Background: Although the understanding of resistance to oxaliplatin (OXA) chemotherapy in colorectal cancer (CRC) has been sought for many years, drug tolerance remains a major challenge for cancer therapy. Revealing the molecular mechanism of OXA resistance could help to explain the poor prognosis of patients.
Methods: Gene expression omnibus (GEO) database was searched, GSE83129, which contains RNA profiling in metastatic CRC patients treated first-line with OXA, was chosen for the following analysis. Differential expressed genes (DEGs) between the adenocarcinoma and adjacent_normal team, respectively, in the OXA responders and no-responders were analyzed. The Gene Ontology (GO) and hub genes in the protein-protein interaction (PPI) network were used for the molecular mechanism of OXA resistance. Tumor-related databases were used for the clinical relevance of the structural maintenance of chromosomes 5 (SMC5) in CRC. The in vitro assays were used to detect the molecular function of SMC5 in CRC cells. Quantitative real-time PCR (qRT-PCR) and western blot were used to detect the expression of the structural maintenance of chromosomes 5/6 (SMC5/6) complex components upon OXA and raltitrexed (RTX) treatment. CCK-8 was used to detect the cell viability of cells with different treatment.
Results: SMC5 was downregulated in CRC tissues of OXA no-response patients. Lower expression of SMC5 was correlated with a poor prognosis in CRC patients, improved this gene expression, inhibited the CRC cell growth and invasion in vitro. Furthermore, SMC5 was downregulated upon OXA treatment in CRC cells, while RTX would reverse its expression, and the combination of these two drugs restored the SMC5 level to the normal situation. Finally, RTX treatment enhanced the OXA cytotoxicity.
Conclusion: SMC5 is a tumor suppressor, that low expression of this gene is benefit for the development of CRC. Combination treatment with RTX and OXA may be more suitable for those OXA no-responders with lower SMC5.
Keywords: SMC5; biomarker; oxaliplatin; raltitrexed; tumor suppressor.
© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.