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Dooil Jeoung - One of the best experts on this subject based on the ideXlab platform.
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mir 200b and Cancer Testis Antigen cage form a feedback loop to regulate the invasion and tumorigenic and angiogenic responses of a Cancer cell line to microtubule targeting drugs
Journal of Biological Chemistry, 2013Co-Authors: Deokbum Park, Jongseon Choe, Munseon Choi, Dooil JeoungAbstract:Cancer/Testis Antigen Cancer-associated gene (CAGE) is known to be involved in various cellular processes, such as proliferation, cell motility, and anti-Cancer drug resistance. However, the mechanism of the expression regulation of CAGE remains unknown. Target scan analysis predicted the binding of microRNA-200b (miR-200b) to CAGE promoter sequences. The expression of CAGE showed an inverse relationship with miR-200b in various Cancer cell lines. miR-200b was shown to bind to the 3′-UTR of CAGE and to regulate the expression of CAGE at the transcriptional level. miR-200b also enhanced the sensitivities to microtubule-targeting drugs in vitro. miR-200b and CAGE showed opposite regulations on invasion potential and responses to microtubule-targeting drugs. Xenograft experiments showed that miR-200b had negative effects on the tumorigenic and metastatic potential of Cancer cells. The effect of miR-200b on metastatic potential involved the expression regulation of CAGE by miR-200b. miR-200b decreased the tumorigenic potential of a Cancer cell line resistant to microtubule-targeting drugs in a manner associated with the down-regulation of CAGE. ChIP assays showed the direct regulation of miR-200b by CAGE. CAGE enhanced the invasion potential of a Cancer cell line stably expressing miR-200b. miR-200b exerted a negative regulation on tumor-induced angiogenesis. The down-regulation of CAGE led to the decreased expression of plasminogen activator inhibitor-1, a TGFβ-responsive protein involved in angiogenesis, and VEGF. CAGE mediated tumor-induced angiogenesis and was necessary for VEGF-promoted angiogenesis. Human recombinant CAGE protein displayed angiogenic potential. Thus, miR-200b and CAGE form a feedback regulatory loop and regulate the response to microtubule-targeting drugs, as well as the invasion, tumorigenic potential, and angiogenic potential.
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Cancer Testis Antigen cage exerts negative regulation on p53 expression through hdac2 and confers resistance to anti Cancer drugs
Journal of Biological Chemistry, 2010Co-Authors: Hyunmi Park, Deokbum Park, Jongseon Choe, Janghee Hahn, Dooil JeoungAbstract:The role of the Cancer/Testis Antigen CAGE in drug resistance was investigated. The drug-resistant human melanoma Malme3M (Malme3MR) and the human hepatic Cancer cell line SNU387 (SNU387R) showed in vivo drug resistance and CAGE induction. Induction of CAGE resulted from decreased expression and thereby displacement of DNA methyltransferase 1(DNMT1) from CAGE promoter sequences. Various drugs induce expression of CAGE by decreasing expression of DNMT1, and hypomethylation of CAGE was correlated with the increased expression of CAGE. Down-regulation of CAGE in these cell lines decreased invasion and enhanced drug sensitivity resulting from increased apoptosis. Down-regulation of CAGE also led to decreased anchorage-independent growth. Down-regulation of CAGE led to increased expression of p53, suggesting that CAGE may act as a negative regulator of p53. Down-regulation of p53 enhanced resistance to drugs and prevented drugs from exerting apoptotic effects. In SNU387R cells, CAGE induced the interaction between histone deacetylase 2 (HDAC2) and Snail, which exerted a negative effect on p53 expression. Chromatin immunoprecipitation assay showed that CAGE, through interaction with HDAC2, exerted a negative effect on p53 expression in Malme3MR cells. These results suggest that CAGE confers drug resistance by regulating expression of p53 through HDAC2. Taken together, these results show the potential value of CAGE as a target for the development of Cancer therapeutics.
