Genetic Approach to Discover ARMC4 as a Novel NF-κB Negative Regulator and Tumor Suppressor in Colorectal Cancer

dc.contributor.advisorLu, Tao
dc.contributor.authorMartin, Matthew Peter
dc.contributor.otherSafa, Ahmad
dc.contributor.otherCorson, Tim
dc.contributor.otherJerde, Travis
dc.contributor.otherPollok, Karen
dc.date.accessioned2020-05-08T12:11:58Z
dc.date.available2020-05-08T12:11:58Z
dc.date.issued2020-04
dc.degree.date2020en_US
dc.degree.disciplinePharmacology & Toxicology
dc.degree.grantorIndiana Universityen_US
dc.degree.levelPh.D.en_US
dc.descriptionIndiana University-Purdue University Indianapolis (IUPUI)en_US
dc.description.abstractThe nuclear factor κB (NF-κB) plays pivotal roles in inflammatory and immune responses and in cancer. Therefore, understanding its regulation holds great promise for disease therapy. Using validation-based insertional mutagenesis (VBIM), a powerful technique established by us, we discovered armadillo repeat containing protein 4 (ARMC4) as a novel negative regulator of NF-κB in colorectal cancer (CRC). ARMC4 is a rarely studied protein only known to date for its role in primary ciliary dyskinesia (PCD) and mouse spermatogenesis. Thus, my work reveals a completely new facet of ARMC4 function that has never been reported before. We showed that ARMC4 overexpression downregulated the expression of NF-κB-dependent genes, many of which are related to cancer. Additionally, compared to the vector control group, overexpression of ARMC4 in HEK293 cells or CRC HT29, DLD1, and HCT116 cells dramatically reduced NF-κB activity, cellular proliferation, anchorage-independent growth, and migratory ability in vitro, and unsurprisingly, significantly decreased xenograft tumor growth in vivo. In contrast, shARMC4 knockdown cells showed quite opposite effect. Furthermore, co-immunoprecipitation (Co-IP) experiment confirmed that ARMC4 may form a complex with the p65 subunit of NF-κB. Importantly, immunohistochemistry (IHC) data exhibited much lower ARMC4 expression level in CRC patient tumor tissues compared to normal tissues, indicating that ARMC4 may function as a tumor suppressor in CRC. To conclude, my important findings for the first time uncovered the negative regulatory function of ARMC4 in NF-κB signaling, and present ARMC4 as an innovative therapeutic target in CRC treatment.en_US
dc.description.embargo2022-05-06
dc.identifier.urihttps://hdl.handle.net/1805/22732
dc.identifier.urihttp://dx.doi.org/10.7912/C2/340
dc.language.isoen_USen_US
dc.subjectcanceren_US
dc.subjectcolorectalen_US
dc.subjectNF-kBen_US
dc.titleGenetic Approach to Discover ARMC4 as a Novel NF-κB Negative Regulator and Tumor Suppressor in Colorectal Canceren_US
dc.typeDissertation
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