Publisher Correction: Atherogenic dyslipidemia promotes autoimmune follicular helper T cell responses via IL-27

Ryu, Heeju,Lim, Hoyong,Choi, Garam,Park, Young-Jun,Cho, Minkyoung,Na, Hyeongjin,Ahn, Chul Won,Kim, Young Chul,Kim, Wan-Uk,Lee, Sang-Hak,Chung, Yeonseok NATURE AMERICA INC 2018 NATURE IMMUNOLOGY Vol.19 No.9

14-3-3 eta depletion sensitizes glioblastoma cells to irradiation due to enhanced mitotic cell death

Park, G-Y,Han, J Y,Han, Y K,Kim, S D,Kim, J S,Jo, W S,Chun, S H,Jeong, D H,Lee, C-W,Yang, K,Lee, C G Nature America, Inc. 2014 Cancer gene therapy Vol.21 No.4

14-3-3 proteins have important roles in several cellular processes such as cell cycle progression, the DNA-damage checkpoint and apoptosis. We have shown previously that depleting 14-3-3η, a 14-3-3 isoform, enhances mitotic cell death, and that combining it with microtubule agents is more effective for anticancer therapeutics. In this study, we investigated whether depleting 14-3-3η can be combined with radiotherapy to enhance its therapeutic efficacy. We found that depleting 14-3-3η resulted in a synergistic radiosensitizing effect when combined with radiotherapy in several glioblastoma cell lines, where its specific expression and correlation of its expression level with malignancy have been reported. The radiosensitizing effect was associated with enhanced mitotic cell death by 14-3-3η depletion but not with mitotic catastrophe, which is one of the major cell death mechanisms observed in response to irradiation of most solid tumors. These results suggest that 14-3-3η may be a therapeutic target to overcome radioresistance in glioblastoma.

Electroporation markedly improves Sleeping Beauty transposon-induced tumorigenesis in mice

Jung, S,Choi, H-J,Park, H-K,Jo, W,Jang, S,Ryu, J-E,Kim, W-J,Yu, E-S,Son, W-C Nature America, Inc. 2014 Cancer gene therapy Vol.21 No.8

The Sleeping Beauty (SB) transposon system is an important tool for genetic studies. It is used to insert a gene of interest into the host chromosome, thus enabling permanent gene expression. However, this system is less useful in higher eukaryotes because the transposition frequency is low. Efforts to improve the efficacy of the SB transposon system have focused on the method of gene delivery, but although electroporation has recently attracted much attention as an in vivo gene delivery tool, the simultaneous use of electroporation and the SB transposon system has not been studied for gene transfer in mice. In this study, electroporation was used in a model of SB transposon-induced insertional tumorigenesis. Electroporation increased the rate of tumor development to three times that of the control group. There was no difference in phenotype between tumors induced with the SB transposon system alone and those induced by the SB transposon and electroporation. Electroporation therefore may be an efficient means of improving the efficacy of gene transfer via the SB transposon system.

Co-delivery of LETM1 and CTMP synergistically inhibits tumor growth in H-ras12V liver cancer model mice

Shin, J-Y,Chung, Y-S,Kang, B,Jiang, H-L,Yu, D-Y,Han, K,Chae, C,Moon, J-H,Jang, G,Cho, M-H Nature America, Inc. 2013 Cancer gene therapy Vol.20 No.3

As hepatocellular carcinoma (HCC) is one of the most common tumors worldwide, development of novel therapeutic approaches for HCC is urgently needed. Two different genes, LETM1 and CTMP, which target mitochondrial functions, were chosen and linked using 2A-peptide sequence. Successful self-cleavage of 2A-peptide induced synergistic antitumor effect in the liver of H-ras12V, the HCC model mice, by simultaneous activation of LETM1 (Leucine zipper/EF hand-containing transmembrane-1) and CTMP (carboxyl-terminal modulator protein). Overexpression of LETM1 and CTMP significantly reduced the incidence of tumorigenesis, which were confirmed by gross and microscopic observations. Morphological changes in mitochondria, such as swelling and loss of cristae, were significant, and the prolonged activation of defects in mitochondrial function led to mitochondria-mediated apoptosis. Furthermore, with CTMP as a direct binding partner of Akt1, and LETM1 as a binding partner of CTMP, LETM1-2A-CTMP downregulated the Akt1 pathway at both Ser473 and Thr308 sites of phosphorylation. Proliferation and angiogenesis, which are important in cancer prognosis, were reduced in tumor sites after introduction of LETM1-2A-CTMP. Taken together, the results indicate that introduction of the mitochondria-targeting genes, LETM1 and CTMP, and self-processing capacity of 2A-peptide sequence exerts an antitumor effect in liver of H-ras12V mice, suggesting its potential as a tool for gene therapy.

