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Transdifferentiation-inducing HCCR-1 oncogene
Seon-Ah Ha, Hyun K Kim, JinAh Yoo, SangHee Kim, Seung M Shin, Youn S Lee, Soo Y Hur, Yong W Kim, Tae E Kim, Yeun J Chung, Shin S Jeun, Dong W Kim, Yong G Park, Jin Kim, Soon Y Shin, Young H Lee, Jin W Kim
BMC Cell Biology , 2010, DOI: 10.1186/1471-2121-11-49
Abstract: We report here that HCCR-1, previously shown to play an oncogenic role in human cancers, induces epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) in human and mouse, respectively. The stem cell factor receptor CD117/c-Kit was induced in this transdifferentiated (EMT) sarcoma tissues. This MET occurring in HCCR-1 transfected cells is reminiscent of the transdifferentiation process during nephrogenesis. Indeed, expression of HCCR-1 was observed during the embryonic development of the kidney. This suggests that HCCR-1 might be involved in the transdifferentiation process of cancer stem cell.Therefore, we propose that HCCR-1 may be a regulatory factor that stimulates morphogenesis of epithelia or mesenchyme during neoplastic transformation.The concept that genetic events cooperate to achieve malignant transformation was proposed over a decade ago. Primary rodent cells are efficiently converted into tumorigenic cells by the co-expression of cooperating oncogenes. However, similar experiments with human cells have consistently failed [1]. In 1999, after more than 15 years of trying, researchers have managed to convert normal human cells into tumor cells by delivering telomerase catalytic subunit in combination with two oncogenes [2]. Although malignant transformation of human cells by a single oncogene may not occur or may require specialized factors, we demonstrated that HCCR-1, associated with various types of human cancers, alone induced tumorigenic conversion of mouse cells [3].We have identified a novel oncogene, human cervical cancer oncogene (HCCR), that was classified into 2 types: HCCR-1 (GenBank accession number AF 195651) and HCCR-2 (GenBank accession number AF 315598) [3]. The HCCR-1 and HCCR-2 overexpressed cells were tumorigenic in nude mice and HCCR transgenic mice developed breast cancers and metastasis [3,4]. Also, HCCR-1 was overexpressed in various types of human malignancies and was found to regulate the p53 tum
TCF/β-catenin plays an important role in HCCR-1 oncogene expression
Goang-Won Cho, Mi-Hwa Kim, Seung Kim, Seon-Ah Ha, Hyun Kim, Sanghee Kim, Jin W Kim
BMC Molecular Biology , 2009, DOI: 10.1186/1471-2199-10-42
Abstract: In this study, we showed how the expression of HCCR-1 is modulated. The luciferase activity assay indicated that the HCCR-1 5'-flanking region at positions -166 to +30 plays an important role in HCCR-1 promoter activity. Computational analysis of this region identified two consensus sequences for the T-cell factor (TCF) located at -26 to -4 (Tcf1) and -136 to -114 (Tcf2). Mutation at the Tcf1 site led to a dramatic decrease in promoter activity. Mobility shift assays (EMSA) revealed that nuclear proteins bind to the Tcf1 site, but not to the Tcf2 site. LiCl, Wnt signal activator by GSK-3β inhibition, significantly increased reporter activities in wild-type Tcf1-containing constructs, but were without effect in mutant Tcf1-containing constructs in HEK/293 cells. In addition, endogenous HCCR-1 expression was also increased by treatment with GSK-3β inhibitor, LiCl or AR-A014418 in HEK/293 and K562 cells. Finally, we also observed that the transcription factor, TCF, and its cofactor, β-catenin, bound to the Tcf1 site.These findings suggest that the Tcf1 site on the HCCR-1 promoter is a major element regulating HCCR-1 expression and abnormal stimulation of this site may induce various human cancers.Proto-oncogenes normally help regulate cell growth and differentiation under well-controlled conditions, including mitogenic signal transductions in cells [1,2]. Uncontrolled expression of proto-oncogenes due to mutations or activation of signaling can give rise to a tumor-inducing agent, which is known as an oncogene [2,3]. For more than a decade, there has been a focus on the transcriptional regulation of oncogenes or proto-oncogenes in search of therapeutic clues against cancers which are induced by over-transcription of their oncogenes.Wnt is known as a proto-oncogene and its signaling pathway is a complex network of proteins with roles in embryogenesis [4-6] and cancer [7]. Wnt and its signaling pathway is also involved in normal physiologic processes, including cell pola