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the Cancer Testis Antigen cage with oncogenic potential stimulates cell proliferation by up regulating cyclins d1 and e in an ap 1 and e2f dependent manner
Journal of Biological Chemistry, 2010Co-Authors: Heejung Byun, Soyoung Jung, Iha Park, Dooil JeoungAbstract:A Cancer/Testis Antigen, CAGE, is widely expressed in various Cancer tissues and Cancer cell lines but not in normal tissues except the Testis. In the present study, ectopic expression of CAGE in fibroblast cells resulted in foci formation, suggesting its cell-transforming ability. Using stable HeLa transfectant clones with the tetracycline-inducible CAGE gene, we found that CAGE overexpression stimulated both anchorage-dependent and -independent cell growth in vitro and promoted tumor growth in a xenograft mouse model. Cell cycle analysis showed that CAGE augments the levels of cyclin D1 and E, thereby activating cyclin-associated cyclin-dependent kinases and subsequently accelerating the G1 to S progression. Moreover, increased cyclin D1 and E levels in CAGE-overexpressing cells were observed even in a growth arrested state, indicating a direct effect of CAGE on G1 cyclin expression. CAGE-induced expression of cyclins D1 and E was found to be mediated by AP-1 and E2F-1 transcription factors, and among the AP-1 members, c-Jun and JunD appeared to participate in CAGE-mediated up-regulation of cyclin D1. CAGE overexpression also enhanced retinoblastoma phosphorylation and subsequent E2F-1 nuclear translocation. In contrast, small interfering RNA-mediated knockdown of CAGE suppressed the expression of G1 cyclins, activation of AP-1 and E2F-1, and cell proliferation in both HeLa cervical Cancer cells and Malme-3M melanoma cells. These results suggest that the Cancer/Testis Antigen CAGE possesses oncogenic potential and promotes cell cycle progression by inducing AP-1- and E2F-dependent expression of cyclins D1 and E.
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promoter hypomethylation of a novel Cancer Testis Antigen gene cage is correlated with its aberrant expression and is seen in premalignant stage of gastric carcinoma
Biochemical and Biophysical Research Communications, 2003Co-Authors: Shinwu Jeong, Yungjue Bang, Kyu Sang Hwang, Gyeong Hoon Kang, Dooil JeoungAbstract:Abstract Previously, we reported the identification and characterization of a novel Cancer/Testis Antigen gene, CAGE4, that was expressed in various histological types of tumors, but not in normal tissues, with the exception of the Testis. To date, molecular mechanisms for the expression of CAGE have never been studied. In our expression analysis, we found that some Cancer cell lines did not express CAGE. The expression of CAGE could be restored in these cell lines by treatment with 5′-aza-2′-deoxycytidine, suggesting that the expression of CAGE is mainly suppressed by hypermethylation. Bisulfite sequencing analysis of the 16 CpG sites of the CAGE promoter in various Cancer cell lines and tissues revealed a close relationship between the methylation status of the CAGE promoter and the expression of CAGE. The transient transfection experiments displayed that the methylation of CpG sites inhibited the CAGE promoter activity in luciferase reporter assays. The methylation of the CpG sites inhibited the binding of transcription factors, shown by a mobility shift assay. A methylation-specific PCR analysis revealed that hypomethylation of the CAGE promoter was present at frequencies of more than 60% in breast, gastric, and lung Cancers, and hepatocellular carcinomas, and at frequencies of less than 40% in prostate, uterine cervical, and laryngeal Cancers. Promoter hypomethylation was found in chronic gastritis (19/55, 34.5%) and liver cirrhosis (13/22, 59%), but not in normal prostate, normal colon, or chronic hepatitis. These results suggest that the methylation status of the CpG sites of CAGE determines its expression, that the hypomethylation of CAGE precedes the development of gastric Cancer and hepatocellular carcinoma, and that the high frequencies of hypomethylation of CAGE, in various Cancers would be valuable as a Cancer diagnostic marker.
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identification and characterization of a novel Cancer Testis Antigen gene cage 1
Biochimica et Biophysica Acta, 2003Co-Authors: Saeyoung Park, Yungjue Bang, Sookwhan Sung, Yeong Wook Song, Dooil JeoungAbstract:Abstract Serological analysis of cDNA expression library (SEREX) was employed to identify Cancer-associated genes. By screening cDNA expression libraries with sera of patients with lung Cancers, we identified a total of 49 genes that specifically reacted with the sera of patients with lung Cancers. Among these, we characterized a novel gene with expression pattern similar to that of Cancer/Testis Antigens. Its open reading frame is 1920 bp in size and encodes for putative protein composed of 639 amino acids. Southern blot analysis reveals that this gene exists as single copy. In vitro transcription/translation and Western blot analysis confirm that this gene encodes a protein of 73 kDa in size. The comparison of cDNA and genomic sequences reveals that it is composed of 11 exons and 10 introns. This gene displays Testis-specific expression among normal tissues, and wide expression among various Cancer tissues and Cancer cell lines. A study using GFP fusion construct reveals mainly nuclear localization of CAGE-1 protein. The expression of this clone is relatively higher in Cancer tissues compared with their surrounding non-Cancerous tissues. This suggests that overexpression of CAGE-1 may be associated with the progression of tumor. Because of its association with Cancer, this gene was named Cancer-associated gene-1 (CAGE-1). Given the fact that several Cancer/Testis Antigens reportedly induce cytolytic T lymphocyte (CTL) reactions, it is reasonable that this gene will be a valuable target for Cancer immunotherapy. The exact functional role of CAGE-1 in tumorigenesis remains to be seen.
