Mindin serves as a tumour suppressor gene during colon cancer progression through MAPK/ERK signalling pathway in mice
Mindin serves as a tumour suppressor gene during colon cancer progression through MAPK/ERK signalling pathway in mice
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Mindin 通过 MAPK/ERK 信号通路在小鼠结肠癌进展过程中充当肿瘤抑制基因
DOI：
10.1111/jcmm.15332
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发表时间：
2020-07-02
影响因子：
5.3
通讯作者：
Guleng, Bayasi
中科院分区：
文献类型：
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作者：
Cheng, Xiao-Shen;Huo, Ya-Ni;Guleng, Bayasi
Mindin在广谱免疫反应中很重要。另一方面，我们以前报道过mindin通过Egr-1介导的调节阻断血管生成来减弱人类结肠癌的发展。然而，在我们最近的研究中，小鼠原始mindin直接抑制同基因结直肠癌（CRC）的生长，我们的目的是进一步确定mindin在小鼠CRC发展过程中的作用。我们建立了具有稳定的mindin敲低或过表达的小鼠同基因CRC CMT 93和CT 26 WT细胞系。这些细胞也被皮下注射到C57 BL/6和BALB/c小鼠，以及建立结肠炎相关的结肠直肠癌（CAC）小鼠模型，用基于慢病毒的过表达和敲低mindin治疗。此外，我们使用具有CAC模型的CRISPR-Cas9系统产生了mindin敲除小鼠。我们的数据显示，mindin的过表达抑制了CMT 93和CT 26 WT结肠癌细胞系中的细胞增殖，而mindin的沉默通过ERK和c-Fos途径和细胞周期控制促进了体外细胞增殖。此外，在皮下移植和AOM/DSS诱导的CAC模型中，mindin的过表达显着抑制体内肿瘤生长。因此，沉默mindin逆转了这些体内观察结果。不出所料，在mindin缺陷小鼠的CAC模型中，肿瘤生长得到了促进。因此，mindin在结肠癌进展过程中起着直接的肿瘤抑制作用，这表明mindin可能被开发为CRC的治疗靶点。
Mindin is important in broad spectrum of immune responses. On the other hand, we previously reported that mindin attenuated human colon cancer development by blocking angiogenesis through Egr-1-mediated regulation. However, the mice original mindin directly suppressed the syngenic colorectal cancer (CRC) growth in our recent study and we aimed to further define the role of mindin during CRC development in mice. We established the mouse syngeneic CRC CMT93 and CT26 WT cell lines with stable mindin knock-down or overexpression. These cells were also subcutaneously injected into C57BL/6 and BALB/c mice as well as established a colitis-associated colorectal cancer (CAC) mouse model treated with lentiviral-based overexpression and knocked-down of mindin. Furthermore, we generated mindin knockout mice using a CRISPR-Cas9 system with CAC model. Our data showed that overexpression of mindin suppressed cell proliferation in both of CMT93 and CT26 WT colon cancer cell lines, while the silencing of mindin promoted in vitro cell proliferation via the ERK and c-Fos pathways and cell cycle control. Moreover, the overexpression of mindin significantly suppressed in vivo tumour growth in both the subcutaneous transplantation and the AOM/DSS-induced CAC models. Consistently, the silencing of mindin reversed these in vivo observations. Expectedly, the tumour growth was promoted in the CAC model on mindin-deficient mice. Thus, mindin plays a direct tumour suppressive function during colon cancer progression and suggesting that mindin might be exploited as a therapeutic target for CRC.