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Alu Methylation in Serum from Patients with Nasopharyngeal Carcinoma
Tiwawech, Danai,Srisuttee, Ratakorn,Rattanatanyong, Prakasit,Puttipanyalears, Charoenchai,Kitkumthorn, Nakarin,Mutirangura, Apiwat Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.22
Background: Nasopharyngeal carcinoma (NPC) is a common cancer in Southern China and Southeast Asia. Alu elements are among the most prevalent repetitive sequences and constitute 11% of the human genome. Although Alu methylation has been evaluated in many types of cancer, few studies have examined the levels of this modification in serum from NPC patients. Objective: To compare the Alu methylation levels and patterns between serum from NPC patients and normal controls. Materials and Methods: Sera from 50 NPC patients and 140 controls were examined. Quantitative combined bisulfite restriction analysis-Alu (qCOBRA-Alu) was applied to measure Alu methylation levels and characterize Alu methylation patterns. Amplified products were classified into four patterns according to the methylation status of 2 CpG sites: hypermethylated (methylation at both loci), partially methylated (methylation of either of the two loci), and hypomethylated (unmethylated at both loci). Results: A comparison of normal control sera with NPC sera revealed that the latter presented a significantly lower methylation level (p=0.0002) and a significantly higher percentage of hypomethylated loci (p=0.0002). The sensitivity of the higher percentage of Alu hypomethyted loci for distinguishing NPC patients from normal controls was 96%. Conclusions: Alu elements in the circulating DNA of NPC patients are hypomethylated. Moreover, Alu hypomethylated loci may represent a potential biomarker for NPC screening.
KAEWPIBOON, CHUTIMA,SRISUTTEE, RATAKORN,MALILAS, WARAPORN,MOON, JEONG,OH, SANGTAEK,JEONG, HYE GWANG,JOHNSTON, RANDAL N.,ASSAVALAPSAKUL, WANCHAI,CHUNG, YOUNG-HWA SPANDIDOS PUBLICATIONS 2015 MOLECULAR MEDICINE REPORTS Vol.11 No.3
<P>Despite efforts to develop efficient chemotherapeutic drug strategies to treat cancer, acquired drug resistance is a commonly encountered problem. In the present study, to investigate this phenomenon, human A549 lung cancer cells resistant to the topoisomerase inhibitor etoposide (A549RT???eto) were used and compared with A549 parental cells. A549RT???eto cells demonstrated increased resistance to etoposide???induced apoptosis when compared with A549 parental cells. Notably, A549RT???eto cells were observed to exhibit greater levels of histone deacetylase 4 (HDAC4), phospho???Stat1 and P???glycoprotein [P???gp; encoded by the multidrug resistance 1 (MDR1) gene], compared with A549 cells. To address whether HDAC4 protein is involved in etoposide resistance in A549 cells, A549RT???eto cells were treated with trichostatin A (TSA; an HDAC inhibitor) during etoposide treatment. The combined treatment was demonstrated to enhance etoposide???induced apoptosis and reduce expression levels of HDAC4, P???gp and phospho???Stat1. In addition, the suppression of Stat1 with siRNA enhanced etoposide???induced apoptosis and reduced the expression levels of HDAC4 and P???gp, suggesting that Stat1 is essential in the regulation of resistance to etoposide, and in the upregulation of P???gp. Notably, TSA treatment reduced P???gp transcript levels but Stat1 siRNA treatment did not, suggesting that P???gp is regulated by HDAC at the transcriptional level and by Stat1 at the post???transcriptional level. These results suggest that the upregulation of Stat1 and HDAC4 determines etoposide resistance through P???gp expression in human A549 lung cancer cells.</P>
Park, E-H,Koh, S S,Srisuttee, R,Cho, I-R,Min, H-J,Jhun, B H,Lee, Y-S,Jang, K L,Kim, C-H,Johnston, R N,Chung, Y-H Nature Publishing Group 2009 Cancer gene therapy Vol.16 No.5
Although reovirus has been used in tests as a potential cancer therapeutic agent against a variety of cancer cells, its application to hepatocellular carcinoma cells, in which the hepatitis B virus (HBV) X (HBX) protein of HBV plays a primary role, has not yet been explored. Here, we describe experiments in which we use reovirus to treat Chang liver carcinoma cells expressing either a vector only (Chang-vec) or a vector encoding HBX protein (Chang-HBX). Although Chang-vec cells readily support reoviral proliferation and undergo apoptosis, Chang-HBX cells are highly resistant to reoviral infection and virus-induced apoptosis, even though HBX protein induces activation of Ras and inactivation of PKR, which are normally thought to enhance reoviral oncolysis. The resistance of Chang-HBX cells to reovirus may instead be explained by HBX-induced downregulation of death receptor 5 and activation of Stat1. Phosphorylated Stat1 activates interferon (IFN)-stimulated regulatory element (ISRE)- and IFN-γ-activated sequence (GAS)-mediated transcription, leading to the production of IFN-β, whereas the reduced expression of Stat1 with its siRNA results in a decrease in IFN-β production, by which Chang-HBX cells eventually succumb to reovirus infection. This result further indicates that HBX induces the establishment of an antiviral state through Stat1 activation. Thus, it appears that active Ras does not override the antiviral effect mediated by the activation of Stat1. Accordingly, we report that HBX, an oncoprotein of HBV, can prevent reoviral oncolysis of hepatocellular carcinoma. This suggests there may be limits to the practical application of reovirus in the treatment of human cancers already expressing other oncoviral proteins.Cancer Gene Therapy (2009) 16, 453–461; doi:10.1038/cgt.2008.95; published online 19 December 2008
Malilas, W,Koh, S S,Srisuttee, R,Boonying, W,Cho, I-R,Jeong, C-S,Johnston, R N,Chung, Y-H Nature America, Inc. 2013 Cancer gene therapy Vol.20 No.2
We have recently found a novel oncogene, named cancer upregulated gene 2 (CUG2), which activates Ras and mitogen-activated protein kinases (MAPKs), including ERK, JNK and p38 MAPK. Because activation of these signaling pathways has previously been shown to enhance cancer cell susceptibility to oncolysis by certain viruses, we examined whether vesicular stomatitis virus (VSV) could function as a potential therapeutic agent by efficiently inducing cytolysis in cells transformed by CUG2. Unexpectedly, NIH3T3 cells stably expressing CUG2 (NIH-CUG2) were resistant to VSV because of the activation of signal transducers and activators of transcription 1 (STAT1). The result was supported by evidence showing that suppression of STAT1 with short interference RNA (siRNA) renders cells susceptible to VSV. Furthermore, 2′–5′ oligoadenylate synthetase-like (OASL) 2 was the most affected by STAT1 expression level among anti-viral proteins and furthermore suppression of OASL2 mRNA level caused NIH-CUG2 cells to succumb to VSV as seen in NIH-CUG2 cells treated with STAT1 siRNA. In addition, Colon26L5 carcinoma cells stably expressing CUG2 (Colon26L5-CUG2) exhibited resistance to VSV, whereas Colon26L5 stably expressing a control vector yielded to VSV infection. Moreover, Colon26L5-CUG2 cells stably suppressing STAT1 succumbed to VSV infection, resulting in apoptosis. Taken together, we propose that VSV treatment combined with the selective regulation of genes such as STAT1 and OASL2 will improve therapeutic outcomes for CUG2-overexpressing tumors.