UCLA

Cancer stem cells (CSCs; also known as cancer initiating cells) are a small population of cancer cells located within a tumor that are highly tumorigenic, capable of tumor initiation and resistant to cancer therapies. Cytokines have been previously shown to be involved in tumorigenesis of many different cancers such as breast, lung, colorectal and ovarian cancers. In this study, to investigate potential involvement of cytokines in oral CSCs, we screened expression of 25 cytokines in CSC-enriched oral squamous cell carcinoma (OSCC) populations. Among them, chemokine (C-C motif) ligand 3 (CCL3) was unequivocally overexpressed in all tested CSC-enriched OSCC populations. Subsequent functional analysis showed that CCL3 enhanced OSCC CSC phenotypes such as self-renewal capacity, migration, and CSC-related gene expression. Moreover, we found that CCL3 receptors were also significantly overexpressed in CSC compared to non-CSC population, and a CCL3 receptor antagonist suppressed the effect on CCL3 on CSC. Mechanistically, CCL3 increased SOX9 whose expression was highly overexpressed in CSC population. Knockdown of SOX9 suppressed CSC phenotypes in OSCC. These findings suggest that CCL3-SOX9 axis is a novel CSC-regulatory pathway in OSCC, and its inhibition may offer an effective means of selectively targeting the OSCC CSC population.