Aerosol delivery of eukaryotic translation initiation factor 4E-binding protein 1 effectively suppresses lung tumorigenesis in K-ras^LA1 mice

Chang, S-H,Kim, J-E,Lee, J-H,Minai-Tehrani, A,Han, K,Chae, C,Cho, Y-H,Yun, J-H,Park, K,Kim, Y-S,Cho, M-H Nature America, Inc. 2013 Cancer gene therapy Vol.20 No.6

Conventional radiotherapy or chemotherapy for the long-term survival of patients with lung cancer is still difficult for treatment in metastatic and advanced tumors. Therefore, the safe and effective approaches to the treatment of lung cancer are needed. In this study, the effect of delivered eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) on lung cancer progression was evaluated. Recombinant adeno-associated virus (rAAV)-M3/4E-BP1 was delivered into 6-week-old K-ras<SUP>LA1</SUP> lung cancer model mice through a nose-only inhalation system twice a week for 4 weeks. Long-term repeated delivery of 4E-BP1 effectively reduced tumor progression in the lungs of K-ras<SUP>LA1</SUP> mice. Reduction of eIF4E by overexpression of 4E-BP1 resulted in suppression of cap-dependent protein expression of basic fibroblast growth factor (bFGF or FGF-2) and vascular endothelial growth factor (VEGF). In addition, delivered 4E-BP1 inhibited the proliferation of lung cancer cells in K-ras<SUP>LA1</SUP> mice model. Our results suggest that long-term repeated viral delivery of 4E-BP1 may provide a useful tool for designing lung cancer treatment.

Cancer upregulated gene 2, a novel oncogene, confers resistance to oncolytic vesicular stomatitis virus through STAT1-OASL2 signaling

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.

c-Cbl shRNA-expressing adenovirus sensitizes TRAIL-induced apoptosis in prostate cancer DU-145 through increases of DR4/5

Kim, S Y,Kim, J-H,Song, J J Nature America, Inc. 2013 Cancer gene therapy Vol.20 No.2

We previously demonstrated that the downregulation of Casitas B-lineage lymphoma (c-Cbl) can sensitize tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in two different ways. One way is to block the rapid degradation of TRAIL receptors, which can sustain TRAIL-induced apoptosis for a long time. Here, we designed a replication-defective adenovirus expressing the short hairpin RNA (shRNA) against c-Cbl to test the possibility of developing a cancer gene therapy that can act as a sensitizer of TRAIL. As expected from the results of our previous study that used a stable cell line with downregulated c-Cbl, infection with the c-Cbl shRNA-expressing adenovirus led to an increase in the death receptor 4 (DR4) and DR5 levels, which is known to be a cause for the increase of TRAIL-induced apoptosis. In conclusion, we demonstrated that c-Cbl shRNA-expressing adenovirus is able to sensitize TRAIL-induced apoptosis in vivo as well as in vitro.

Determinants of residential indoor and transportation activity times in Korea

Yang, Wonho,Lee, Kiyoung,Yoon, Chungsik,Yu, Seungdo,Park, Kyunghwa,Choi, Wookhee Nature America, Inc. 2011 Journal of exposure science & environmental epidem Vol.21 No.3

Information on time spent in microenvironments has a critical role for personal exposure to environmental pollutants. Unlike several large-scale studies in Western countries, no comprehensive research on time-activity patterns for exposure assessment has been conducted in Korea. We investigated determinants of residential indoor and transportation times of individuals over 10-years old in the Korean population. The population-based study collected time-activity patterns of 31,634 Koreans for two consecutive days. The residential indoor and transportation times were collected for a weekday and a weekend day. The impact of sociodemographic factors on time-activity was assessed using multiple linear regression models. The residential indoor times were 14.23 h for the weekday and 16.13 h for the weekend and shorter than those in Western countries. The transportation times were 1.75 h for the weekday and 1.68 h for the weekend day. The most significant factors in residential indoor time were employment status, age, monthly income, and gender for the weekday and employment status and gender for the weekend day. The factors in transportation were gender, employment status, and monthly income for the weekday and gender, employment status, age, and marriage status for the weekend day. Determinants of the time-activity pattern need to be taken into account in exposure assessment, epidemiological analyses, and exposure simulations, as well as in the development of preventive strategies. As Korean population activity patterns are substantially different from those in Western countries such as USA, Germany, and UK, this information could be critical for exposure assessment in Korea and other Asian countries.

Prenatally diagnosed left ventricular diverticulum with thoracoabdominal wall defect: a case and review of the literature

Nam, K H,Kwon, J Y,Son, G H,Cho, N H,Park, Y W,Kim, Y H Nature America, Inc. 2010 Journal of perinatology Vol.30 No.11

Suppression of tumor growth in xenograft model mice by programmed cell death 4 gene delivery using folate-PEG-baculovirus

Kim, Y-K,Kwon, J-T,Choi, J Y,Jiang, H-L,Arote, R,Jere, D,Je, Y H,Cho, M-H,Cho, C-S Nature America, Inc. 2010 Cancer gene therapy Vol.17 No.11

Cancer gene therapy using tumor suppressor genes is considered to be an attractive approach for arresting cell growth and inducing apoptosis. Programmed cell death 4 (Pdcd4) is a tumor suppressor gene, which prevents tumorigenesis and tumor progression. To address the issue of whether expression of PDCD4 protein induces apoptosis in cancerous cells, the Pdcd4 gene was delivered using folate-PEG-baculovirus. Folate-PEG-baculovirus containing Pdcd4 gene (F-P-Bac-Pdcd4) was constructed by attachment of F-PEG to the baculovirus surface using chemical modification. The F-P-Bac-Pdcd4 showed enhanced transduction efficiency, efficiently expressed PDCD4 protein, and induced apoptosis in human epidermal carcinoma (KB) cells as compared with an unmodified baculovirus. In a tumor xenograft study, injection of F-P-Bac-Pdcd4 into tumors established from the KB cell line by subcutaneous implantation significantly suppressed tumor growth and induced apoptosis. Thus, this study shows a new baculovirus-mediated tumor suppressor gene delivery system for cancer therapy.