Xiao Song - One of the best experts on this subject based on the ideXlab platform.
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Post-transcriptional regulation of Cancer/Testis Antigen MAGEC2 expression by TRIM28 in tumor cells.
BMC Cancer, 2018Co-Authors: Xiao Song, Yutian Zheng, Ying WangAbstract:Background Cancer/Testis Antigen MAGEC2 (also known as HCA587) is highly expressed in a wide variety of tumors and plays an active role in promoting growth and metastasis of tumor cells. However, little is known for the regulation of MAGEC2 expression in Cancer cells.
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Cancer‑Testis Antigen HCA587/MAGEC2 interacts with the general transcription coactivator TAF9 in Cancer cells.
Molecular Medicine Reports, 2017Co-Authors: Pumei Zeng, Yutian Zheng, Ying Wang, Xiao SongAbstract:: Hepatocellular carcinoma-associated Antigen 587/melanoma Antigen gene (HCA587/MAGEC2) is a Cancer‑Testis Antigen, which is highly expressed in various types of tumors, but not in normal tissues with the exception of male germ‑line cells. HCA587/MAGEC2 has been previously recognized as a tumor‑specific target for immunotherapy; however, its biological functions have been relatively understudied. To investigate the function of HCA587/MAGEC2, the amino acid sequence of HCA587/MAGEC2 was analyzed by bioinformatics and it was demonstrated that HCA587/MAGEC2 contains a 9‑amino acid transactivation domain which may mediate the interaction of most transcription factors with TATA‑box binding protein associated factor 9 (TAF9), a general transcription coactivator. Co‑immunoprecipitation experiments revealed that HCA587/MAGEC2 interacted with TAF9 in transfected 293T and in A375 melanoma cells endogenously expressing HCA587/MAGEC2, and confirmed the endogenous interaction of HCA587/MAGEC2 and TAF9 within cells. Endogenous HCA587/MAGEC2 and TAF9 were demonstrated to be co‑localized principally in the nucleus of tumor cells using immunofluorescence. Glutathione-S-transferase pull‑down experiments demonstrated that HCA587/MAGEC2 interacts with TAF9 directly and the conserved region in the TAF9 may becrucial for HCA587/MAGEC2 binding. The present study demonstrated that the Cancer‑Testis Antigen HCA587/MAGEC2 directly interacted with TAF9, which may provide novel information for identifying the oncogenic functions of HCA587/MAGEC2 in tumor cells.
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the Cancer Testis Antigen magec2 promotes amoeboid invasion of tumor cells by enhancing stat3 signaling
Oncogene, 2017Co-Authors: Xiao Song, J Wang, Yu Wang, Q He, H Tang, Yanyan Li, Yuwen ZhangAbstract:The Cancer/Testis Antigen MAGEC2 promotes amoeboid invasion of tumor cells by enhancing STAT3 signaling
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The Cancer/Testis Antigen MAGEC2 promotes amoeboid invasion of tumor cells by enhancing STAT3 signaling
Oncogene, 2016Co-Authors: Xiao Song, J Wang, Q He, H Tang, Ying Wang, Yin Li, Yuwen ZhangAbstract:The Cancer/Testis Antigen MAGEC2 promotes amoeboid invasion of tumor cells by enhancing STAT3 signaling
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Cancer Testis Antigen mage c2 binds rbx1 and inhibits ubiquitin ligase mediated turnover of cyclin e
Oncotarget, 2015Co-Authors: Xiao Song, Jingjing Wang, Yan Li, Bing Li, Yu ZhangAbstract:Cancer-Testis Antigen MAGE-C2 is normally expressed in Testis but aberrantly expressed in various kinds of tumors. Its functions in tumor cells are mostly unknown. Here, we show that MAGE-C2 binds directly to the RING domain protein Rbx1, and participates in Skp1-Cullin1-F box protein (SCF) complex. Furthermore, MAGE-C2 can inhibit the E3 ubiquitin ligase activity of SCF complex. Ablation of endogenous MAGE-C2 decreases the level of cyclin E and accelerates cyclin E turnover by inhibiting ubiquitin-mediated proteasome degradation. Overexpression of MAGE-C2 increases the level of cyclin E and promotes G1-S transition and cell proliferation, and the results are further confirmed by knockdown of MAGE-C2. Overall, the study indicates that MAGE-C2 is involved in SCF complex and increases the stability of cyclin E in tumor cells.
