Clinical Implication and Mitotic Effect of CD44 Cleavage in Relation to Osteopontin/CD44 Interaction and Dysregulated Cell Cycle Protein in Gastrointestinal Stromal Tumor

CD44 and osteopontin (OPN) are functionally related molecules that, alone or in combination, play miscellaneous biological and pathophysiologic roles. CD44 cleavage, one unique feature of CD44, occurs in human cancers, but its function remains unclear. This study aimed to assess the clinicopathologic significance and mechanism of CD44 cleavage in gastrointestinal stromal tumor (GIST) with respect to OPN and OPN/CD44 interaction. CD44 cleavage was evaluated by immunoblotting in 31 primary GIST tumor specimens with paired normal tissues. OPN/CD44 interaction was examined by in situ proximity ligation assay. The associations of CD44 cleavage activity with clinicopathologic parameters, cyclin D1 expression, beta-catenin expression, OPN expression, and OPN/CD44 interaction were analyzed. CD44 cleavage activity was demonstrated in 87.1% of GIST, in contrast to its absence in normal tissues. Increased CD44 cleavage activity was significantly associated with enhanced mitosis by multivariate analysis, in addition to being related to tumor size, recurrence, high-risk status, and poor survival by univariate analysis. Mitosis was significantly higher in GIST with increased CD44 cleavage activity, which also positively correlated with tumor-specific beta-catenin and cyclin D1 overexpression, indicating a mitotic effect through aberrant cell cycle. Both OPN and OPN/CD44 interactions were significantly associated with CD44 cleavage. Our study demonstrates the clinicopathological significance of CD44 cleavage in GIST. There is a significantly increased mitosis associated with CD44 cleavage in relation to OPN/CD44 interaction and dysregulated cell cycle in GIST.