Background: IL-32␣ is known to interact with FAK1, and IL-32␣ overexpression in chronic myeloid leukemia cells increases natural killer cell-mediated killing. Results: IL-32␣ interacted with PKC⑀ and STAT3, mediated STAT3 phosphorylation, and thereby augmented IL-6 production. Conclusion: IL-32␣ elevated IL-6 production through interaction with PKC⑀ and STAT3. Significance: The interaction of IL-32␣ with PKC⑀ and STAT3 reveals a new intracellular mediatory role of IL-32␣.

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Redox regulation in cancer stem cells (CSCs) is viewed as a good target for cancer therapy because redox status plays an important role in cancer stem-cell maintenance. Here, we investigated the role of Peroxiredoxin II (Prx II), an antioxidant enzyme, in association with maintenance of liver CSCs. Our study demonstrates that Prx II overexpressed in liver cancer cells has high potential for self-renewal activity. Prx II expression significantly corelated with expression of epithelial-cell adhesion molecules (EpCAM) and cytokerain 19 in liver cancer tissues of hepatocellular carcinoma (HCC) patients. Downregulation of Prx II in Huh7 cells with treatment of siRNA reduced expression of EpCAM and CD133 as well as Sox2 in accordance with increased ROS and apoptosis, which were reversed in Huh7-hPrx II cells. Huh7-hPrx II cells exhibited strong sphere-formation activity compared with mock cells. Vascular endothelial growth factor (VEGF) exposure enhanced sphere formation, cell-surface expression of EpCAM and CD133, and pSTAT3 along with activation of VEGF receptor 2 in Huh7-hPrx II cells. The result also emerged in Huh7-H-ras G12V and SK-HEP-1-H-ras G12V cells with high-level expression of Prx II. Prx II was involved in regulation of VEGF driving cancer stem cells through VEGFR-2/STAT3 signaling to upregulate Bmi1 and Sox2. In addition, knockdown of Prx II in Huh7-H-ras G12V cells showed significant reduction in cell migration in vitro and in tumorigenic potential in vivo. Taken together, all the results demonstrated that Prx II plays a key role in the CSC self-renewal of HCC cells through redox regulation. STEM CELLS 2016;34:1188-1197 SIGNIFICANCE STATEMENTThis study demonstrates that Peroxiredoxin II (Prx II), an antioxidant enzyme, overexpressed in liver cancer cells has high potential for self-renewal activity. Prx II expression significantly correlated with expression of epithelial-cell adhesion molecules and cytokine 19 in liver cancer tissues of hepatocellular carcinoma patients, induced expression of stem cell markers, and exhibited strong sphere-formation activity in liver cancer cells. In addition, Prx II was involved in regulation of vascular endothelial growth factor (VEGF) driving cancer stem cells through VEGFR-2/STAT3 signaling to upregulate Bmi1 and Sox2. Thus, our finding suggests that Prx II may be essential for maintenance of stemness by redox regulation in liver cancer.

Background: IL-32␤ promotes IL-10 production in myeloid cells. Results: IL-32␤-mediated C/EBP␣ serine 21 phosphorylation by PKC␦ induced the dissociation of C/EBP␣ from IL-10 promoter, thereby promoting IL-10 production. Conclusion: IL-32␤ suppressed the inhibitory effect of C/EBP␣ on IL-10 production by mediating C/EBP␣ serine 21 phosphorylation by PKC␦. Significance: Our data suggest that IL-32␤ functions as an intracellular regulator of IL-10 production.

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Interleukin (IL)-32 is a well-known cytokine associated with inflammation, virus infections and cancer. IL-32θ is a newly identified isoform of IL-32, whose function has yet to be elucidated. In this study, we investigated IL-32θ function in colon cancer stem cells. Using samples from colon cancer patients, we found that the expression of IL-32θ mRNAs was significantly suppressed in tumor regions. We investigated the effects of IL-32θ on colon cancer. Ectopic expression of IL-32θ attenuated invasion, migration in vitro and in vivo tumorigenicity of colon cancer cells. IL-32θ inhibited epithelial-mesenchymal transition (EMT), resulting in the suppression of their migratory and invasive capabilities of HT29 colon cancer cells. In addition, IL-32θ altered various properties of CSCs, including sphere formation and expression of stemness related genes. IL-32θ directly bound to STAT3 and inhibited its nuclear translocation, leading to inhibited transcription of downstream factors, including Bmi1 and ZEB1. We showed that IL-32θ inhibited the STAT3-ZEB1 pathway and consequently inhibited key factors of stemness and EMT. Taken together, our findings reveal that IL-32θ can be a tumor suppressor, indicating that IL-32θ could possibly be used in therapies for colon cancer.

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