Zhiqing Wang - One of the best experts on this subject based on the ideXlab platform.
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the spermatozoa protein sllp1 is a novel Cancer Testis Antigen in hematologic malignancies
Blood, 2004Co-Authors: Zhiqing Wang, Yana Zhang, Arabinda Mandal, Jian Zhang, Francis J Giles, John C HerrAbstract:SLLP1 is a unique non-bacteriolytic c-lysozyme-like protein isolated from human spermatozoa. Antisera to SLLP1 blocks binding in the hamster egg penetration assay, suggesting that SLLP1 may be involved in sperm/egg adhesion. A recent study by dot blot analysis on RNA showed that SLLP1 was expressed only in the Testis and in Burkitt lymphoma Raji cell line, suggesting that further studies are warranted to determine and characterize SLLP1 expression in tumor cells, in particular, fresh tumor specimens. Using a pair of sequence-specific primers in RT-PCR, we found that SLLP1 transcripts could be detected in 5/8 myeloma cell lines, suggesting that SLLP1 may be expressed in tumor cells from some hematologic malignancies. When we applied the investigations to 52 primary hematologic malignant specimens, SLLP1 transcripts were detected in 6/17 myeloma, 4/14 CML, 3/11 CLL, 2/9 AML and 0/1 hairy cell leukemia. In contrast, SLLP1 transcripts were not detected in the peripheral blood (n=12) or bone marrow (n=3) from any healthy donors. The specificity of the PCR products was confirmed by either sequence analysis or restriction digest with Pvu II. SLLP1 transcripts were translated into its corresponding protein in these tumor cells. Using tumor cell lysate in Western blot analysis, we detected SLLP1 protein in the myeloma cell lines and also in fresh malignant specimens, although positivities were only observed in specimens with high RT-PCR signals. All PCR-negative specimens were also negative in Western blot analysis. The specificity of the Western blot signals were confirmed in all cases by blocking assays with a high concentration of recombinant SLLP1 protein. We next investigated the expression of SLLP1 in a large panel of normal tissues using RT-PCR and real time quantitative PCR. Both approaches showed that SLLP1 is a novel Cancer-Testis Antigen in hematologic malignancies. SLLP1 was detected, at a level of 8206 copies/0.25 mcg total RNA, only in normal Testis. We also found that the SLLP1 mRNA copy numbers in fresh hematologic tumor specimens were up to 2316 copies/0.25 mcg total RNA, i.e. more than 25% of the level found in normal Testis. We cloned and generated SLLP1 recombinant protein from E coli and used the purified recombinant SLLP1 in an ELISA system to detect anti-SLLP1 antibodies. Using sera from 24 healthy donors and the mean + 2SD as the cut-off signal intensities, we found that high titer IgG antibodies directed at SLLP1 could be detected in the sera from 2/9 AML, 5/23 CLL, 6/27 CML and 14/51 myeloma patients. The specificity of the antibodies was confirmed in Western blot analysis. Probably due to the decreased sensitivity of the detection system in Western blot analysis, only 1/2 AML, 3/5 CLL, 4/6 CML and 7/14 myeloma SLLP1 antibody+ sera produced a signal in the Western blot analysis. Interesting, IgG2 was by far the commonest SLLP1 antibodies in these patients. There was a good correlation between SLLP1 gene expression and immune responses. In summary, SLLP1 is a novel CT Antigen in hematologic malignancies and is capable of eliciting B-cell immune responses in vivo in Cancer-bearing patients. Our results support SLLP1 as a protein target appropriate for further in vitro study to define its suitability for immunotherapy.
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the spermatozoa protein sllp1 is a novel Cancer Testis Antigen in hematologic malignancies
Clinical Cancer Research, 2004Co-Authors: Zhiqing Wang, Yana Zhang, Arabinda Mandal, Jian Zhang, Francis J Giles, John C HerrAbstract:Purpose: Neoplastic cells often aberrantly express normal testicular proteins. Because these proteins have a very restricted normal tissue expression, they may be suitable targets for immunotherapy. SLLP1 is an intra-acrosomal, nonbacteriolytic, c lysozyme–like protein recently isolated from human spermatozoa. In this study, we determined whether SLLP1 is a novel Cancer–Testis Antigen in hematologic malignancies Experimental Design: SLLP1 expression in hematologic tumor cells and normal tissues was determined using a combination of reverse transcription-PCR, real-time PCR, and Western blot analysis. The presence of antibodies against SLLP1 was determined by ELISA analysis. Results: SLLP1 was aberrantly expressed in the tumor cells from 2 of 9 acute myeloid leukemia, 3 of 11 chronic lymphocytic leukemia, 4 of 14 chronic myeloid leukemia, and 6 of 17 multiple myeloma. In contrast, they were not detected in corresponding specimens from any healthy donors. SLLP1 exhibited a very restricted normal tissue expression, being found only in Testis/spermatozoa. SLLP1 was expressed in some tumor cells at a level of >25%. High titer IgG antibodies against SLLP1 were also detected in the sera of some of these patients. Conclusions: SLLP1 is a novel Cancer–Testis Antigen in hematologic malignancies and is capable of eliciting B-cell immune responses in vivo in Cancer-bearing individuals. Our results, therefore, support SLLP1 as a protein target appropriate for additional in vitro study to define its suitability for immunotherapy.