Oncoprotein HCCR-1 expression in breast cancer is well correlated with known breast cancer prognostic factors including the HER2 overexpression, p53 mutation, and ER/PR status
Seon-Ah Ha, Youn Lee, Seung Shin, Hyun Kim, Sanghee Kim, Hong Namkoong, Hae Kim, Sang Jung, Yu Lee, Yeun Chung, Sang Jung, Jin Kim
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-51
Abstract: Oncogene HCCR-1 expression levels were determined in normal breast tissues, breast cancer tissues and cancer cell lines. We examined whether HCCR-1 protein expression in breast cancer is related to different biological characteristics, including ER, PR, p53 genotype, and HER2 status in 104 primary breast cancer tissues using immunohistochemical analyses.HCCR-1 was upregulated in breast cancer cells and tissues compared with normal breast tissues. In this study, overexpression of HCCR-1 was well correlated with known breast cancer prognostic markers including the presence of steroid receptors (ER and PR), p53 mutation and high HER2 overexpression. HCCR-1 was not detected in the ER-negative, PR-negative, p53 negative and low HER2 breast cancer tissues. These data indicate that the level of HCCR-1 in breast cancer tissues is relatively well correlated with known breast cancer factors, including the HER2 overexpression, p53 mutation, and ER/PR status.Determination of HCCR-1 levels as options for HER2 testing is promising although it needs further evaluation.Cells expressing HCCR-1 are tumorigenic in nude mice [1]. The functional role of this oncogene in tumorigenesis is manifested as a negative regulator of the p53 tumor suppressor [1]. In the previous study, we investigated HCCR-1 protein expression in breast cancer and the possibility of using HCCR-1 as a useful biomarker for human breast cancer [2]. We also examined whether HCCR-1 protein expression in breast cancer is related to different biological characteristics including ER, PR, p53 genotype, and the HER2 status. Northern and Western blot analyses and immunohistochemical studies indicate that the HCCR-1 mRNA and protein are overexpressed in breast cancer tissues compared to the normal breast tissues [1,2]. Serological studies revealed an 86.8% sensitivity for HCCR-1 in breast cancer, which was higher than 21.0% for CA15-3 [2,3]. The HCCR-1 assay has an advantage over CA15-3 in diagnosing breast cancer. These res
Immunization with a Recombinant Vaccinia Virus That Encodes Nonstructural Proteins of the Hepatitis C Virus Suppresses Viral Protein Levels in Mouse Liver  [PDF]
Satoshi Sekiguchi, Kiminori Kimura, Tomoko Chiyo, Takahiro Ohtsuki, Yoshimi Tobita, Yuko Tokunaga, Fumihiko Yasui, Kyoko Tsukiyama-Kohara, Takaji Wakita, Toshiyuki Tanaka, Masayuki Miyasaka, Kyosuke Mizuno, Yukiko Hayashi, Tsunekazu Hishima, Kouji Matsushima, Michinori Kohara
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0051656
Abstract: Chronic hepatitis C, which is caused by infection with the hepatitis C virus (HCV), is a global health problem. Using a mouse model of hepatitis C, we examined the therapeutic effects of a recombinant vaccinia virus (rVV) that encodes an HCV protein. We generated immunocompetent mice that each expressed multiple HCV proteins via a Cre/loxP switching system and established several distinct attenuated rVV strains. The HCV core protein was expressed consistently in the liver after polyinosinic acid–polycytidylic acid injection, and these mice showed chronic hepatitis C-related pathological findings (hepatocyte abnormalities, accumulation of glycogen, steatosis), liver fibrosis, and hepatocellular carcinoma. Immunization with one rVV strain (rVV-N25), which encoded nonstructural HCV proteins, suppressed serum inflammatory cytokine levels and alleviated the symptoms of pathological chronic hepatitis C within 7 days after injection. Furthermore, HCV protein levels in liver tissue also decreased in a CD4 and CD8 T-cell-dependent manner. Consistent with these results, we showed that rVV-N25 immunization induced a robust CD8 T-cell immune response that was specific to the HCV nonstructural protein 2. We also demonstrated that the onset of chronic hepatitis in CN2-29(+/?)/MxCre(+/?) mice was mainly attributable to inflammatory cytokines, (tumor necrosis factor) TNF-α and (interleukin) IL-6. Thus, our generated mice model should be useful for further investigation of the immunological processes associated with persistent expression of HCV proteins because these mice had not developed immune tolerance to the HCV antigen. In addition, we propose that rVV-N25 could be developed as an effective therapeutic vaccine.
