In addition to being refractory to treatment, melanoma cancer stem cells (CSC) are known to suppress host antitumor immunity, the underlying mechanisms of which need further elucidation. In this study, we established a novel role for miR-92 and its associated gene networks in immunosuppression. CSCs were isolated from the B16-F10 murine melanoma cell line based on expression of the putative CSC marker CD133 (Prominin-1). CD133⁺ cells were functionally distinct from CD133⁻ cells and showed increased proliferation in vitro and enhanced tumorigenesis in vivo. CD133⁺ CSCs also exhibited a greater capacity to recruit immunosuppressive cell types during tumor formation, including FoxP3⁺ Tregs, myeloid-derived suppressor cells (MDSC), and M2 macrophages. Using microarray technology, we identified several miRs that were significantly downregulated in CD133⁺ cells compared with CD133⁻ cells, including miR-92. Decreased expression of miR-92 in CSCs led to higher expression of target molecules integrin α_V and α₅ subunits, which, in turn, enhanced TGFβ activation, as evidenced by increased phosphorylation of SMAD2. CD133⁺ cells transfected with miR-92a mimic and injected in vivo showed significantly decreased tumor burden, which was associated with reduced immunosuppressive phenotype intratumorally. Using The Cancer Genome Atlas database of patients with melanoma, we also noted a positive correlation between integrin α₅ and TGFβ1 expression levels and an inverse association between miR-92 expression and integrin alpha subunit expression. Collectively, this study suggests that a miR-92–driven signaling axis involving integrin activation of TGFβ in CSCs promotes enhanced tumorigenesis through induction of intratumoral immunosuppression. Significance: CD133⁺ cells play an active role in suppressing melanoma antitumor immunity by modulating miR-92, which increases influx of immunosuppressive cells and TGFβ1 expression.

Lunasin is a novel therapeutic agent for targeting melanoma cancer stem cells

The soy-derived peptide Lunasin inhibits invasive potential of melanoma initiating cells

Background: Coenzyme Q10 (CoQ10) is a ubiquitous molecule in living organisms serving as a cofactor in energy production. Epidemiological studies have reported low CoQ10 levels being associated with an increased risk of various cancers. We conducted the first study to evaluate the association of CoQ10 concentrations with lung cancer risk.Methods: A nested case‐control study including 201 lung cancer cases and 395 matched controls from the Southern Community Cohort Study was conducted. Plasma CoQ10 levels were measured using high‐performance liquid chromatography with photo‐diode array detection. Conditional logistic regression models were applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between plasma CoQ10 levels and lung cancer risk.Results: Plasma CoQ10 concentration was inversely associated with the risk of lung cancer. After adjusting for age, sex, race, and socioeconomic status, the OR (95% CI) comparing the third to first tertile was 0.57 (0.36–0.91, P for trend = 0.02). Further adjustments for smoking, alcohol, chronic obstructive pulmonary disease, and body mass index attenuated the point estimate slightly (OR = 0.60, 95% CI = 0.34–1.08, P for trend = 0.11), comparing third to first tertiles. Stratified analyses identified a significant inverse association between plasma CoQ10 levels and lung cancer risk in current smokers, but not in former/never smokers. The association was more evident in cases who were diagnosed within 1 year of blood draw than in cases diagnosed after 1 year.Conclusions: Low plasma CoQ10 was significantly associated with increased lung cancer risk, particularly among current smokers. The stronger association seen shortly following the blood draw suggests that CoQ10 may be related to disease progression.

Background : Lunasin is a naturally occurring peptide present in soybean that has both chemopreventive and therapeutic activities that can prevent cellular transformation and inhibit the growth of several human cancer types. Recent studies indicate that Lunasin has several distinct potential modes of action including suppressing integrin signaling and epigenetic effects driven by modulation of histone acetylation. In addition to direct effects on cancer cells, Lunasin also has effects on innate immunity that may contribute to its ability to inhibit tumor growth in vivo. Methods : Standard assays for cell proliferation and colony formation were used to assess Lunasin’s in vitro activity against murine Lewis lung carcinoma (LLC) and B16-F0 melanoma cells. Lunasin’s in vivo activity was assessed by comparing the growth of tumors initiated by subcutaneous implantation of LLC or B16-F0 cells in Lunasin-treated and untreated C57BL/6 mice. Results : Lunasin was found to inhibit growth of murine LLC cells and murine B16-F0 melanoma cells in vitro and in wild-type C57BL/6 mice. The effects of Lunasin in these two mouse models were very similar to those previously observed in studies of human non-small cell lung cancer and melanoma cell lines. Conclusions : We have now validated two established syngeneic mouse models as being responsive to Lunasin treatment. The validation of these two in vivo syngeneic models will allow detailed studies on the combined therapeutic and immune effects of Lunasin in a fully immunocompetent mouse model.