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The Spermatozoa Protein, SLLP1, Is a Novel Cancer–Testis Antigen in Hematologic Malignancies
Clinical Cancer Research, 2004Co-Authors: Zhiqing Wang, Yana Zhang, Arabinda Mandal, Jian Zhang, Francis J Giles, John C HerrAbstract:Purpose: Neoplastic cells often aberrantly express normal testicular proteins. Because these proteins have a very restricted normal tissue expression, they may be suitable targets for immunotherapy. SLLP1 is an intra-acrosomal, nonbacteriolytic, c lysozyme–like protein recently isolated from human spermatozoa. In this study, we determined whether SLLP1 is a novel Cancer–Testis Antigen in hematologic malignancies Experimental Design: SLLP1 expression in hematologic tumor cells and normal tissues was determined using a combination of reverse transcription-PCR, real-time PCR, and Western blot analysis. The presence of antibodies against SLLP1 was determined by ELISA analysis. Results: SLLP1 was aberrantly expressed in the tumor cells from 2 of 9 acute myeloid leukemia, 3 of 11 chronic lymphocytic leukemia, 4 of 14 chronic myeloid leukemia, and 6 of 17 multiple myeloma. In contrast, they were not detected in corresponding specimens from any healthy donors. SLLP1 exhibited a very restricted normal tissue expression, being found only in Testis/spermatozoa. SLLP1 was expressed in some tumor cells at a level of >25%. High titer IgG antibodies against SLLP1 were also detected in the sera of some of these patients. Conclusions: SLLP1 is a novel Cancer–Testis Antigen in hematologic malignancies and is capable of eliciting B-cell immune responses in vivo in Cancer-bearing individuals. Our results, therefore, support SLLP1 as a protein target appropriate for additional in vitro study to define its suitability for immunotherapy.
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sperm protein 17 is a novel Cancer Testis Antigen in multiple myeloma
Blood, 2001Co-Authors: Zhiqing Wang, Maurizio ChirivainternatiAbstract:Various studies have demonstrated the aberrant expression of normal testicular proteins in neoplastic cells. These proteins collectively form the new class of tumor Antigens called Cancer-Testis (CT) Antigens. Their selective normal tissue expression makes them ideal Antigens for immune targeting of the malignant disease. In this study, the expression of a spermatozoa protein, Sp17, in multiple myeloma was investigated. It was found that Sp17 is detectable in tumor cells from 12 of 47 (26%) myeloma patients. Reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis detected Sp17 transcripts and proteins, respectively. Northern blot analysis and RT-PCR demonstrated that Sp17 transcripts were detected only in normal Testis, supporting its tissue specificity. Since a high proportion of normal individuals develop antibodies against Sp17 following vasectomy, Sp17 is likely to be a highly immunogenic protein in vivo. Sp17 is therefore a novel member of the CT Antigen family and should be an ideal target for immunotherapy of multiple myeloma.
Maurizio Chirivainternati - One of the best experts on this subject based on the ideXlab platform.
