Complement C5 is a novel biomarker for liver metastasis of colorectal cancer.

ABSTRACT

Background: Colorectal cancer (CRC) is one of the most prominent malignant diseases, with a high incidence and a dismal prognosis. Metastasis to the liver is the leading cause of death in CRC patients. This study aimed to identify accurate metastatic biomarkers of CRC and investigate the potential molecular mechanisms of liver metastasis of colorectal cancer (LMCRC). Methods: Three independent datasets were screened and downloaded from the Gene Expression Omnibus (GEO) database. The GEO2R tool was used to identify differentially expressed genes (DEGs) in CRC tissues and liver metastases. Next, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Furthermore, the protein-protein interactions (PPIs) of the DEGs were analyzed using the Search Tool for the Retrieval of Interacting Genes (STRING) database, Cytoscape, and Molecular Complex Detection (MCODE). Next, the expression levels and Kaplan-Meier survival analysis of the target gene between normal colon and CRC tissues were performed by UALCAN. The expression of the target gene in tissues and cell lines was verified by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blot, and immunohistochemistry (IHC) assay. The impact of the target gene on the proliferation, invasion, and migration ability of COAD cells was explored in vitro. Results: A total of 92 common DEGs were found in the three independent datasets. GO/KEGG enrichment analysis showed that the DEGs were mainly involved in 14 different pathways. The protein-protein interaction (PPI) network revealed that complement 5 (C5), the upstream gene of C8A in the complement system, was associated with C8 and other key hub genes. Meanwhile, the online UALCAN resource showed that C5 was up-regulated and facilitated malignant progression in COAD samples. Next, we confirmed that C5 remarkably increased and promoted cell proliferation, migration, and invasion in CRC cell lines, SW620 and SW480. The IHC assay showed C5 was also highly expressed in a majority of LMCRC tissues compared with paired CRC tissues. Conclusions: The findings of our integrated bioinformatics study suggest that complement C5 might serve as a potential therapeutic target in patients with CRC.