CD147 plays a critical role in the invasive and metastatic activity of malignant melanoma cells by stimulating the surrounding fibroblasts to express matrix metalloproteinases and vascular endothelial growth factor. We developed a system that blocks CD147 in the human malignant melanoma cell line, A375, using RNA interference. By transfecting melanoma cells with the small interfering RNA (siRNA) that targets human CD147, we were able to establish two stable clones in which CD147 expression was significantly downregulated. This resulted in the decreased proliferation and invasion of A375 cells in vitro. CD147 siRNA also downregulated the expression of vascular endothelial growth factor in these cells and reduced the migration of vascular endothelial cells. The reduction in the CD147 level suppressed the size of s.c. tumors and the microvessel density in an A375 s.c. nude mouse xenograft model. In addition, the in vivo metastatic potential of A375 cells transfected with CD147 siRNA was suppressed in a nude mouse model of pulmonary metastasis. (Cancer Res 2006; 66(23): 11323-30)

Psoriasis is a common and chronic inflammatory skin disease that is complicated by gene–environment interactions. Although genomic, transcriptomic, and proteomic analyses have been performed to investigate the pathogenesis of psoriasis, the role of metabolites in psoriasis, particularly of lipids, remains unclear. Lipids not only comprise the bulk of the cellular membrane bilayers but also regulate a variety of biological processes such as cell proliferation, apoptosis, immunity, angiogenesis, and inflammation. In this study, an untargeted lipidomics approach was used to study the lipid profiles in psoriasis and to identify lipid metabolite signatures for psoriasis through ultra-performance liquid chromatography-tandem quadrupole mass spectrometry. Plasma samples from 90 participants (45 healthy and 45 psoriasis patients) were collected and analyzed. Statistical analysis was applied to find different metabolites between the disease and healthy groups. In addition, enzyme-linked immunosorbent assay was performed to validate differentially expressed lipids in psoriatic patient plasma. Finally, we identified differential expression of several lipids including lysophosphatidic acid (LPA), lysophosphatidylcholine (LysoPC), phosphatidylinositol (PI), phosphatidylcholine (PC), and phosphatidic acid (PA); among these metabolites, LPA, LysoPC, and PA were significantly increased, while PC and PI were down-regulated in psoriasis patients. We found that elements of glycerophospholipid metabolism such as LPA, LysoPC, PA, PI, and PC were significantly altered in the plasma of psoriatic patients; this study characterizes the circulating lipids in psoriatic patients and provides novel insight into the role of lipids in psoriasis.

In a previous study, we found that microRNA (miRNA)-200a suppresses Wnt/β-catenin signaling by interacting with β-catenin, thereby inhibiting migration, invasion and proliferation. However, the mechanism involved in this suppression remains unclear. In the present study, we investigated the underlying mechanism of miR-200a regulation of epithelial-mesenchymal transition (EMT) in gastric carcinoma cells, and confirmed the tumor suppressor role of miR-200a in vivo. The expressions of miRNA-200a, -200b and -200c, identified by fluorescent in situ hybridization, were downregulated and inversely correlated with WHO grades of gastric adenocarcinoma (GA). The expression of the potential miR-200a target genes ZEB1 and ZEB2 was detected immunohistochemically. These examinations used the same tissue microarrays to analyze the relationships between miR-200a and potential target genes. The expression of miR-200a and ZEB1/ZEB2 in the same GA tissue microarrays was inversely related. Restored miR-200a expression inhibited tumor growth in nude mice harboring subcutaneous SGC7901 xenografts. The expression of N-cadherin, β-catenin, Twist1 and Snail2 decreased, and E-cadherin levels increased, when miR-200a was elevated, as tested by fluorescence microscopy and immunohistochemistry. Similar results were observed in vivo. We found upregulated miR-200a expression to increase E-cadherin and suppress the Wnt/β-catenin pathway by targeting ZEB1 and ZEB2 in GA, thus delaying tumor growth in vivo. The effect of miR-200a on Wnt/β-catenin signaling may provide a therapeutic target against EMT.

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Highlights d ADORA1 inhibition promotes immune escape by regulating tumor PD-L1 via ATF3 d ADORA1 or ATF3 screening may be used to assess PD-1 mAb therapy efficacy d Combination of an ADORA1 antagonist and a PD-1 mAb provides therapeutic benefit

No abstract

Abbreviations: miR-33a/b, microRNA 33a/b; HIF-1a, hypoxia inducible factor 1, a subunit Background: Our previous findings showed that miR-33 expressed abnormally in clinical specimens of melanoma, but the exact molecular mechanism has not been elucidated. Object: To determine miR-33's roles in melanoma and confirm whether HIF-1a is a direct target gene of miR-33a. Methods: First miR-33a/b expression levels were detected in HM, WM35, WM451, A375 and SK-MEL-1. Then lentiviral vectors were constructed to intervene miR-33a expression in melanoma cells. Cell proliferation, invasion and metastasis were detected. A375 cells mice model was performed to test the tumorigenesis of melanoma in vivo. Finally the dual reporter gene assay was carried out to confirm whether HIF-1a is a direct target gene of miR-33a. Results: MiR-33a/b exhibited a lower expression in WM35, WM451, A375 and SK-MEL-1 of the metastatic skin melanoma cell lines than that in HM. Then inhibition of miR-33a expression in WM35 and WM451 cell lines could promote cell proliferation, invasion and metastasis. Conversely, increased expression of miR-33a in A375 cells could inhibit cellproliferation, invasion and metastasis. In vivo tests also confirmed that overexpression of miR-33a in A375 cells significantly inhibited melanoma tumorigenesis. Finally, we confirmed that HIF-1a is a direct target gene of miR-33a. Conclusion: The newly identified miR-33a/HIF-1a axis might provide a new strategy for the treatment of melanoma.

Traditional Chinese medicines (TCMs) have important therapeutic value in long-term clinical practice. However, because TCMs contain diverse ingredients and have complex effects on the human body, the molecular mechanisms of TCMs are poorly understood. In this work, we determined the gene expression profiles of cells in response to TCM components to investigate TCM activities at the molecular and cellular levels. MCF7 cells were separately treated with 102 different molecules from TCMs, and their gene expression profiles were compared with the Connectivity Map (CMAP). To demonstrate the reliability and utility of our approach, we used nitidine chloride (NC) from the root of Zanthoxylum nitidum, a topoisomerase I/II inhibitor and α-adrenoreceptor antagonist, as an example to study the molecular function of TCMs using CMAP data as references. We successfully applied this approach to the four ingredients in Danshen and analyzed the synergistic mechanism of TCM components. The results demonstrate that our newly generated TCM data and related methods are valuable in the analysis and discovery of the molecular actions of TCM components. This is the first work to establish gene expression profiles for the study of TCM components and serves as a template for general TCM research.