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the Cancer Testis Antigen sperm protein 17 a new biomarker and immunological target in head and neck squamous cell carcinoma
Oncotarget, 2017Co-Authors: Christopher A Schutt, Leonardo Mirandola, Jose A Figueroa, Diane D Nguyen, Joehassin Cordero, Klauss Bumm, Benjamin L Judson, Maurizio ChirivainternatiAbstract:// Christopher A. Schutt 1, * , Leonardo Mirandola 2, * , Jose A. Figueroa 2 , Diane D. Nguyen 2 , Joehassin Cordero 3 , Klauss Bumm 4 , Benjamin L. Judson 1 and Maurizio Chiriva-Internati 2, 5 1 Division Otolaryngology, Department of Surgery, Yale School of Medicine, New Haven, CT, USA 2 Kiromic, Inc., Houston, TX, USA 3 Department of Otolaryngology (ENT), TTUHSC, Lubbock, TX, USA 4 CaritasKlinikum Saarbrucken, Saarbrucken, Germany 5 Department of Multiple Myeloma & Lymphoma, University of Texas, MDACC, Houston, TX, USA * These authors have contributed equally to this work Correspondence to: Maurizio Chiriva-Internati, email: mchiriva@kiromic.com Keywords: Cancer/Testis Antigens; head and neck squamous cell carcinoma; immunotherapy; biomarker; sperm surface protein 17 Received: August 01, 2017 Accepted: September 15, 2017 Published: October 31, 2017 ABSTRACT Head and Neck Squamous Cell Carcinoma is a deadly and locally aggressive malignancy that frequently portends a poor prognosis. Since current treatment modalities including surgery, chemotherapy and radiation are heavily debilitating and often result in recurrence intense efforts have been put into the development of novel less toxic and more lasting treatment strategies. Recently, immunotherapy has been proposed as a promising alternative that could potentially meet these requirements. SP17 is a validated Cancer-Testis Antigen in multiple myeloma, ovarian Cancer and non-small cell lung Cancer. We aim at studying SP17 expression in HNSCC and its immunogenicity as a possible future target for HNSCC therapeutic vaccines. SP17 expression was evaluated in tissue specimens of HNSCC patients and controls. Moreover, SP17 immunogenicity was studied by generating autologous dendritic cells in vitro from the peripheral blood mononucleated cells of HNSCC patients and testing their ability to induce SP17 specific cytotoxic lymphocytes capable of killing autologous tumor cells in vitro . SP17specific immune responses were also evaluated in HNSCC patients as circulating anti-SP17 autoantibodies. SP17 was expressed in HNSCC tissues of HNSCC patients. Autologous dendritic cells pulsed with SP17 Antigen induced powerful SP17 MHC class-I restricted, perforin-dependent, cytotoxic T-cells capable of efficiently killing autologous tumor cells in vitro . SP17-specific autoantibodies were detectable in the serum of HNSCC patients irrespective of tumor site or TNM stage. In conclusion, SP17 is an ideal immunotherapeutic target for HNSCC and a potential serological biomarker of the disease.
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identification of akap 4 as a new Cancer Testis Antigen for detection and immunotherapy of prostate Cancer
The Prostate, 2012Co-Authors: Maurizio Chirivainternati, Leonardo Mirandola, Yuefei Yu, Martin J. Cannon, Everardo Cobos, Martin W Kast, Nicholas Dcunha, Fred HardwickeAbstract:BACKGROUND Prostate Cancer (PC) is the second most common Cancer in older men, after skin Cancer. PC is difficult to diagnose because the prostate-specific Antigen screening method is associated with many false positives. In addition there is a need to develop new and more effective treatments. Among presently available new treatments, immunotherapy is a promising approach. We investigated the expression of the Cancer/Testis Antigen, AKAP-4, in PC patients to evaluate the possibility of exploiting AKAP-4 as a target for immunotherapy. METHODS We analyzed normal prostate tissues, 15 patients with PC and the LnCAP PC cell line by immunohistochemistry. We tested AKAP-4 immunogenicity through indirect ELISA on sera from patients and healthy subjects, and we generated in vitro AKAP-4-specific cytotoxic lymphocytes from peripheral blood mononuclear cells. RESULTS AKAP-4 was shown both at the cytoplasmic and surface levels of the LnCAP PC cell line. AKAP-4 was also highly expressed in PC cells from patients. We detected specific anti-AKAP-4 circulating immunoglobulins in AKAP-4 positive subjects. Using recombinant AKAP-4 loaded autologous dendritic cells, we generated AKAP-4-specific and HLA-I-restricted cytotoxic T lymphocytes able to kill PC cells in vitro. Further characterization indicated a Th-1 skewing in the cytokine secretion profile of these cells. CONCLUSIONS We demonstrate the aberrant expression of AKAP-4 in PC, which will potentially be developed as a biomarker in PC. We provide evidence that AKAP-4 is a potential target for PC adoptive immunotherapy or anti-tumor vaccination. Prostate 72:12–23, 2012. © 2011 Wiley Periodicals, Inc.
