title: KRAS mutation leads to decreased expression of regulator of calcineurin 2, resulting in tumor proliferation in colorectal cancer.
abstract: KRAS mutations occur in 30-40% of all cases of human colorectal cancer (CRC). However, to date, specific therapeutic agents against KRAS-mutated CRC have not been developed. We previously described the generation of mouse models of colon cancer with and without Kras mutations (CDX2P-G22Cre;Apc(flox/flox); LSL-Kras(G12D) and CDX2P-G22Cre;Apc(flox/flox) mice, respectively). Here, the two mouse models were compared to identify candidate genes, which may represent novel therapeutic targets or predictive biomarkers. Differentially expressed genes in tumors from the two mouse models were identified using microarray analysis, and their expression was compared by quantitative reverse transcription-PCR (qRT-PCR) and immunohistochemical analyses in mouse tumors and surgical specimens of human CRC, with or without KRAS mutations, respectively. Furthermore, the functions of candidate genes were studied using human CRC cell lines. Microarray analysis of 34 000 transcripts resulted in the identification of 19 candidate genes. qRT-PCR analysis data showed that four of these candidate genes (Clps, Irx5, Bex1 and Rcan2) exhibited decreased expression in the Kras-mutated mouse model. The expression of the regulator of calcineurin 2 (RCAN2) was also observed to be lower in KRAS-mutated human CRC. Moreover, inhibitory function for cancer cell proliferation dependent on calcineurin was indicated with overexpression and short hairpin RNA knockdown of RCAN2 in human CRC cell lines. KRAS mutations in CRC lead to a decrease in RCAN2 expression, resulting in tumor proliferation due to derepression of calcineurin-nuclear factor of activated T cells (NFAT) signaling. Our findings suggest that calcineurin-NFAT signal may represent a novel molecular target for the treatment of KRAS-mutated CRC.
authors.affiliation: Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Niitsu
authors.affiliation: Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.|Department of Surgery, Institute for Clinical Research, National Hospital Organization Kure Medical Center and Chu-goku Cancer Center, Kure City, Hiroshima, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Hinoi
authors.affiliation: Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.|Department of Surgery, Tsuchiya General Hospital, Hiroshima, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kawaguchi
authors.affiliation: Department of Molecular Pathology, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Sentani
authors.affiliation: Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Yuge
authors.affiliation: Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kitadai
authors.affiliation: Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Sotomaru
authors.affiliation: Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Adachi
authors.affiliation: Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.|Department of Surgery, Hiroshima General Hospital of West Japan Railway Company, Hiroshima, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.|Department of Surgery, Hiroshima City Funairi Citizens Hospital, Hiroshima, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Miguchi
authors.affiliation: Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kochi
authors.affiliation: Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Sada
authors.affiliation: Department of Surgery, National Hospital Organization Higashihiroshima Medical Center, Hiroshima, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Shimomura
authors.affiliation: Department of Molecular Pathology, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Oue
authors.affiliation: Department of Molecular Pathology, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: W
authors.initials: W
authors.lastname: Yasui
authors.affiliation: Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Ohdan