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Abstract：
Lung metastasis is the second most common type of metastasis in colorectal cancer. Specific treatments for lung metastasis have not been developed since the underlying mechanisms are poorly understood. The present study aimed to elucidate the molecular basis of lung metastasis in colorectal cancer. In a mouse model, cell lines that were highly metastatic to the lungs were established by injecting colorectal cancer cells through the tail vein and removing them from the lungs. Differential gene expression comparing the transfected cells with their parental cells was investigated using DNA microarrays. The results were functionally interpreted using gene enrichment analysis and validated using reverse transcription-quantitative PCR (RT-qPCR). The isoforms of the identified genes were examined by melting curve analysis. The present study established colorectal cancer cell lines that were highly metastatic to the lungs. DNA microarray experiments revealed that genes (N-cadherin, VE-cadherin, Six4, Akt and VCAM1) involved in motility, proliferation and adhesion were upregulated, and genes (tissue inhibitor of metalloproteinase-3 and PAX6) with tumor-suppressive functions were downregulated in metastatic cells. Profilin 2 (PFN2) expression was upregulated in multiple metastatic cell lines using RT-qPCR. Two PFN2 isoforms were overexpressed in metastatic cells. In vitro and in vivo models were established and genes associated with lung metastasis were identified to overcome the heterogeneity of the disease. Overall, aberrant PFN2 expression is unreported in lung metastasis in colorectal cancer. In the present study, two PFN2 isoforms with differential tissue distribution were upregulated in metastatic cells, suggesting that they promote lung metastasis in colorectal cancer.
摘要：
肺转移是结直肠癌中第二常见的转移类型。由于对潜在的机制知之甚少，因此尚未开发出针对肺转移的特异性治疗方法。本研究旨在阐明结直肠癌肺转移的分子基础。在老鼠模型中，通过尾静脉注射结直肠癌细胞并将其从肺中取出，建立了向肺高度转移的细胞系。使用DNA微阵列研究了将转染的细胞与其亲本细胞进行比较的差异基因表达。使用基因富集分析对结果进行功能解释，并使用逆转录定量PCR（RT-qPCR）进行验证。通过熔解曲线分析检查鉴定的基因的同种型。本研究建立了高度转移到肺部的结直肠癌细胞系。DNA微阵列实验表明，基因(N-cadherin，VE-钙黏着蛋白,Six4，Akt和VCAM1）参与运动，增殖和粘附上调，具有肿瘤抑制功能的基因（金属蛋白酶3和PAX6的组织抑制剂）在转移细胞中下调。使用RT-qPCR,Profilin2(PFN2)表达在多个转移细胞系中上调。两种PFN2亚型在转移细胞中过表达。建立了体外和体内模型，并鉴定了与肺转移相关的基因，以克服疾病的异质性。总的来说,在结直肠癌的肺转移中未报道PFN2的异常表达。在本研究中,两种具有不同组织分布的PFN2亚型在转移细胞中上调，提示它们促进结直肠癌的肺转移。
