Comparable roles of CD44v8-10 and CD44s in the development of bone metastases in a mouse model

Abstract

Abstract. Cluster of differentiation (CD)44 has been implicated in cancer metastasis to bone. Clinical and experimental studies have suggested that the standard isoform of CD44 (CD44s) and the variant isoform of CD44 (CD44v) enhance metastasis. The present study examined the differential roles of CD44s and CD44v, particularly CD44v8-10, in the development of bone metastases. For this purpose, MDA-MB-231 human breast cancer cells and A549 human lung cancer cells were stably transduced with epithelial splicing regulatory protein 1 (ESRP1), which regulates the alternative splicing of several genes, including CD44. The introduction of ESRP1 induced a splicing switch from CD44s to CD44v, particularly to CD44v8-10, while the total amount of CD44 was rarely affected. However, ESRP1 did not significantly affect cell proliferation, migration, invasion or tumor sphere formation in vitro. Furthermore, ESRP1 did not cause significant differences in the development of bone metastases in a mouse model. As an alternative approach, cancer cells transduced with the CD44v8-10 gene were also established. The overexpression of CD44v8-10 in MCF-7 human breast cancer cells, which rarely express any isoform of CD44, promoted cell migration and sphere formation, whereas the overexpression of CD44v8-10 in MDA-MB-231 cells, which endogenously express high levels of CD44s, did not exert these effects.The results of the present study collectively suggest that the ability of CD44v8-10 to promote tumor aggressiveness and bone metastases is similar to that of CD44s. CD44v8-10 and CD44s may represent potential therapeutic targets for the treatment of bone metastases. IntroductionCluster of differentiation (CD)44 is a transmembrane glycoprotein that functions as an adhesion molecule for extracellular matrices, primarily hyaluronan (1,2). The expression of CD44 in cancer cells has also been implicated in cell migration, invasion and metastasis (1,2). Furthermore, CD44 has recently been recognized as a major marker for cancer stem cells (CSCs) in several types of cancer (2,3).The CD44 gene consists of 20 exons, 10 of which (exons 1-5 and 16-20) encode the shortest and ubiquitously expressed standard isoform of CD44 (CD44s) (1,2). The other 10 exons (exons 6-15, also referred to as exons v1-v10) are variant exons inserted by alternative splicing in various combinations, thereby generating various variant isoforms of CD44 (CD44v) (1,2). The insertion of variant exons lengthens the extracellular domain and alters the binding and signaling properties of CD44. The expression of CD44v is restricted to a few epithelial tissues, including several types of cancer (2). Although extensive research has been conducted, the association between the expression of CD44v and tumor aggressiveness remains controversial (1,2,4-6).CD44v8-10, also known as CD44R1 and CD44E, is one of the isoforms of CD44v, and contains the variant exons 13-15 (v8-v10) (1,2). Clinical studies have demonstrated that CD44v8-10 is expressed in various human epithelial cancers, including...

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