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Cancer Testis Antigen vaccination affords long term protection in a murine model of ovarian Cancer
PLOS ONE, 2010Co-Authors: Maurizio Chirivainternati, Leonardo Mirandola, Yuefei Yu, Marjorie R. Jenkins, Martin J. Cannon, Caroline J Chapman, Everardo Cobos, Martin W KastAbstract:Sperm protein (Sp17) is an attractive target for ovarian Cancer (OC) vaccines because of its over-expression in primary as well as in metastatic lesions, at all stages of the disease. Our studies suggest that a Sp17-based vaccine can induce an enduring defense against OC development in C57BL/6 mice with ID8 cells, following prophylactic and therapeutic treatments. This is the first time that a mouse counterpart of a Cancer Testis Antigen (Sp17) was shown to be expressed in an OC mouse model, and that vaccination against this Antigen significantly controlled tumor growth. Our study shows that the CpG-adjuvated Sp17 vaccine overcomes the issue of immunologic tolerance, the major barrier to the development of effective immunotherapy for OC. Furthermore, this study provides a better understanding of OC biology by showing that Th-17 cells activation and contemporary immunosuppressive T-reg cells inhibition is required for vaccine efficacy. Taken together, these results indicate that prophylactic and therapeutic vaccinations can induce long-standing protection against OC and delay tumor growth, suggesting that this strategy may provide additional treatments of human OC and the prevention of disease onset in women with a family history of OC.
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sperm protein 17 is a novel Cancer Testis Antigen in multiple myeloma
Blood, 2001Co-Authors: Zhiqing Wang, Maurizio ChirivainternatiAbstract:Various studies have demonstrated the aberrant expression of normal testicular proteins in neoplastic cells. These proteins collectively form the new class of tumor Antigens called Cancer-Testis (CT) Antigens. Their selective normal tissue expression makes them ideal Antigens for immune targeting of the malignant disease. In this study, the expression of a spermatozoa protein, Sp17, in multiple myeloma was investigated. It was found that Sp17 is detectable in tumor cells from 12 of 47 (26%) myeloma patients. Reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis detected Sp17 transcripts and proteins, respectively. Northern blot analysis and RT-PCR demonstrated that Sp17 transcripts were detected only in normal Testis, supporting its tissue specificity. Since a high proportion of normal individuals develop antibodies against Sp17 following vasectomy, Sp17 is likely to be a highly immunogenic protein in vivo. Sp17 is therefore a novel member of the CT Antigen family and should be an ideal target for immunotherapy of multiple myeloma.
John C Herr - One of the best experts on this subject based on the ideXlab platform.
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the spermatozoa protein sllp1 is a novel Cancer Testis Antigen in hematologic malignancies
Blood, 2004Co-Authors: Zhiqing Wang, Yana Zhang, Arabinda Mandal, Jian Zhang, Francis J Giles, John C HerrAbstract:SLLP1 is a unique non-bacteriolytic c-lysozyme-like protein isolated from human spermatozoa. Antisera to SLLP1 blocks binding in the hamster egg penetration assay, suggesting that SLLP1 may be involved in sperm/egg adhesion. A recent study by dot blot analysis on RNA showed that SLLP1 was expressed only in the Testis and in Burkitt lymphoma Raji cell line, suggesting that further studies are warranted to determine and characterize SLLP1 expression in tumor cells, in particular, fresh tumor specimens. Using a pair of sequence-specific primers in RT-PCR, we found that SLLP1 transcripts could be detected in 5/8 myeloma cell lines, suggesting that SLLP1 may be expressed in tumor cells from some hematologic malignancies. When we applied the investigations to 52 primary hematologic malignant specimens, SLLP1 transcripts were detected in 6/17 myeloma, 4/14 CML, 3/11 CLL, 2/9 AML and 0/1 hairy cell leukemia. In contrast, SLLP1 transcripts were not detected in the peripheral blood (n=12) or bone marrow (n=3) from any healthy donors. The specificity of the PCR products was confirmed by either sequence analysis or restriction digest with Pvu II. SLLP1 transcripts were translated into its corresponding protein in these tumor cells. Using tumor cell lysate in Western blot analysis, we detected SLLP1 protein in the myeloma cell lines and also in fresh malignant specimens, although positivities were only observed in specimens with high RT-PCR signals. All PCR-negative specimens were also negative in Western blot analysis. The specificity of the Western blot signals were confirmed in all cases by blocking assays with a high concentration of recombinant SLLP1 protein. We next investigated the expression of SLLP1 in a large panel of normal tissues using RT-PCR and real time quantitative PCR. Both approaches showed that SLLP1 is a novel Cancer-Testis Antigen in hematologic malignancies. SLLP1 was detected, at a level of 8206 copies/0.25 mcg total RNA, only in normal Testis. We also found that the SLLP1 mRNA copy numbers in fresh hematologic tumor specimens were up to 2316 copies/0.25 mcg total RNA, i.e. more than 25% of the level found in normal Testis. We cloned and generated SLLP1 recombinant protein from E coli and used the purified recombinant SLLP1 in an ELISA system to detect anti-SLLP1 antibodies. Using sera from 24 healthy donors and the mean + 2SD as the cut-off signal intensities, we found that high titer IgG antibodies directed at SLLP1 could be detected in the sera from 2/9 AML, 5/23 CLL, 6/27 CML and 14/51 myeloma patients. The specificity of the antibodies was confirmed in Western blot analysis. Probably due to the decreased sensitivity of the detection system in Western blot analysis, only 1/2 AML, 3/5 CLL, 4/6 CML and 7/14 myeloma SLLP1 antibody+ sera produced a signal in the Western blot analysis. Interesting, IgG2 was by far the commonest SLLP1 antibodies in these patients. There was a good correlation between SLLP1 gene expression and immune responses. In summary, SLLP1 is a novel CT Antigen in hematologic malignancies and is capable of eliciting B-cell immune responses in vivo in Cancer-bearing patients. Our results support SLLP1 as a protein target appropriate for further in vitro study to define its suitability for immunotherapy.
