Molecular pathogenesis in the initiation and progression of colorectal cancer

Abstract

Colorectal cancer (CRC) cases are among the third most common malignancies worldwide and a leading cause of cancer-related mortality. CRC is typically classified into precursor lesions such as adenomas, high-grade dysplasia, or carcinoma in situ, and malignant forms like adenocarcinomas, reflecting the progressive nature of colorectal tumorigenesis.. The incidence and mortality rates are reflected at the national level, with CRC being the deadliest cancer among males in the United Arab Emirates (UAE). The specific etiology of CRC is still largely unclear. However, Researchers generally agree that the primary contributors to colorectal cancer include genetic predisposition, dietary patterns, particularly those high in processed or red meats, and underlying non-cancerous conditions such as inflammatory bowel disease, as well as lifestyle factors like smoking, excessive alcohol consumption, physical inactivity, and obesity.. In particular, dysregulation of the nuclear factor- κB (NF-κB) pathway is thought to play a highly complex role in CRC. The CARD11-BCL10- MALT1 (CBM) signalosome complex is critical for NF-κB activation in lymphocytes, particularly T and B cells. The CARD11 gene is a crucial part of this complex and is also speculated to be involved in CRC onset and development. However, the specific CARD11 effects in CRC are poorly researched compared to other cancers. Thus, this study aimed to elucidate how CARD11 overexpression exacerbates the prognosis of CRC. To identify the cellular pathways influenced by CARD11, transcriptomic analysis was carried out on CARD11– overexpressed HCT-116 and HT-29 CRC cell lines alongside empty vector- transfected cell lines. Furthermore, transcriptomic data was compared from adenoma and carcinoma CRC patients with low- CARD11 (CARD11-) and high- CARD11 (CARD11+) expression. The results indicated that CARD11 plays a key role in CRC progression. Absolute GSEA (absGSEA) on HCT-116 transcriptomics data revealed that CARD11 overexpression promotes cell growth and tissue remodeling and enhances immune response. Key genes co- expressed with CARD11, such as EP300, KDM5A, HIF1A, NFKBIZ, and DUSP1, were identified as mediators of these processes. In the HT-29 cell line, CARD11 overexpression activated pathways involved in chemotaxis and extracellular matrix (ECM) organization, marked by IL1RN, MDK, SPP1, and chemokines like CXCL1, CXCL3, and CCL22, which were shown to contribute to the more invasive stage of CRC. In patient samples, adenoma patients exhibited increased expression of genes associated with the tumor immune microenvironment, such as IL6ST, collagen family members, and CRC transition markers like GLI3 and PIEZO2 Transcriptomics analysis indicated distinct expression profiles in both cell lines with CARD11 overexpression. The analysis showed there were relatively more genes upregulated in HCT-116 compared to the HT-29 cell line, indicating that CARD11 overexpression has a more pronounced effect on the HCT-116. While HT-29 maintained a more stable expression pattern, HCT-116 showed significant activation of pathways related to immune responses.in CARD11+ adenoma patients. Carcinoma patients showed a dramatic increase in the expression of MAPK8IP2 in CARD11+ carcinoma patients alongside other cancer-related genes, including EMB, EPHB6, and CPEB4. For the various stages of CRC study, the transcriptional co-regulatory mechanisms pathway exhibited differentially expressed genes (DEGs) in the adenocarcinoma cohorts. These included CEBPZ, MED10, and PAWR. In contrast, SIRT6, ARRB1, TADA2A, CTBP1, and CTBP2 were upregulated genes in adenoma samples. The protein kinase functional pathways exhibited downregulation of OBSCN, ERN1, ERN2, and CAM2KG genes in the adenocarcinoma cohorts. In conclusion, this study reveals CARD11 as a key regulator in colorectal cancer progression, influencing diverse pathways tied to immune modulation, ECM remodeling, and tumor invasiveness. Besides stage-specific transcriptomic profiling, these findings highlight distinct molecular patterns between adenoma and carcinoma, providing a deeper understanding of CRC pathogenesis and affirming the value of CARD11 as both a biomarker and a potential therapeutic target.