The differential regulation of tumor suppressor genes (SAMD9, SPRED1, TGFBI, DUSP6, CDX2, TP53) and MAPK/ERK signaling pathway in colorectal cancer
Mahmood Rasool1*, Khalid I Alhassan2, Sajjad Karim1, Absarul Haque3, Mohammed HZ Mutwakil2, Mohammed Alharthi4, Adeel G Chaudhary1, Peter Natesan Pushparaj1
1Center of Excellence in Genomic Medicine Research, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
2Department of Biological Science, King Abdulaziz University, Jeddah, Saudi Arabia
3King Fahd Medical Research Center, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
4Faculty of Medicine, King Abdulaziz University Hospital, King Abdulaziz University, Jeddah, Saudi Arabia
Abstract
Despite considerable advancements in research, particularly in oncology, colorectal cancer (CRC) remains a formidable and deadly disease. It is crucial to delve deeper into the effects of targeted therapies, signaling pathways, and genetic regulation to ensure the effectiveness of cancer treatments. In this study, we obtained microarray data for four patient-derived CRC organoids from the Gene Expression Omnibus (GEO) database (accession number: GSE114060). We then used several next-generation knowledge discovery (NGKD) tools, such as GEO2R, Metascape, WebGestalt, and Ingenuity Pathway Analysis (IPA) software, to investigate the underlying molecular mechanisms in colorectal cancer-derived organoids treated with trametinib compared to those treated with DMSO. Our NGKD analysis revealed upregulation of SAMD, TP53, and SPTLC3 and downregulation of SPRED1, TGFBI, and DUSP6. The MAPK/ERK signaling pathway was significantly downregulated and was associated with reduced expression of CDX2 in CRC organoids treated with trametinib. We concluded that SAMD9, SPRED1, TGFBI, TP53, and DUSP6 are differentially regulated and can play a pivotal role in the downregulation of the MAPK/ERK signaling pathway to suppress CRC. The use of targeted therapies to regulate the specific gene signatures identified in the current study may be beneficial in the CRC associated tumor suppression . On the other hand, upregulation of SPTLC3 may be induced by MEK inhibitors and may cause hepatotoxicity alongside nonalcoholic steatohepatitis.
