Although metastasis-associated lung adenocarcinoma transcript (MALAT)-1 is known to be consistently upregulated in several epithelial malignancies, little is known about its function or regulation. We therefore examined the relationship between MALAT-1 expression and candidate modulators such as DNA tumor virus oncoproteins human papillomavirus (HPV)-16 E6 and E7, BK virus T antigen (BKVTAg), mouse polyoma virus middle T antigen (MPVmTAg) and tumor suppressor genes p53 and pRb. Using suppressive subtractive hybridization (SSH) and real-time reverse transcriptase polymerase chain reaction (RT-PCR) assays, MALAT-1 was shown to be increased in viral oncongene-expressing salivary gland biopsies from humans and mice. The results also indicated that MALAT-1 transcripts and promoter activity were increased in vitro when viral oncongene-expressing plasmids were introduced into different cell types. These same viral oncogenes in addition to increasing MALAT-1 transcription have also been shown to inhibit p53and/or pRb function. In p53 mutant or inactive cell lines MALAT-1 was also shown to be highly upregulated. We hypothesize that there is a correlation between MALAT-1 over-expression and p53 deregulation. In conclusion, we show that disruption of p53, by both polyoma and papilloma oncoproteins appear to play an important role in the up-regulation of MALAT-1. MALAT-1 might therefore represent a biomarker for p53 deregulation within malignancies.
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L. Jeffers, K. Duan, L. Ellies, W. Seaman, R. Burger-Calderon, L. Diatchenko and J. Webster-Cyriaque, "Correlation of Transcription of MALAT-1, a Novel Noncoding RNA, with Deregulated Expression of Tumor Suppressor p53 in Small DNA Tumor Virus Models," Journal of Cancer Therapy, Vol. 4 No. 3, 2013, pp. 774-786. doi: 10.4236/jct.2013.43094.
 P. Ji, S. Diederichs, W. Wang, S. Boing, R. Metzger, P. M. Schneider, N. Tidow, B. Brandt, H. Buerger, E. Bulk, M. Thomas, W. E. Berdel, H. Serve and C. Muller-Tidow, “MALAT-1, a Novel Noncoding RNA, and Thymosin Beta4 Predict Metastasis and Survival in Early-Stage Non-Small Cell Lung Cancer,” Oncogene, Vol. 22, No. 39, 2003, pp. 8031-8041. doi:10.1038/sj.onc.1206928
 J. N. Hutchinson, A. W. Ensminger, C. M. Clemson, C. R. Lynch, J. B. Lawrence and A. Chess, “A Screen for Nuclear Transcripts Identifies Two Linked Noncoding RNAs Associated with SC35 Splicing Domains,” BMC Genomics, Vol. 8, 2007, p. 39. doi:10.1186/1471-2164-8-39
 J. E. Wilusz, S. M. Freier and D. L. Spector, “3’ End Processing of a Long Nuclear-Retained Noncoding RNA Yields a tRNA-Like Cytoplasmic RNA,” Cell, Vol. 135, No. 5, 2008, pp. 919-932. doi:10.1016/j.cell.2008.10.012
 J. Fellenberg, L. Bernd, G. Delling, D. Witte and A. Zahlten-Hinguranage, “Prognostic Significance of DrugRegulated Genes in High-Grade Osteosarcoma,” Modern Pathology, Vol. 20, No. 10, 2007, pp. 1085-1094.
 R. Lin, S. Maeda, C. Liu, M. Karin and T. S. Edgington, “A Large Noncoding RNA Is a Marker for Murine Hepatocellular Carcinomas and a Spectrum of Human Carcinomas,” Oncogene, Vol. 26, No. 6, 2007, pp. 851-858.
 D. S. Perez, T. R. Hoage, J. R. Pritchett, A. L. DucharmeSmith, M. L. Halling, S. C. Ganapathiraju, P. S. Streng and D. I. Smith, “Long, Abundantly Expressed NonCoding Transcripts Are Altered in Cancer,” Human Molecular Genetics, Vol. 17, No. 5, 2008, pp. 642-655.
 K. Yamada, J. Kano, H. Tsunoda, H. Yoshikawa, C. Okubo, T. Ishiyama and M. Noguchi, “Phenotypic Characterization of Endometrial Stromal Sarcoma of the Uterus,” Cancer Science, Vol. 97, No. 2, 2006, pp. 106-112.
