Indiana University-Purdue University Indianapolis (IUPUI) / The 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. / 2022-05-06
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/22732 |
| Date | 04 1900 |
| Creators | Martin, Matthew Peter |
| Contributors | Lu, Tao, Safa, Ahmad, Corson, Tim, Jerde, Travis, Pollok, Karen |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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