Transcriptome Profiling Associated with CARD11 Overexpression in Colorectal Cancer Implicates a Potential Role for Tumor Immune Microenvironment and Cancer Pathways Modulation via NF-κB

The immune system plays a critical role in inflammation by initiating responses to infections or tissue damage. The nuclear factor-κB (NF-κB) pathway plays a key role in inflammation and innate immunity, as well as other cellular activities. Dysregulation of this well-choreographed pathway has been implicated in various diseases, including cancer. CARD11 is a key molecule in the BCL10-MALT1 complex, which is involved in transducing the signal downstream of the NF-κB pathway. This study aims to elucidate how <i>CARD11</i> overexpression exacerbates the prognosis of colorectal cancer (CRC). To identify the cellular pathways influenced by <i>CARD11</i>, transcriptomic analysis in both CRC cell lines and patients was carried out on <i>CARD11</i>- overexpressed HCT-116 and HT-29 CRC cell lines alongside empty vector-transfected cell lines. Furthermore, a comparison of transcriptomic data from adenoma and carcinoma CRC patients with low- (<i>CARD11</i>-) and high-(<i>CARD11</i>+) <i>CARD11</i> expression was carried out. Whole transcriptomics and bioinformatics analysis results indicate that <i>CARD11</i> appears to play a key role in CRC progression. Absolute GSEA (absGSEA) on HCT-116 transcriptomics data revealed that <i>CARD11</i> overexpression promotes cell growth and tissue remodeling and enhances immune response. Key genes co-expressed with <i>CARD11</i>, such as <i>EP300</i>, <i>KDM5A</i>, <i>HIF1A</i>, <i>NFKBIZ</i>, and <i>DUSP1</i>, were identified as mediators of these processes. In the HT-29 cell line, <i>CARD11</i> overexpression activated pathways involved in chemotaxis and extracellular matrix (ECM) organization, marked by <i>IL1RN</i>, <i>MDK</i>, <i>SPP1</i>, and chemokines like <i>CXCL1</i>, <i>CXCL3,</i> and <i>CCL22</i>, 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, such as <i>GLI3</i> and <i>PIEZO2,</i> in <i>CARD11</i>+ adenoma patients. Carcinoma patients showed a dramatic increase in the expression of <i>MAPK8IP2</i> in <i>CARD11</i>+ carcinoma patients alongside other cancer-related genes, including <i>EMB</i>, <i>EPHB6</i>, and <i>CPEB4</i>.