A Novel Interaction between hScrib and PP1γ Downregulates ERK Signaling and Suppresses Oncogene-Induced Cell Transformation  [PDF]
Kazunori Nagasaka, Takayuki Seiki, Aki Yamashita, Paola Massimi, Vanitha Krishna Subbaiah, Miranda Thomas, Christian Kranjec, Kei Kawana, Shunsuke Nakagawa, Tetsu Yano, Yuji Taketani, Tomoyuki Fujii, Shiro Kozuma, Lawrence Banks
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0053752
Abstract: Previous studies have shown that the cell polarity regulator hScrib interacts with, and consequently controls, the ERK signaling pathway. This interaction occurs through two well-conserved Kinase Interacting Motifs, which allow hScrib to bind ERK1 directly, resulting in a reduction in the levels of phospho-ERK. This suggests that hScrib might recruit a phosphatase to regulate this signaling pathway. Using a proteomic approach we now show that Protein Phosphatase 1γ (PP1γ) is a major interacting partner of hScrib. This interaction is direct and occurs through a conserved PP1γ interaction motif on the hScrib protein, and this interaction appears to be required for hScrib's ability to downregulate ERK phosphorylation. In addition, hScrib also controls the pattern of PP1γ localization, where loss of hScrib enhances the nuclear translocation of PP1γ. Furthermore, we also show that the ability of hScrib to interact with PP1γ is important for the ability of hScrib to suppress oncogene-induced transformation of primary rodent cells. Taken together, these results demonstrate that hScrib acts as a scaffold to integrate the control of the PP1γ and ERK signaling pathways and explains how disruption of hScrib localisation can contribute towards the development of human malignancy.
