IL-32γ suppresses lung cancer stem cell growth via inhibition of ITGAV-mediated STAT5 pathway

The cancer stem cells (CSCs) are thought to be responsible for cancer initiation, recurrence, and metastasis via a multifactorial process. IL-32 gamma has been known to inhibit several tumor developments. However, the role of IL-32 gamma in CSCs is unknown. The role of IL-32 gamma on tumor development was assessed in IL-32 gamma transgenic (Tg) mice allograft and xenograft model. In the in vitro assay, we analyzed CSC growth and apoptosis in cells with IL-32 gamma overexpression by cell viability assay and tumor-sphere formation assay. In addition, expression of cell proliferation, apoptosis markers, and signaling molecules was determined by western blot analysis. IL-32 gamma suppressed CD133+ CSC-induced allograft model in IL-32 gamma Tg mice and xenograft model. Tumor-sphere formation and cell viability assay revealed a greater inhibition of CSC proliferation and antineoplastic activity of IL-32 gamma in CD133+ CSCs as compared with normal cancer cells. The inhibitory effects of IL-32 gamma on tumor development were associated with inhibition of the STAT5 pathway. In addition, inhibition of STAT5 increased cleavage of caspase-3, but suppressed CD133 expression and colony formation. Web-based gene network analysis showed that IL-32 is correlated with ITGAV, an integrin gene. Our result revealed that knockdown of ITGAV by siRNA inhibited the phosphorylation of STAT5. Moreover, we identified that ITGAV overexpression reversed the effect of IL-32 gamma on phosphorylation of STAT5 and the expression of CD133. Our results demonstrate that IL-32 gamma negatively regulates CD133+ CSC proliferation and tumor development and suggest that IL-32 gamma has great potential for use in the treatment of cancer progression.