Fengyun Liu

The NOX family includes seven unique members that are involved in a multitude of physiological functions, including extensive interaction with UVR and the skin. NOX1 is uniquely present and activated by UVB radiation with biphasic expression of the enzyme immediately and then after a several-hour delay. Specific inhibition of both early and late NOX1 activation leads to evidence of decreased photocarcinogenesis in in vitro keratinocytes and in well-characterized mouse models in which antitumor efficacy has been shown; inhibiting only late NOX activation does not exhibit such effects. These results suggest a crucial function of early NOX activation in transducing a signal for cellular protection after UVB carcinogenesis provocation. We term this an intrinsic cellular ROS priming function for quenching DNA damage and promoting survival. Evolutionally, this type of priming function may be essential for addressing various types of stimuli from adverse environments.

The human cationic antimicrobial protein LL-37 is a multifunctional host defense peptide with a wide range of immunomodulatory activities. Previous work has shown that LL-37 exerts both pro- and anti-inflammatory effects. The role of mitochondria in the skin inflammatory effects of LL-37 has not been well studied. Therefore, our aim was to investigate the immunomodulatory effect of LL-37 in HaCaT cells and to delineate the underlying mechanisms related to mitochondrial function. Immunohistochemistry results from tissue microarrays showed strong cytoplasmic LL-37 staining in inflammatory cells in chronic dermatic inflammation. Using exogenous LL-37 stimulation and LL-37 knockdown and overexpression, LL-37 was demonstrated to dramatically reduce the mRNA levels and protein secretion of inflammatory cytokines including IL-6, IL-8, IL-1α and tumor necrosis factor-α, which are induced by lipopolysaccharides. The anti-inflammatory effects of LL-37 are dependent upon its ability to increase mitochondrial biogenesis and to maintain mitochondrial homeostasis. Furthermore, we observed that LL-37 enhances the LPS-induced phosphorylation of extracellular signal-regulated kinase and mammalian target of rapamycin. The mTOR inhibitor rapamycin can neutralize the protective effects of LL-37 on mitochondria. In conclusion, these results suggest that high LL-37 expression levels correlate with chronic skin inflammation; mitochondrial dysfunction occurs in HaCaT cells during inflammation; and LL-37 attenuates inflammatory impairment by stimulating mitochondrial biogenesis and protecting mitochondrial function, which are dependent upon mTOR signaling. These findings provide new insights into targeting mitochondria with LL-37 to prevent skin inflammatory reactions. © 2014 Elsevier Ltd.

Both SKP2 and transforming growth factor-β1 play important roles in cancer metastasis through different mechanisms: TGF-β1 via induction of epithelial-mesenchymal transition and SKP2 via downregulating p27kip1. Recent studies indicated that c-Myc and Akt1 were active players in metastasis. In this study we demonstrated a crosstalk between these pathways. Specifically, we found that TGF-β1 treatment increased SKP2 expression accompanied with increased phosphorylation of Akt1 and c-Myc protein accumulation during EMT. We demonstrated that Akt1 was required for TGF-β1-mediated SKP2 upregulation and that c-Myc transcription factor specifically bound to the promoter of SKP2 for its enhanced transcription. Analysis of 25 samples of normal human skin, nevi, and melanomas revealed a positive correlation between c-Myc and SKP2 accumulation. Furthermore, accumulation of SKP2 and c-Myc proteins was significantly higher in metastatic melanoma samples as compared with that in primary melanomas, which again was higher than that in normal skin or nevi. In summary, our results integrated TGF-β1 signals to SKP2 via Akt1 and c-Myc during EMT, and provided, to our knowledge, a previously unreported mechanistic molecular event for TGF-β1-induced metastasis in human melanoma. © 2014 The Society for Investigative Dermatology.

Nox1 mRNA, protein, and activities were compared in the paired primary and metastatic colon adenocarcinoma cell lines SW480 and SW620, and in normal colon tissues and colon cancer tissues. Our results demonstrated that Nox1 levels were higher in the primary SW480 cells than that in metastatic SW620 cells and were not associated with colon cancer progression. We further discovered that vinculin protein level in SW620 was much higher than that in SW480 cells, whereas E-cadherin was lower. We conclude that vinculin and E-cadherin, but not Nox1, may serve as biomarkers for colon cancer progression. © 2013 Informa Healthcare USA, Inc.