Splenic Abscess: A Rare Complication of the UVC in Newborn  [PDF]
Ameer Aslam,Emad Sadek Ahmed Shatla,Sameera Imanullah,Elsaid M. A. Bedair
Case Reports in Pediatrics , 2014, DOI: 10.1155/2014/903421
Abstract: Splenic abscess is one of the rarest complications of the UVC in a newborn and it is hypothesized that it could be due to an infection or trauma caused by a catheter. The case that is being reported presented with abdominal distension and recurrent desaturation with suspicion of neonatal sepsis versus necrotizing enterocolitis. However, the final diagnosis was splenic abscess as a complication of an inappropriate UVC insertion which was discovered by abdominal ultrasound. The patient was given broad spectrum antibiotics empirically and the symptoms were resolved without any surgical intervention. Such cases and controlled studies need to be reported in order to identify further causes and risk factors associated with splenic abscess in a patient with UVC which can eventually help us adopt preventive strategies to avoid such complications. 1. Introduction Common complications of UVCs in a newborn are infection, hemorrhage, vessel perforation, creation of a false luminal tract [1], hepatic abscess or necrosis [2], air embolism, catheter tip embolism, portal venous thrombosis [3], dysrhythmia, and pericardial tamponade or perforation. Splenic abscess can occur in a newborn without any significant symptom and can resolve without any significant intervention but it could per se be the fatal and lethal complication in patients with UVC. Splenic abscess usually is caused by hematogenous embolization and contagious spread. As saving the central lines in newborn is the most common and integral part of any NICU for treatments and nutrition, but care should be taken to avoid the morbidity and mortality related to UVC. 2. Case Report A Sudanese female neonate born at 25 weeks of gestation with birth weight of 980 grams whose mother was known to have autoimmune hepatitis and primary biliary cirrhosis. The patient developed respiratory distress at birth which needed endotracheal intubation connected to mechanical ventilator after giving surfactant followed by UVC and UAC insertion. She was started on Ampicillin and Amikacin after sepsis screen. Moreover, caffeine citrate and total parental nutrition were started from the first day of life. Initial chest X-ray showed ETT in situ, bilateral hazy lung field but normal abdominal gas pattern. Next day, she developed jaundice without any set up which resolved with phototherapy in 2 days. Cranial ultrasound was reported as normal while insignificant PDA was reported by echocardiography. Abdominal X-ray to localize the position of the UVC showed it to be directed to the left side in splenic vein which was corrected
Epidermal growth factor induces HCCR expression via PI3K/Akt/mTOR signaling in PANC-1 pancreatic cancer cells
Zekuan Xu, Yi Zhang, Jiakai Jiang, Yang Yang, Ruihua Shi, Bo Hao, Zhihong Zhang, Zuhu Huang, Jin W Kim, Guoxin Zhang
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-161
Abstract: A polyclonal antibody against HCCR protein was raised by immunizing Balb/c mice with the purified recombinant protein pMBPc-HCCR. Tissue samples were constructed on a tissue chip, and the expression of HCCR was investigated by immunohistochemistry assay and Western blotting. Pancreatic cell line, PANC-1 cells were stably transfected with plasmids containing sense-HCCR-1 fragment and HCCR siRNA fragment. MTT and transwell assay were used to investigate the proliferation and invasion of stable tansfectants. The specific inhibitor of PI3K and mTOR was used to see if PI3K/mTOR signal transduction was involved in the induction of HCCR gene expression. A Luciferase assay was used to see if Akt can enhance the HCCR promoter activity.HCCR was up-regulated in pancreatic tumor tissues (mean Allred score 4.51 ± 1.549 vs. 2.87 ± 2.193, P < 0.01), especially with high expression in poorly differentiated pancreatic cancer. The growth of cells decreased in HCCR-1 siRNA transfected cells compared with vector transfectants. The number of invasion cells was significantly lower in HCCR-1 siRNA transfected cells (24.4 ± 9.9) than that in vector transfectants (49.1 ± 15.4). Treatment of PANC-1 cells with epidermal growth factor increased HCCR protein level in a dose- and time-dependent