Bocuk Derya, Wolff Alexander, Krause Petra, Salinas Gabriela, Bleckmann Annalen, Hackl Christina, Beissbarth Tim, Koenig Sarah
Department of General, Visceral and Paediatric Surgery, University Medical Centre, Georg - August - University Goettingen, Göttingen, Germany.
Statistical Bioinformatics, Department of Medical Statistics, University Medical Centre, Georg - August - University Goettingen, Göttingen, Germany.
BMC Cancer. 2017 May 19;17(1):342. doi: 10.1186/s12885-017-3342-1.
Colorectal cancer (CRC) is the second leading cause of cancer-related death in men and women. Systemic disease with metastatic spread to distant sites such as the liver reduces the survival rate considerably. The aim of this study was to investigate the changes in gene expression that occur on invasion and expansion of CRC cells when forming metastases in the liver.
The livers of syngeneic C57BL/6NCrl mice were inoculated with 1 million CRC cells (CMT-93) via the portal vein, leading to the stable formation of metastases within 4 weeks. RNA sequencing performed on the Illumina platform was employed to evaluate the expression profiles of more than 14,000 genes, utilizing the RNA of the cell line cells and liver metastases as well as from corresponding tumour-free liver.
A total of 3329 differentially expressed genes (DEGs) were identified when cultured CMT-93 cells propagated as metastases in the liver. Hierarchical clustering on heat maps demonstrated the clear changes in gene expression of CMT-93 cells on propagation in the liver. Gene ontology analysis determined inflammation, angiogenesis, and signal transduction as the top three relevant biological processes involved. Using a selection list, matrix metallopeptidases 2, 7, and 9, wnt inhibitory factor, and chemokine receptor 4 were the top five significantly dysregulated genes.
Bioinformatics assists in elucidating the factors and processes involved in CRC liver metastasis. Our results support the notion of an invasion-metastasis cascade involving CRC cells forming metastases on successful invasion and expansion within the liver. Furthermore, we identified a gene expression signature correlating strongly with invasiveness and migration. Our findings may guide future research on novel therapeutic targets in the treatment of CRC liver metastasis.
结直肠癌（CRC）是男性和女性癌症相关死亡的第二大主要原因。发生转移扩散至肝脏等远处部位的全身性疾病会显著降低生存率。本研究的目的是调查CRC细胞在肝脏形成转移灶时侵袭和扩散过程中发生的基因表达变化。
通过门静脉向同基因C57BL/6NCrl小鼠的肝脏接种100万个CRC细胞（CMT-93），4周内可稳定形成转移灶。利用Illumina平台进行RNA测序，以细胞系细胞、肝脏转移灶以及相应的无瘤肝脏的RNA评估14000多个基因的表达谱。
当培养的CMT-93细胞在肝脏中转移增殖时，共鉴定出3329个差异表达基因（DEG）。热图上的层次聚类显示了CMT-93细胞在肝脏中增殖时基因表达的明显变化。基因本体分析确定炎症、血管生成和信号转导为涉及的前三个相关生物学过程。使用一个选择列表，基质金属肽酶2、7和9、Wnt抑制因子和趋化因子受体4是前五个显著失调的基因。
生物信息学有助于阐明CRC肝转移所涉及的因素和过程。我们的结果支持这样一种观点，即侵袭-转移级联反应涉及CRC细胞在肝脏内成功侵袭和扩展后形成转移灶。此外，我们鉴定出了一种与侵袭性和迁移密切相关的基因表达特征。我们 的发现可能会为未来CRC肝转移治疗新靶点的研究提供指导。