 J. J. Tseng, Y. T. Hsieh, S. L. Hsu and M. M. Chou, “Metastasis Associated Lung Adenocarcinoma Transcript 1 Is Up-Regulated in Placenta Previa Increta/Percreta and Strongly Associated with Trophoblast-Like Cell Invasion in Vitro,” Molecular Human Reproduction, Vol. 15, No. 11, 2009, pp. 725-731. doi:10.1093/molehr/gap071
 C. Xu, M. Yang, J. Tian, X. Wang and Z. Li, “MALAT-1: A Long Non-Coding RNA and Its Important 3’ End Functional Motif in Colorectal Cancer Metastasis,” International Journal of Oncology, Vol. 39, No. 1, 2011, pp. 169-175.
 R. H. Breuer, P. E. Postmus and E. F. Smit, “Molecular Pathology of Non-Small-Cell Lung Cancer,” Respiration, Vol. 72, No. 3, 2005, pp. 313-330.
 F. S. Liu, M. F. Kohler, J. R. Marks, R. C. Bast Jr., J. Boyd and A. Berchuck, “Mutation and Overexpression of the p53 Tumor Suppressor Gene Frequently Occurs in Uterine and Ovarian Sarcomas,” Obstetrics & Gynecology, Vol. 83, No. 1, 1994, pp. 118-124.
 T. Soussi, “p53 Alterations in Human Cancer: More Questions than Answers,” Oncogene, Vol. 26, No. 15, 2007, pp. 2145-2156. doi:10.1038/sj.onc.1210280
 P. M. Howley and D. M. Livingston, “Small DNA Tumor Viruses: Large Contributors to Biomedical Sciences,” Virology, Vol. 384, No. 2, 2009, pp. 256-259.
 D. P. Lane and L. V. Crawford, “T Antigen Is Bound to a Host Protein in SV40-Transformed Cells,” Nature, Vol. 278, No. 5701, 1979, pp. 261-263. doi:10.1038/278261a0
 M. T. S. Robles and J. M. Pipas, “T Antigen Transgenic Mouse Models,” Seminars in Cancer Biology, Vol. 19, No. 4, 2009, pp. 229-235.
 C. V. Shivakumar and G. C. Das, “Interaction of Human Polyomavirus BK with the Tumor-Suppressor Protein p53,” Oncogene, Vol. 13, No. 2, 1996, pp. 323-332.
 W. Qian and K. G. Wiman, “Polyoma Virus Middle T and Small t Antigens Cooperate to Antagonize p53-Induced Cell Cycle Arrest and Apoptosis,” Cell Growth & Differentiation, Vol. 11, No. 1, 2000, pp. 31-39.
 P. Sarnow, C. A. Sullivan and A. J. Levine, “A Monoclonal Antibody Detecting the Adenovirus Type 5-E1b58Kd Tumor Antigen: Characterization of the E1b-58Kd Tumor Antigen in Adenovirus-Infected and -Transformed Cells,” Virology, Vol. 120, No. 2, 1982, pp. 510-517.
 B. A. Werness, A. J. Levine and P. M. Howley, “Association of Human Papillomavirus Types 16 and 18 E6 Proteins with p53,” Science, Vol. 248, No. 4951, 1990, pp. 76-79. doi:10.1126/science.2157286
 P. Sdek, Z. Y. Zhang, J. Cao, H. Y. Pan, W. T. Chen and J. W. Zheng, “Alteration of Cell-Cycle Regulatory Proteins in Human Oral Epithelial Cells Immortalized by HPV16 E6 and E7,” International Journal of Oral and Maxillofacial Surgery, Vol. 35, No. 7, 2006, pp. 653-657.
 D. R. Lowy, R. Kirnbauer and J. T. Schiller, “Genital Human Papillomavirus Infection,” Proceedings of National Academy of Sciences of USA, Vol. 91, No. 7, 1994, pp. 2436-2440. doi:10.1073/pnas.91.7.2436
 J. Rautava and S. Syrjanen, “Human Papillomavirus Infections in the Oral Mucosa,” Journal of the American Dental Association, Vol. 142, No. 8, 2011, pp. 905-914.
 A. Caputo, A. Corallini, M. P. Grossi, L. Carra, P. G. Balboni, M. Negrini, G. Milanesi, G. Federspil and G. Barbanti-Brodano, “Episomal DNA of a BK Virus Variant in a Human Insulinoma,” Journal of Medical Virology, Vol. 12, No. 1, 1983, pp. 37-49.
 A. Corallini, M. Pagnani, P. Viadana, E. Silini, M. Mottes, G. Milanesi, G. Gerna, R. Vettor, G. Trapella, V. Silvani, et al., “Association of BK Virus with Human Brain Tumors and Tumors of Pancreatic Islets,” International Journal of Cancer, Vol. 39, No. 1, 1987, pp. 60-67.
