The role of KCNQ1 in mouse and human gastrointestinal cancers
Kcnq1 , which encodes for the pore-forming α-subunit of a voltage-gated potassium channel, was identified as a gastrointestinal (GI) tract cancer susceptibility gene in multiple Sleeping Beauty DNA transposon-based forward genetic screens in mice. To confirm that Kcnq1 has a functional role in GI tr...
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Veröffentlicht in: | Oncogene 2014-07, Vol.33 (29), p.3861-3868 |
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Zusammenfassung: | Kcnq1
, which encodes for the pore-forming α-subunit of a voltage-gated potassium channel, was identified as a gastrointestinal (GI) tract cancer susceptibility gene in multiple
Sleeping Beauty
DNA transposon-based forward genetic screens in mice. To confirm that
Kcnq1
has a functional role in GI tract cancer, we created
Apc
Min
mice that carried a targeted deletion mutation in
Kcnq1
. Results demonstrated that
Kcnq1
is a tumor suppressor gene as
Kcnq1
mutant mice developed significantly more intestinal tumors, especially in the proximal small intestine and colon, and some of these tumors progressed to become aggressive adenocarcinomas. Gross tissue abnormalities were also observed in the rectum, pancreas and stomach. Colon organoid formation was significantly increased in organoids created from
Kcnq1
mutant mice compared with wild-type littermate controls, suggesting a role for
Kcnq1
in the regulation of the intestinal crypt stem cell compartment. To identify gene expression changes due to loss of
Kcnq1
, we carried out microarray studies in the colon and proximal small intestine. We identified altered genes involved in innate immune responses, goblet and Paneth cell function, ion channels, intestinal stem cells, epidermal growth factor receptor and other growth regulatory signaling pathways. We also found genes implicated in inflammation and in cellular detoxification. Pathway analysis using Ingenuity Pathway Analysis and Gene Set Enrichment Analysis confirmed the importance of these gene clusters and further identified significant overlap with genes regulated by
MUC2
and
CFTR
, two important regulators of intestinal homeostasis. To investigate the role of
KCNQ1
in human colorectal cancer (CRC), we measured protein levels of KCNQ1 by immunohistochemistry in tissue microarrays containing samples from CRC patients with liver metastases who had undergone hepatic resection. Results showed that low expression of KCNQ1 expression was significantly associated with poor overall survival. |
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ISSN: | 0950-9232 1476-5594 |
DOI: | 10.1038/onc.2013.350 |