Transcriptome and Network Dissection of Microsatellite Stable and Highly Instable Colorectal Cancer

Abstract

Background: Colorectal cancer (CRC) is one of the most common cancers worldwide with high number of mortality<br />every year. Microsatellite instability (MSI) is a considerable feature of CRC which affects prognosis and treatment.<br />High level of MSI or MSI-high (MSI-H) colorectal cancer has better prognosis and immunotherapy response, while<br />microsatellite stable (MSS) CRC has better response to 5-fluorouracil (5-FU)-based chemotherapy. More studies are<br />needed, specifically on MSS CRC which has worse prognosis, to further reveal biological differences and similarities<br />between MSS and MSI colorectal cancer, which may equip us with the knowledge to develop more promising therapeutic<br />approaches to target both types or be more effective for each type. Methods: We aimed to find affected biological<br />processes and their regulators in both type, MSS and MSI-H, of CRC; as well as reveal specific ones in each type.<br />We applied meta- and network analysis on freely available transcriptome data in MSS and MSI-H colorectal cancer<br />from gene expression omnibus (GEO) database to detect common differentially expressed genes (DEGs) and critical<br />biological processes and predict their most significant regulators. Results: Our results demonstrate considerable up<br />and downregulation in cell cycle and lipid catabolism processes, respectively; and introduced MYC and FOXM1<br />as two central and up-stream regulators of DEGs in both type of CRC. Chemokine-mediated processes displayed<br />up-regulation in MSI-H type, while metastasis-related processes showed more activation in MSS CRC. Additionally,<br />DACH1 and TP53 were detected as two important transcription factors that differentially expressed just in MSS and<br />MSI-H, respectively. Conclusion: Our results can explain why MSI and MSS CRC display different immunotherapy<br />response, prognosis, and metastasis feature. Moreover, our predicted up-stream regulators in the regulatory networks<br />may be promising therapeutic targets.