 D. Das, R. B. Shah and M. J. Imperiale, “Detection and Expression of Human BK Virus Sequences in Neoplastic Prostate Tissues,” Oncogene, Vol. 23, No. 42, 2004, pp. 7031-7046. doi:10.1038/sj.onc.1207920
 K. Dorries, G. Loeber and J. Meixensberger, “Association of Polyomaviruses JC, SV40, and BK with Human Brain Tumors,” Virology, Vol. 160, No. 1, 1987, pp. 268-270.
 T. Flaegstad, P. A. Andresen, J. I. Johnsen, S. K. Asomani, G. E. Jorgensen, S. Vignarajan, A. Kjuul, P. Kogner and T. Traavik, “A Possible Contributory Role of BK Virus Infection in Neuroblastoma Development,” Cancer Research, Vol. 59, No. 5, 1999, pp. 1160-1163.
 M. Negrini, P. Rimessi, C. Mantovani, S. Sabbioni, A. Corallini, M. A. Gerosa and G. Barbanti-Brodano, “Characterization of BK Virus Variants Rescued from Human Tumours and Tumour Cell Lines,” Journal of General Virology, Vol. 71, No. 11, 1990, pp. 2731-2736.
 P. Monini, L. de Lellis, A. Rotola, D. Di Luca, T. Ravaioli, B. Bigoni and E. Cassai, “Chimeric BK Virus DNA Episomes in a Papillary Urothelial Bladder Carcinoma,” Intervirology, Vol. 38, No. 5, 1995, pp. 304-308.
 M. J. Imperiale and E. O. Major, “Polyomaviruses,” In: A. M. Field, D. M. Knipe and P. M. Howley, Eds., Wolers Kluwer Health/Lippincott Williams & Wilkins, Philadelphia, 2007, p. 3091.
 J. E. Maglione, D. Moghanaki, L. J. Young, C. K. Manner, L. G. Ellies, S. O. Joseph, B. Nicholson, R. D. Cardiff and C. L. MacLeod, “Transgenic Polyoma Middle-T Mice Model Premalignant Mammary Disease,” Cancer Research, Vol. 61, No. 22, 2001, pp. 8298-8305.
 K. Shirasuna, M. Sato and T. Miyazaki, “A Neoplastic Epithelial Duct Cell Line Established from an Irradiated Human Salivary Gland,” Cancer, Vol. 48, No. 3, 1981, pp. 745-752.
 D. E. Rollison, U. Utaipat, C. Ryschkewitsch, J. Hou, P. Goldthwaite, R. Daniel, K. J. Helzlsouer, P. C. Burger, K. V. Shah and E. O. Major, “Investigation of Human Brain Tumors for the Presence of Polyomavirus Genome Sequences by Two Independent Laboratories,” International Journal of Cancer, Vol. 113, No. 5, 2005, pp. 769-774.
 L. K. Jeffers, V. Madden and J. Webster-Cyriaque, “BK Virus Has Tropism for Human Salivary Gland Cells in Vitro: Implications for Transmission,” Virology, Vol. 394, No. 2, 2009, pp. 183-193. doi:10.1016/j.virol.2009.07.022
 L. Diatchenko, Y. F. Lau, A. P. Campbell, A. Chenchik, F. Moqadam, B. Huang, S. Lukyanov, K. Lukyanov, N. Gurskaya, E. D. Sverdlov and P. D. Siebert, “Suppression Subtractive Hybridization: A Method for Generating Differentially Regulated or Tissue-Specific cDNA Probes and Libraries,” Proceedings of National Academy of Sciences of USA, Vol. 93, No. 12, 1996, pp. 6025-6030.
 D. Farre, R. Roset, M. Huerta, J. E. Adsuara, L. Rosello, M. M. Alba and X. Messeguer, “Identification of Patterns in Biological Sequences at the ALGGEN Server: PROMO and MALGEN,” Nucleic Acids Research, Vol. 31, No. 13, 2003, pp. 3651-3653. doi:10.1093/nar/gkg605
 J. Lin, J. Chen, B. Elenbaas and A. J. Levine, “Several Hydrophobic Amino Acids in the p53 Amino-Terminal Domain Are Required for Transcriptional Activation, Binding to mdm-2 and the Adenovirus 5 E1B 55-kD Protein,” Genes & Development, Vol. 8, No. 10, 1994, pp. 1235-1246. doi:10.1101/gad.8.10.1235
 G. Lozano, “The Oncogenic Roles of p53 Mutants in Mouse Models,” Current Opinion in Genetics & Development, Vol. 17, No. 1, 2007, pp. 66-70.
