KRAS mutation leads to decreased expression of regulator of calcineurin 2, resulting in tumor proliferation in colorectal cancer.
KRAS mutation leads to decreased expression of regulator of calcineurin 2, resulting in tumor proliferation in colorectal cancer.
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DOI：
10.1038/oncsis.2016.47
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发表时间：
2016-08-15
期刊：
影响因子：
6.2
通讯作者：
Ohdan, H.
中科院分区：
文献类型：
--
作者：
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.
KRAS突变发生在30-40%的人结直肠癌（CRC）病例中。然而，迄今为止，尚未开发针对KRAS突变的CRC的特异性治疗剂。我们先前描述了具有和不具有Kras突变的结肠癌小鼠模型的产生（分别为CDX 2 P-G22 Cre;Apcflox/flox; LSL-KrasG 12 D和CDX 2 P-G22 Cre;Apcflox/flox小鼠）。在这里，比较了两种小鼠模型以鉴定候选基因，这些基因可能代表新的治疗靶点或预测性生物标志物。使用微阵列分析鉴定来自两种小鼠模型的肿瘤中的差异表达基因，并通过定量逆转录-PCR（qRT-PCR）和免疫组织化学分析比较它们在小鼠肿瘤和人CRC手术标本（分别具有或不具有KRAS突变）中的表达。此外，使用人CRC细胞系研究候选基因的功能。34000个转录本的微阵列分析导致19个候选基因的鉴定。qRT-PCR分析数据显示，这些候选基因中的4个（Clps、Irx 5、Bex 1和Rcan 2）在Kras突变小鼠模型中表现出表达降低。在KRAS突变的人CRC中也观察到钙调磷酸酶2（RCAN 2）的调节剂的表达较低。此外，依赖于钙调磷酸酶的癌细胞增殖的抑制功能在人CRC细胞系中通过RCAN 2的过表达和短发夹RNA敲低来指示。CRC中的KRAS突变导致RCAN 2表达降低，从而由于钙调神经磷酸酶-活化T细胞核因子（NFAT）信号传导的去抑制而导致肿瘤增殖。我们的研究结果表明，钙调神经磷酸酶-NFAT信号可能是一种新的分子靶点，用于治疗KRAS突变的CRC。
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;Apcflox/flox; LSL-KrasG12D and CDX2P-G22Cre;Apcflox/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.
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