G9a is a mammalian histone methyltransferase that contributes to the epigenetic silencing of tumor suppressor genes. Emerging evidence suggests that G9a is required to maintain the malignant phenotype, but the role of G9a function in mediating tumor metastasis has not been explored. Here, we show that G9a is expressed in aggressive lung cancer cells, and its elevated expression correlates with poor prognosis. RNAi-mediated knockdown of G9a in highly invasive lung cancer cells inhibited cell migration and invasion in vitro and metastasis in vivo. Conversely, ectopic G9a expression in weakly invasive lung cancer cells increased motility and metastasis. Mechanistic investigations suggested that repression of the cell adhesion molecule Ep-CAM mediated the effects of G9a. First, RNAi-mediated knockdown of Ep-CAM partially relieved metastasis suppression imposed by G9a suppression. Second, an inverse correlation between G9a and Ep-CAM expression existed in primary lung cancer. Third, Ep-CAM repression was associated with promoter methylation and an enrichment for dimethylated histone H3K9. G9a knockdown reduced the levels of H3K9 dimethylation and decreased the recruitment of the transcriptional cofactors HP1, DNMT1, and HDAC1 to the Ep-CAM promoter. Our findings establish a functional contribution of G9a overexpression with concomitant dysregulation of epigenetic pathways in lung cancer progression. Cancer Res; 70(20); 7830-40. ©2010 AACR.
Platinum-based chemotherapy is the first-line treatment for non-small cell lung cancer, but recurrence occurs in most patients. Recent evidence suggests that CD133 þ cells are the cause of drug resistance and tumor recurrence. However, the correlation between chemotherapy and regulation of CD133 þ cells has not been investigated methodically. In this study, we revealed that CD133 þ lung cancer cells labeled by a human CD133
N-α-acetyltransferase 10 protein, Naa10p, is an N-acetyltransferase known to be involved in cell cycle control. We found that Naa10p was expressed lower in varieties of malignancies with lymph node metastasis compared with non-lymph node metastasis. Higher Naa10p expression correlates the survival of lung cancer patients. Naa10p significantly suppressed migration, tumor growth, and metastasis independent of its enzymatic activity. Instead, Naa10p binds to the GIT-binding domain of PIX, thereby preventing the formation of the GIT-PIX-Paxillin complex, resulting in reduced intrinsic Cdc42/Rac1 activity and decreased cell migration. Forced expression of PIX in Naa10-transfected tumor cells restored the migration and metastasis ability. We suggest that Naa10p functions as a tumor metastasis suppressor by disrupting the migratory complex, PIX-GIT- Paxillin, in cancer cells.
Background: Light-emitting diodes (LEDs) deliver higher levels of blue light to the retina than do conventional domestic light sources. Chronic exposure to high-intensity light (2,000–10,000 lux) has previously been found to result in light-induced retinal injury, but chronic exposure to relatively low-intensity (750 lux) light has not been previously assessed with LEDs in a rodent model.Objective: We examined LED-induced retinal neuronal cell damage in the Sprague-Dawley rat using functional, histological, and biochemical measurements.Methods: We used blue LEDs (460 nm) and full-spectrum white LEDs, coupled with matching compact fluorescent lights, for exposures. Pathological examinations included electroretinogram, hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC), and transmission electron microscopy (TEM). We also measured free radical production in the retina to determine the oxidative stress level.Results: H&E staining and TEM revealed apoptosis and necrosis of photoreceptors, which indicated blue-light induced photochemical injury of the retina. Free radical production in the retina was increased in LED-exposed groups. IHC staining demonstrated that oxidative stress was associated with retinal injury. Although we found serious retinal light injury in LED groups, the compact fluorescent lamp (CFL) groups showed moderate to mild injury.Conclusion: Our results raise questions about adverse effects on the retina from chronic exposure to LED light compared with other light sources that have less blue light. Thus, we suggest a precautionary approach with regard to the use of blue-rich “white” LEDs for general lighting.Citation: Shang YM, Wang GS, Sliney D, Yang CH, Lee LL. 2014. White light–emitting diodes (LEDs) at domestic lighting levels and retinal injury in a rat model. Environ Health Perspect 122:269–276; http://dx.doi.org/10.1289/ehp.1307294