 K. Otsuka, S. Kato, Y. Kakudo, S. Mashiko, H. Shibata and C. Ishioka, “The Screening of the Second-Site Suppressor Mutations of the Common p53 Mutants,” International Journal of Cancer, Vol. 121, No. 3, 2007, pp. 559-566. doi:10.1002/ijc.22724
 P. Hainaut and M. Hollstein, “P53 and Human Cancer: The First Ten Thousand Mutations,” Advances in Cancer Research, Vol. 77, 2000, pp. 81-86, 86a, 87-137.
 A. Sigal and V. Rotter, “Oncogenic Mutations of the p53 Tumor Suppressor: The Demons of the Guardian of the Genome,” Cancer Research, Vol. 60, No. 24, 2000, pp. 6788-6793.
 Y. Sun, J. Wu, S. H. Wu, A. Thakur, A. Bollig, Y. Huang and D. J. Liao, “Expression Profile of MicroRNAs in c-Myc Induced Mouse Mammary Tumors,” Breast Cancer Research and Treatment, Vol. 118, No. 1, 2009, pp. 185-196. doi:10.1007/s10549-008-0171-6
 F. Guo, Y. Li, Y. Liu, J. Wang and G. Li, “Inhibition of Metastasis-Associated Lung Adenocarcinoma Transcript 1 in CaSki Human Cervical Cancer Cells Suppresses Cell Proliferation and Invasion,” Acta Biochimica et Biophysica Sinica, Vol. 42, No. 3, 2010, pp. 224-229.
 R. R. Nordal, G. B. Kristensen, A. E. Stenwig, C. G. Trope and J. M. Nesland, “Immunohistochemical Analysis of p53 Protein in Uterine Sarcomas,” Gynecologic Oncology, Vol. 70, No. 1, 1998, pp. 45-48.
 S. Katiyar, B. C. Dash, V. Thakur, R. C. Guptan, S. K. Sarin and B. C. Das, “P53 Tumor Suppressor Gene Mutations in Hepatocellular Carcinoma Patients in India,” Cancer, Vol. 88, No. 7, 2000, pp. 1565-1573.
 M. Overholtzer, P. H. Rao, R. Favis, X. Y. Lu, M. B. Elowitz, F. Barany, M. Ladanyi, R. Gorlick and A. J. Levine, “The Presence of p53 Mutations in Human Osteosarcomas Correlates with High Levels of Genomic Instability,” Proceedings of the National Academy of Science of USA, Vol. 100, No. 20, 2003, pp. 11547-11552.
 A. L. Borresen-Dale, “TP53 and Breast Cancer,” Human Mutation, Vol. 21, No. 3, 2003, pp. 292-300.
 J. P. Morton, P. Timpson, S. A. Karim, R. A. Ridgway, D. Athineos, B. Doyle, N. B. Jamieson, K. A. Oien, A. M. Lowy, V. G. Brunton, M. C. Frame, T. R. Evans and O. J. Sansom, “Mutant p53 Drives Metastasis and Overcomes Growth Arrest/Senescence in Pancreatic Cancer,” Proceedings of the National Academy of Science of USA, Vol. 107, No. 1, 2010, pp. 246-251.
 B. Iacopetta, “TP53 Mutation in Colorectal Cancer,” Human Mutation, Vol. 21, No. 3, 2003, pp. 271-276.
 A. G. Aprikian, A. S. Sarkis, W. R. Fair, Z. F. Zhang, Z. Fuks and C. Cordon-Cardo, “Immunohistochemical Determination of p53 Protein Nuclear Accumulation in Prostatic Adenocarcinoma,” The Journal of Urology, Vol. 151, No. 5, 1994, pp. 1276-1280.
 J. A. Eastham, A. M. Stapleton, A. E. Gousse, T. L. Timme, G. Yang, K. M. Slawin, T. M. Wheeler, P. T. Scardino and T. C. Thompson, “Association of p53 Mutations with Metastatic Prostate Cancer,” Clinical Cancer Research, Vol. 1, No. 10, 1995, pp. 1111-1118.
 M. Scheffner, B. A. Werness, J. M. Huibregtse, A. J. Levine and P. M. Howley, “The E6 Oncoprotein Encoded by Human Papillomavirus Types 16 and 18 Promotes the Degradation of p53,” Cell, Vol. 63, No. 6, 1990, pp. 11291136. doi:10.1016/0092-8674(90)90409-8