ADAM9 functions as a transcriptional regulator to drive angiogenesis in esophageal squamous cell carcinoma.

Hypoxia and angiogenesis play key roles in the pathogenesis of esophageal squamous cell carcinoma (ESCC), but regulators linking these two pathways to drive tumor progression remain elusive. Here we provide evidence of ADAM9's novel function in ESCC progression. Increasing expression of ADAM9 was correlated with poor clinical outcomes in ESCC patients. Suppression of ADAM9 function diminished ESCC cell migration and in vivo metastasis in ESCC xenograft mouse models. Using cellular fractionation and imaging, we found a fraction of ADAM9 was present in the nucleus and was uniquely associated with gene loci known to be linked to the angiogenesis pathway demonstrated by genome-wide ChIP-seq. Mechanistically, nuclear ADAM9, triggered by hypoxia-induced translocation, functions as a transcriptional repressor by binding to promoters of genes involved in the negative regulation of angiogenesis, and thereby promotes tumor angiogenesis in plasminogen/plasmin pathway. Moreover, ADAM9 suppresses plasminogen activator inhibitor-1 gene transcription by interacting with its transcription factors at the promoter. Our findings uncover a novel regulatory mechanism of ADAM9 as a transcriptional regulator in angiogenesis and highlight ADAM9 as a promising therapeutic target for ESCC treatment.

ADAM9 promotes lung cancer progression through vascular remodeling by VEGFA, ANGPT2, and PLAT.

Lung cancer has a very high prevalence of brain metastasis, which results in a poor clinical outcome. Up-regulation of a disintegrin and metalloproteinase 9 (ADAM9) in lung cancer cells is correlated with metastasis to the brain. However, the molecular mechanism underlying this correlation remains to be elucidated. Since angiogenesis is an essential step for brain metastasis, microarray experiments were used to explore ADAM9-regulated genes that function in vascular remodeling. The results showed that the expression levels of vascular endothelial growth factor A (VEGFA), angiopoietin-2 (ANGPT2), and tissue plasminogen activator (PLAT) were suppressed in ADAM9-silenced cells, which in turn leads to decreases in angiogenesis, vascular remodeling, and tumor growth in vivo. Furthermore, simultaneous high expression of ADAM9 and VEGFA or of ADAM9 and ANGPT2 was correlated with poor prognosis in a clinical dataset. These findings suggest that ADAM9 promotes tumorigenesis through vascular remodeling, particularly by increasing the function of VEGFA, ANGPT2, and PLAT.

Characterization of PCDD/Fs and dioxin-like PCBs emitted from two woodchip boilers in Taiwan.

This study investigates the formation and removal of PCDD/Fs and dl-PCBs in two woodchips boilers during different operating periods. Results indicate that combustion condition affects PCDD/F and dl-PCB formation within the woodchip combustion process. PCDD/F and dl-PCB concentrations during the start-up period are much higher than those measured during normal operation and shut-down periods due to unstable combustion. PCDD/F and dl-PCB concentrations at APCDs inlet of Plant A are significantly higher than that of Plant B due to the lower combustion temperature (500-850 °C) compared with Plant B (850-925 °C). Major PCDD/F congeners at APCDs inlet of both plants during normal operation are O8CDD, 1,2,3,4,6,7,8-H7CDD and 1,2,3,4,6,7,8-H7CDF, while major dl-PCBs are TeCB-77, PeCB-118 and PeCB-126. The removal efficiencies of PCDD/F and PCBs achieved with the APCDs of Plant A are 95.6% and 88.6%, respectively, while those of Plant B are 99.3% and 94.9%. Possibly, the AC concentration of Plant A exceeds the optimal AC concentration and, PCDD/Fs and dl-PCBs might be formed because the AC injected can supply additional reaction area and carbon source. Also, this may be due to different operating temperatures of APCDs, which affects removal efficiency of PCDD/F and dl-PCB congeners. The emission factors (PCDD/Fs + dl-PCBs) of Plants A and B are calculated as 17.86 and 1.25 µg I-TEQ/ton, respectively. Concentrations of PCDD/Fs in the BF ash of Plants A and B during normal operation are measured as 98.57 and 38.06 ng I-TEQ/g, which are significantly higher than the standard limit (1.0 ng I-TEQ/g) promulgated by Taiwan EPA.

Aryl Hydrocarbon Receptor Activates NDRG1 Transcription under Hypoxia in Breast Cancer Cells.

Hypoxia has been intensively investigated over the past several decades based on the observations that hypoxic tumors are more resistant to therapy and have a worse prognosis. Previously, we reported that N-myc downstream-regulated gene 1 (NDRG1) is strongly up-regulated under hypoxia and may play an important role in tumor adaptation to fluctuating oxygen concentrations. However, the regulatory mechanism of NDRG1 under hypoxia remains elusive. Therefore, the purpose of this study was to identify the transcription factors that regulate NDRG1 and to investigate the functional roles of NDRG1 in hypoxia. We showed that binding sites of aryl hydrocarbon receptor (AHR) were predicted in the NDRG1 promoter. Nuclear AHR was up-regulated in the presence of cobalt and hypoxia. AHR translocated to nuclei and bound between base pairs -412 and -388 of the NDRG1 promoter in hypoxia. Moreover, hypoxia-mimetic induction of NDRG1 was attenuated by knockdown of AHR expression. Also, overexpression of AHR facilitated cell proliferation and migration via up-regulation of NDRG1. These results showed for the first time that AHR positively regulates NDRG1 transcription through an AHR binding site by way of hypoxia-mimetic signaling, which may lead to development of a specific therapeutic regimen to prevent tumor malignancy under hypoxia.

Induction of apoptosis by HAC-Y6, a novel microtubule inhibitor, through activation of the death receptor 4 signaling pathway in human hepatocellular carcinoma cells.

The present data showed that a novel synthesized compound, 6-acetyl-9-(3,4,5-trimethoxybenzyl)-9H-pyrido [2,3-b]indole (HAC-Y6), exhibited potent antitumor activity against human hepatocellular carcinoma (HCC) cells in vitro. Western blot and immunofluorescence experiments showed that HAC-Y6 depolymerized microtubules similarly to the effects of colchicine. HAC-Y6-treatment in Hep3B cells resulted in the accumulation of the G2/M phase and induced apoptosis. In addition, HAC-Y6-treatment influenced the expression of cell cycle and apoptosis related proteins in Hep3B cells. HAC-Y6 exposure increased caspases-3, -8, -9 and Bax protein levels, while reducing levels of Bcl-2 family proteins. Moreover, Bid, a substrate of caspase-8, was also activated by HAC-Y6. Treatment of cells caused the up-regulation of the death receptor 4 (DR4) and phosphorylation of p38. Taken together, we show that HAC-Y6 exhibited its antitumor activity by disrupting microtubule assembly, causing cell cycle arrest and apoptosis through both extrinsic and intrinsic pathways in Hep3B cells. Therefore, the novel compound HAC-Y6 is a promising microtubule inhibitor that has great potential for treatment of HCC.