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2016 ; 5
(8
): e253
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KRAS mutation leads to decreased expression of regulator of calcineurin 2,
resulting in tumor proliferation in colorectal cancer
#MMPMID27526107
Niitsu H
; Hinoi T
; Kawaguchi Y
; Sentani K
; Yuge R
; Kitadai Y
; Sotomaru Y
; Adachi T
; Saito Y
; Miguchi M
; Kochi M
; Sada H
; Shimomura M
; Oue N
; Yasui W
; Ohdan H
Oncogenesis
2016[Aug]; 5
(8
): e253
PMID27526107
show ga
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.