Lung cancer, one of the leading causes of death worldwide, is often associated with a state of immune suppression, but the molecular and functional basis remains enigmatic. Evidence is provided in this paper supporting the role of lung cancer-derived soluble lectin, galectin-1, as a culprit in dendritic cell (DC) anergy. We have shown that galectin-1 is highly expressed in lung cancer cell lines, together with the serum and surgical samples from lung cancer patients. Functionally, lung cancer-derived galectin-1 has been shown to alter the phenotypes of monocyte-derived DCs (MdDCs) and impair alloreactive T cell response, concomitant with the increase of CD4+CD25+FOXP3+ regulatory T cells. The regulatory effect of galectin-1 is mediated, in part, through its ability to induce, in an Id3 (inhibitor of DNA binding 3)-dependent manner, the expression of IL-10 in monocytes and MdDCs. This effect is inhibited by the addition of lactose, which normalizes the phenotypic and functional alterations seen in MdDCs. Of note, significant upregulation of IL-10 was seen in tumor-infiltrating CD11c+ DCs in human lung cancer samples. This was also noted in mice transplanted with lung cancer cells, but not in those receiving tumor cells with galectin-1 knockdown. Furthermore, a significant reduction was noted in lung cancer incidence and in the levels of IL-10–expressing, tumor-infiltrating DCs, in mice receiving galectin-1–silenced tumor cells. These results thus suggest that the galectin-1/IL-10 functional axis may be crucial in lung cancer-mediated immune suppression, and that galectin-1 may serve as a target in the development of lung cancer immunotherapy.
Purpose: To correlate quantitative OCT angiography (OCTA) biomarkers with clinical features and to predict the extent of visual improvement after ranibizumab treatment for diabetic macular edema (DME) with OCTA biomarkers. Design: Retrospective, longitudinal study in Taiwan. Participants: Fifty eyes of 50 patients with DME and 22 eyes of 22 healthy persons, with the exception of cataract and refractive error, from 1 hospital. Methods: Each eye underwent OCT angiography (RTVue XR Avanti System with AngioVue software version 2017.1; Optovue, Fremont, CA), and 3 × 3-mm2 en face OCTA images of the superficial layer and the deep layer were obtained at baseline and after 3 monthly injections of ranibizumab in the study group. OCT angiography images also were acquired from the control group. Main Outcome Measures: Five OCTA biomarkers, including foveal avascular zone (FAZ) area (FAZ-A), FAZ contour irregularity (FAZ-CI), average vessel caliber (AVC), vessel tortuosity (VT), and vessel density (VD), were analyzed comprehensively. Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) also were obtained. Student t tests were used to compare the OCTA biomarkers between the study group and the control group. Linear regression models were used to evaluate the correlations between the baseline OCTA biomarkers and the changes of BCVA and CRT after treatment. Results: Eyes with DME had larger AVC, VT, FAZ-A, and FAZ-CI and lower VD than those in the control group (P < 0.001 for all). After the loading ranibizumab treatment, these OCTA biomarkers improved but did not return to normal levels. Among all biomarkers, higher inner parafoveal VD in the superficial layer at baseline correlated most significantly with visual gain after treatment in the multiple regression model with adjustment for CRT and ellipsoid zone disruption (P < 0.001). To predict visual improvement, outer parafoveal VD in the superficial layer at the baseline showed the largest area under the receiver operating characteristic curve (0.787; P = 0.004). No baseline OCTA biomarkers showed any significant correlation specifically with anatomic improvement. Conclusions: For eyes with DME, parafoveal VD in the superficial layer at baseline was an independent predictor for visual improvement after the loading ranibizumab treatment.
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