manner. However, application of LY294002 and rapamycin caused a dramatic reduction of epidermal growth factor-induced HCCR expression. Over-expression of exogenous constitutively active Akt increased the HCCR promoter activity; in contrast, dominant negative Akt decreased the promoter activity.EGF-induced HCCR-1 over-expression is mediated by PI3K/AKT/mTOR signaling which plays a pivotal role in pancreatic tumor progression, suggesting that HCCR-1 could be a potential target for cancer therapeutics.Pancreatic cancer is one of most common malignant tumors with poor prognosis, and its incidence is on the rise globally. The five-year survival rate is less than 5 percent among pancreatic cancer patients with
人参皂苷Re对UVC辐射损伤细胞的保护作用  [PDF]
张洪长,王恩鹏,陈 新,唐 燕,王洪鑫,王炫策,许 新
吉林大学学报(医学版) , 2013, DOI: 10.7694/jldxyxb20130317
Abstract: 目的:研究人参皂苷Re对短波紫外线(UVC)辐射损伤人胚胎纤维芽细胞RSa的保护作用,探讨人参皂苷Re抗UVC辐射的作用机制。方法:采用不同强度的UVC辐射RSa细胞,在辐射前后给予50mg?L-1的人参皂苷Re(UVC+Re组),同时设UVC模型组和UVC+Rg1组,利用MTT法检测细胞生存率,采用流式细胞术(FCM)检测细胞周期和凋亡情况;酶生化法检测细胞内超氧化物歧化酶(SOD)的活性,集落形成分析法检测SOD抑制剂作用细胞后细胞的生存率。结果:MTT法,与UVC模型组比较,UVC+Re和UVC+Rg1组细胞生存率比较差异有统计学意义(P<0.05,P<0.01)。FCM,不同剂量(5、10和15J?m-2)的UVC辐射可引起RSa细胞早期的凋亡,UVC+Re组细胞凋亡率小于UVC模型组。细胞周期检测,UVC辐射可导致G2期细胞百分比增加(P<0.01),UVC+Re组G2期细胞百分比例明显小于UVC模型组(P<0.01)。UVC+Re组SOD活性明显高于UVC模型组(P<0.01)。结论:人参皂苷Re有较好的抗UVC效果,能够有效提高RSa细胞的生存率,减少UVC辐射引起的细胞早期凋亡,增加RSa细胞内SOD活性。
Inactivation of Poxviruses by Upper-Room UVC Light in a Simulated Hospital Room Environment  [PDF]
James J. McDevitt, Donald K. Milton, Stephen N. Rudnick, Melvin W. First
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003186
Abstract: In the event of a smallpox outbreak due to bioterrorism, delays in vaccination programs may lead to significant secondary transmission. In the early phases of such an outbreak, transmission of smallpox will take place especially in locations where infected persons may congregate, such as hospital emergency rooms. Air disinfection using upper-room 254 nm (UVC) light can lower the airborne concentrations of infective viruses in the lower part of the room, and thereby control the spread of airborne infections among room occupants without exposing occupants to a significant amount of UVC. Using vaccinia virus aerosols as a surrogate for smallpox we report on the effectiveness of air disinfection, via upper-room UVC light, under simulated real world conditions including the effects of convection, mechanical mixing, temperature and relative humidity. In decay experiments, upper-room UVC fixtures used with mixing by a conventional ceiling fan produced decreases in airborne virus concentrations that would require additional ventilation of more than 87 air changes per hour. Under steady state conditions the effective air changes per hour associated with upper-room UVC ranged from 18 to 1000. The surprisingly high end of the observed range resulted from the extreme susceptibility of vaccinia virus to UVC at low relative humidity and use of 4 UVC fixtures in a small room with efficient air mixing. Increasing the number of UVC fixtures or mechanical ventilation rates resulted in greater fractional reduction in virus aerosol and UVC effectiveness was higher in winter compared to summer for each scenario tested. These data demonstrate that upper-room UVC has the potential to greatly reduce exposure to susceptible viral aerosols. The greater survival at baseline and greater UVC susceptibility of vaccinia under winter conditions suggest that while risk from an aerosol attack with smallpox would be greatest in winter, protective measures using UVC may also be most efficient at this time. These data may also be relevant to influenza, which also has improved aerosol survival at low RH and somewhat similar sensitivity to UVC.
The Oncogene Mcts1
Ali Hachem and Suvobroto Nandi
Translational Oncogenomics , 2012,
Abstract: The oncogene MCTS1, discovered as an amplified product in a subset of T-cell lymphoma lines, has been implicated in cell cycle progression and conferring a growth advantage in lymphomas and breast cancer. Recent research shows that it modulates the MAPK pathway and acts as a translational activator both in vivo and in vitro. In breast cancer cells, expression of MCTS1 confers aggressive properties and inhibits apoptosis. This article will review these data and its implications on our understanding of cancer.
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