Loss of SATB2 is associated with MUC16 upregulation in the invasive component of colitis-associated colorectal carcinoma.

Colitis-associated colorectal carcinoma (CAC) arises in the setting of long-standing inflammatory bowel disease and shows clinicopathological and molecular differences from sporadic colorectal carcinoma. Loss of SATB2 expression is increasingly recognized in a subset of CACs, but its biological significance remains unclear. This study aimed to investigate gene expression profiles of CACs, focusing on differences between SATB2-negative and SATB2-positive tumors. Formalin-fixed, paraffin-embedded CAC samples stratified by SATB2 immunohistochemical expression status underwent bulk RNA sequencing. Differential expression analysis identified 580 genes with significant differences between the two groups. SATB2 expression was markedly reduced in the SATB2-negative group, confirming appropriate stratification. SATB2-negative CACs showed upregulation of lineage-associated and mucin-related genes, including MUC16, CLDN18, and MUC5AC, with MUC16 showing the most prominent increase. MUC16 is a membrane-tethered mucin containing CA125 epitopes. Immunohistochemical validation demonstrated that MUC16 expression was mainly confined to the invasive components of a subset of SATB2-negative CACs, with minimal expression in dysplastic or non-invasive epithelium. These findings suggest that MUC16 expression is more closely related to tumor invasion than to early tumorigenesis. SATB2-negative CACs represent a biologically distinct subset characterized by altered differentiation and upregulation of invasion-associated markers such as MUC16. Loss of SATB2 and gain of MUC16 expression appear to occur within the same tumor lineage, suggesting coordinated phenotypic changes during tumor progression. Overall, these findings support a role for SATB2 loss in colitis-associated tumorigenesis and identify MUC16 as a potential marker of invasive progression in CAC.