Loss of Tumor Suppressor C9orf9 Promotes Metastasis in Colorectal Cancer.
Loss of Tumor Suppressor C9orf9 Promotes Metastasis in Colorectal Cancer.
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DOI：
10.3390/biom13020312
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发表时间：
2023-02-07
期刊：
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
肿瘤样本的全基因组测序鉴定出数千种体细胞突变。然而，这些基因或突变在调节癌症进展中的功能仍不清楚。我们之前在结直肠癌患者中进行了外显子组测序，并在C9 orf 9中发现了一个剪接突变。随后基于50例样本验证队列的C9 orf 9基因靶向测序也发现了两个功能突变，表明野生型C9 orf 9的缺失可能参与结直肠癌的肿瘤发生。在本研究中，我们旨在进一步证实C9 orf 9在CRC表型中的功能。我们对肿瘤和匹配的正常样品的Q-PCR分析发现，C9 orf 9在CRC样品中下调。功能分析表明，C9 orf 9主要对癌细胞的迁移和侵袭发挥其抑癌作用，并且其缺失对于某些肿瘤微环境信号诱导体内EMT和转移是必需的。RNA测序显示，稳定表达的C9 orf 9可以抑制几种转移相关基因和途径的表达，包括血管内皮生长因子A（VEGFA），其是在正常生理和肿瘤血管生成中起关键作用的必需内皮细胞有丝分裂原之一。总之，我们的结果表明，C9 orf 9的丢失有助于CRC的恶性表型。C9 orf 9可能是一种新的结直肠癌转移抑制因子。
The whole genome sequencing of tumor samples identifies thousands of somatic mutations. However, the function of these genes or mutations in regulating cancer progression remains unclear. We previously performed exome sequencing in patients with colorectal cancer, and identified one splicing mutation in C9orf9. The subsequent target sequencing of C9orf9 gene based on a validation cohort of 50 samples also found two function mutations, indicating that the loss of wild-type C9orf9 may participate in the tumorigenesis of colorectal cancer. In this research, we aimed to further confirm the function of C9orf9 in the CRC phenotype. Our Q-PCR analysis of the tumor and matched normal samples found that C9orf9 was downregulated in the CRC samples. Function assays revealed that C9orf9 exerts its tumor suppressor role mainly on cancer cell migration and invasion, and its loss was essential for certain tumor-microenvironment signals to induce EMT and metastasis in vivo. RNA-sequencing showed that stable-expressing C9orf9 can inhibit the expression of several metastasis-related genes and pathways, including vascular endothelial growth factor A (VEGFA), one of the essential endothelial cell mitogens which plays a critical role in normal physiological and tumor angiogenesis. Overall, our results showed that the loss of C9orf9 contributes to the malignant phenotype of CRC. C9orf9 may serve as a novel metastasis repressor for CRC.
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