vitro and also in the CAM assay in vivo. Taken together, our results suggest that modulation of S100P/RAGE signaling by M2AA offers therapeutic potential as anti-metastatic agents. In summary, this dissertation provides new insights on the molecular events that link inflammation pathways and microRNAs to colon cancer as well as show that therapeutic strategies targeting these pathways could be effective in treatment of neoplasia.
Type:
text; Electronic Dissertation
Keywords:
COX-2; EP4; miR-101; miR-155; S100P; Cancer Biology; Colon cancer
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Cancer Biology
Degree Grantor:
University of Arizona

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleThe Contribution of Inflammatory Pathway Signaling and Microrna Changes to Colon Cancer Progressionen_US
dc.creatorOnyeagucha, Benjamin Chidien_US
dc.contributor.authorOnyeagucha, Benjamin Chidien_US
dc.date.issued2013en
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.releaseRelease after 09-Jul-2015en_US
dc.description.abstractInflammation and aberrant microRNAs expressions promote colon cancer growth and progression. However, the molecular mechanisms that link these pathways remain to be determined. In this dissertation, the causal relationship between inflammation and aberrant microRNAs expressions were explored. Elevated expression of prostaglandin E₂ (PGE₂) receptor EP4 has been seen in human colon cancer. However, the mechanism by which EP4 receptor protein is deregulated is not known. Experiments in this dissertation demonstrate, for the first time, that the EP4 receptor is negatively regulated by miR-101.In previous work, we show that S100P is induced by stimulation of the PGE₂/EP4 receptor signaling pathway. S100P is a ligand for Receptor for Advance Glycation End-products (RAGE). However, little is known about the downstream targets of S100P/RAGE signaling. Here, we demonstrated that S100P/RAGE receptor signaling induces expression of miR-155 via the transcription factor AP-1. In addition, we investigated the genes that are downstream of S100P/RAGE/miR-155 pathway. Our microarrays and bioinformatics analyses identified two novel miR-155 targets, WNK1 and ZNF493 that are down-regulated upon activation of the S100P/RAGE/miR-155 pathway. Lastly, we investigated whether inhibition of S100P/RAGE signaling pathway would be beneficial as a cancer therapy using methyl-2-acetamidoacrylate (M2AA). M2AA treatments decreased colon cancer cells viability and also suppressed colon tumor growth and metastasis in vitro and also in the CAM assay in vivo. Taken together, our results suggest that modulation of S100P/RAGE signaling by M2AA offers therapeutic potential as anti-metastatic agents. In summary, this dissertation provides new insights on the molecular events that link inflammation pathways and microRNAs to colon cancer as well as show that therapeutic strategies targeting these pathways could be effective in treatment of neoplasia.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectCOX-2en_US
dc.subjectEP4en_US
dc.subjectmiR-101en_US
dc.subjectmiR-155en_US
dc.subjectS100Pen_US
dc.subjectCancer Biologyen_US
dc.subjectColon canceren_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineCancer Biologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
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