MACC1 promotes carcinogenesis of colorectal cancer via β-catenin signaling pathway.
MACC1 promotes carcinogenesis of colorectal cancer via β-catenin signaling pathway.
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MACC1通过β-catenin信号通路促进了大肠癌的致癌作用。
DOI：
10.18632/oncotarget.1993
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发表时间：
2014-06-15
期刊：
影响因子：
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通讯作者：
Han A
中科院分区：
文献类型：
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作者：
Zhen T;Dai S;Li H;Yang Y;Kang L;Shi H;Zhang F;Yang D;Cai S;He Y;Liang Y;Han A
在此，我们证实了结肠癌转移相关蛋白1（MACC 1）和β-连环蛋白在结直肠癌（CRC）细胞和组织中的表达分别高于正常结肠上皮细胞系和邻近非肿瘤结直肠粘膜（ANM）组织。MACC 1表达与组织学分化（p<0.001）、UICC分期（p=0.029）、T分类（p=0.017）和N分类（p=0.023）显著相关。考克斯回归分析显示，MACC 1/异常β-连环蛋白高表达是CRC患者总生存率降低的最强独立预后指标。大肠癌组织中MACC 1的表达与β-catenin的异常表达呈正相关。MACC 1基因敲除在体内和体外均显著抑制细胞增殖、迁移、侵袭、集落形成和肿瘤发生，但诱导CRC细胞凋亡。此外，MACC 1过表达增加了Met、β-catenin及其下游基因（包括c-Myc、细胞周期蛋白D1和MMP 9）的表达，以及其上游基因c-GSK 3 β（Ser 9）的表达。此外，MACC 1增加HCT 116细胞中的波形蛋白并抑制E-钙粘蛋白。MACC 1的沉默逆转了所有这些变化。我们的研究结果首次提示MACC 1通过β-catenin信号通路和间质-上皮转化在结直肠癌的发生发展中发挥重要作用。
Here we confirmed that metastasis-associated in colon cancer 1 (MACC1) and β-catenin expression were higher in colorectal cancer (CRC) cells and tissues than those in normal colonic epithelial cell line and adjacent non-tumour colorectal mucosa (ANM) tissues, respectively. MACC1 expression was significantly related to histological differentiation (p<0.001), UICC stage (p=0.029), T classification (p=0.017), and N classification (p=0.023). Cox regression analysis demonstrated that high MACC1/abnormal β-catenin expression was the strongest independent prognostic indicator for reduced overall survival in CRC patients. Significant positive correlation between MACC1 expression and abnormal β-catenin expression was found in CRC tissues. MACC1 knockdown dramatically inhibited cellular proliferation, migration, invasion, colony formation, and tumorigenesis, both in vitro and in vivo, but induced apoptosis in CRC cells. Further MACC1 over-expression increased Met, β-catenin, and its downstream genes including c-Myc, cyclin D1, and MMP9 expression, and its upstream gene phos-GSK3β (Ser9) expression. In addition, MACC1 increased vimentin and suppressed E-cadherin in HCT116 cells. Silencing of MACC1 reversed all these changes. Our results firstly suggest that MACC1 plays an important role in carcinogenesis and progression of CRC through β-catenin signaling pathway and mesenchymal-epithelial transition.