Abstract
The cancer stem cells (CSCs) are thought to be responsible for cancer initiation, recurrence, and metastasis via a multifactorial process. IL-32γ has been known to inhibit several tumor developments. However, the role of IL-32γ in CSCs is unknown. The role of IL-32γ on tumor development was assessed in IL-32γ transgenic (Tg) mice allograft and xenograft model. In the in vitro assay, we analyzed CSC growth and apoptosis in cells with IL-32γ 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-32γ suppressed CD133+ CSC-induced allograft model in IL-32γ Tg mice and xenograft model. Tumor-sphere formation and cell viability assay revealed a greater inhibition of CSC proliferation and antineoplastic activity of IL-32γ in CD133+ CSCs as compared with normal cancer cells. The inhibitory effects of IL-32γ 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-32γ on phosphorylation of STAT5 and the expression of CD133. Our results demonstrate that IL-32γ negatively regulates CD133+ CSC proliferation and tumor development and suggest that IL-32γ has great potential for use in the treatment of cancer progression.
Highlights
Interleukin-32 (IL-32), a proinflammatory cytokine, was formerly termed as natural killer cells transcript 4 (NK4)[1]
Another cancer stem cells (CSCs) biomarkers, aldehyde dehydrogenase 1 family, member A1 (ALDH1A1), Sox[2] and Oct[4], were significantly reduced in IL-32γ-transfected CD133+ A549 CSCs (Fig. 1d). These results show that IL32γ plays a key role in the inhibition of CSC progression through it halts the characteristics of cancer stem/progenitor-like cells
We found that the expression of integrin alpha V (ITGAV) was decreased in CD133+ CSC-inoculated IL-32γ-Tg mice compared with non-Tg mice (Fig. 6d, upper lane), and in IL-32γexpressing CD133+ CSC- inoculated nude mice (Fig. 6d, lower lane)
Summary
Interleukin-32 (IL-32), a proinflammatory cytokine, was formerly termed as natural killer cells transcript 4 (NK4)[1]. IL-32 has nine alternative spliced isoforms, such as IL-32α, IL-32β, IL-32γ, IL-32δ, IL-32ε, IL-32ζ, IL-32η, IL-. 32θ, and IL-32 small (sm)[3]. Four major isoforms such as IL-32α, IL-32β, IL-32γ, and IL-32δ were initially described from human NK cells[4]. Among these isoforms, IL-32γ is the largest isoform that in the absence of splicing between exon 3 and exon 4, consists of 234 amino acids. IL-32δ lacks the ATG codon located on exon 2, leading to a shift of the ATG codon in exon 3. One of the most important isoform IL-32γ is involved in the numerous biophysiological functions, Official journal of the Cell Death Differentiation Association
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