Characterization of ITIH6, a novel inter-α-inhibitor family member with prognostic significance in cholangiocarcinoma.

The family of inter-α-trypsin inhibitors (ITI) includes proteins with a conserved light chain and a variable number of heavy chains. Here, we present the first characterization of ITIH6, a previously uncharacterized member of the ITI heavy chain (ITIH) family, using different bioinformatics analysis tools. ITIH6 contains the two canonical domains characteristic of ITIH proteins (VIT, vWA), but also harbors a large central region between the vWA domain and the C-terminus that is unique to ITIH6. Phylogenetic analysis further revealed that ITIH6 is most closely related to ITIH5, forming a separate subfamily. Protein expression profiling of human tissue samples demonstrated that ITIH6 is expressed in a tissue-specific manner, with abundant expression in salivary glands, kidney, colon, and stomach, particularly within glandular structures of the digestive tract. Extending our previous findings on the clinical relevance of ITIH5 in cholangiocarcinoma (CCA), we identified an overlapping yet distinct expression pattern of ITIH6 in CCA. Importantly, elevated ITIH6 expression correlates with favorable prognosis and was more pronounced in tumors with single lesions, suggesting its potential utility as a prognostic biomarker in CCA. Taken together, these findings highlight the unique structural and functional features of ITIH6 and emphasize its potential clinical significance in cancer biology.