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the spermatozoa protein sllp1 is a novel Cancer Testis Antigen in hematologic malignancies
Clinical Cancer Research, 2004Co-Authors: Zhiqing Wang, Yana Zhang, Arabinda Mandal, Jian Zhang, Francis J Giles, John C HerrAbstract:Purpose: Neoplastic cells often aberrantly express normal testicular proteins. Because these proteins have a very restricted normal tissue expression, they may be suitable targets for immunotherapy. SLLP1 is an intra-acrosomal, nonbacteriolytic, c lysozyme–like protein recently isolated from human spermatozoa. In this study, we determined whether SLLP1 is a novel Cancer–Testis Antigen in hematologic malignancies Experimental Design: SLLP1 expression in hematologic tumor cells and normal tissues was determined using a combination of reverse transcription-PCR, real-time PCR, and Western blot analysis. The presence of antibodies against SLLP1 was determined by ELISA analysis. Results: SLLP1 was aberrantly expressed in the tumor cells from 2 of 9 acute myeloid leukemia, 3 of 11 chronic lymphocytic leukemia, 4 of 14 chronic myeloid leukemia, and 6 of 17 multiple myeloma. In contrast, they were not detected in corresponding specimens from any healthy donors. SLLP1 exhibited a very restricted normal tissue expression, being found only in Testis/spermatozoa. SLLP1 was expressed in some tumor cells at a level of >25%. High titer IgG antibodies against SLLP1 were also detected in the sera of some of these patients. Conclusions: SLLP1 is a novel Cancer–Testis Antigen in hematologic malignancies and is capable of eliciting B-cell immune responses in vivo in Cancer-bearing individuals. Our results, therefore, support SLLP1 as a protein target appropriate for additional in vitro study to define its suitability for immunotherapy.
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The Spermatozoa Protein, SLLP1, Is a Novel Cancer–Testis Antigen in Hematologic Malignancies
Clinical Cancer Research, 2004Co-Authors: Zhiqing Wang, Yana Zhang, Arabinda Mandal, Jian Zhang, Francis J Giles, John C HerrAbstract:Purpose: Neoplastic cells often aberrantly express normal testicular proteins. Because these proteins have a very restricted normal tissue expression, they may be suitable targets for immunotherapy. SLLP1 is an intra-acrosomal, nonbacteriolytic, c lysozyme–like protein recently isolated from human spermatozoa. In this study, we determined whether SLLP1 is a novel Cancer–Testis Antigen in hematologic malignancies Experimental Design: SLLP1 expression in hematologic tumor cells and normal tissues was determined using a combination of reverse transcription-PCR, real-time PCR, and Western blot analysis. The presence of antibodies against SLLP1 was determined by ELISA analysis. Results: SLLP1 was aberrantly expressed in the tumor cells from 2 of 9 acute myeloid leukemia, 3 of 11 chronic lymphocytic leukemia, 4 of 14 chronic myeloid leukemia, and 6 of 17 multiple myeloma. In contrast, they were not detected in corresponding specimens from any healthy donors. SLLP1 exhibited a very restricted normal tissue expression, being found only in Testis/spermatozoa. SLLP1 was expressed in some tumor cells at a level of >25%. High titer IgG antibodies against SLLP1 were also detected in the sera of some of these patients. Conclusions: SLLP1 is a novel Cancer–Testis Antigen in hematologic malignancies and is capable of eliciting B-cell immune responses in vivo in Cancer-bearing individuals. Our results, therefore, support SLLP1 as a protein target appropriate for additional in vitro study to define its suitability for immunotherapy.
