In pleomorphic adenomas of the salivary glands (PASG) recurrent chromosomal rearrangements affecting either 8q12 or 12q14~15 lead to an overexpression of the genes of the genuine transcription factor PLAG1 or the architectural transcription factor HMGA2, respectively. Both genes are also affected by recurrent chromosomal rearrangements in benign adipocytic tumors as e. g. lipomas and lipoblastomas. Herein, we observed a strong correlation between the expression of HMGA2 and PLAG1 in 14 benign and 23 malignant thyroid tumors. To address the question if PLAG1 can be activated by HMGA2, the expression of both genes was quantified in 32 uterine leiomyomas 17 of which exhibited an overexpression of HMGA2. All leiomyomas with HMGA2 overexpression also revealed an activation of PLAG1 in the absence of detectable chromosome 8 abnormalities affecting the PLAG1 locus. To further investigate if the overexpression of PLAG1 is inducible by HMGA2 alone, HMGA2 was transiently overexpressed in MCF-7 cells. An increased PLAG1 expression was observed 24 and 48 h after transfection. Likewise, stimulation of HMGA2 by FGF1 in adipose tissue-derived stem cells led to a simultaneous increase of PLAG1 mRNA. Altogether, these data suggest that HMGA2 is an upstream activator of PLAG1. Accordingly, this may explain the formation of tumors as similar as lipomas and lipoblastomas resulting from an activation of either of both genes by chromosomal rearrangements.
References
[1]
Stenman G, Mark J, Ekedhal C (1984) Relationships between chromosomal patterns and protooncogenes in human benign salivary gland tumors. Tumour Biol 5: 103–117.
[2]
Sandros J, Stenman G, Mark J (1990) Cytogenetic and molecular observations in human and experimental salivary gland tumors. Cancer Genet Cytogenet 44: 153–167. doi: 10.1016/0165-4608(90)90042-9
[3]
Bullerdiek J, Wobst G, Meyer-Bolte K, Chilla R, Haubrich J, et al. (1993) Cytogenetic subtyping of 220 salivary gland pleomorphic adenomas: correlation to occurrence, histological subtype, and in vitro cellular behavior. Cancer Genet Cytogenet 65: 27–31. doi: 10.1016/0165-4608(93)90054-p
[4]
Bullerdiek J, Bartnitzke S, Weinberg M, Chilla R, Haubrich J, et al. (1987) Rearrangements of chromosome region 12q13→q15 in pleomorphic adenomas of the human salivary gland (PSA). Cytogenet Cell Genet 45: 187–190. doi: 10.1159/000132452
[5]
Bullerdiek J, Chilla R, Haubrich J, Meyer K, Bartnitzke S (1989) A causal relationship between chromosomal rearrangements and the genesis of salivary gland pleomorphic adenomas. Arch Otorhinolaryngol 245: 244–249. doi: 10.1007/bf00463936
[6]
Bullerdiek J, Takla G, Bartnitzke S, Brandt G, Chilla R, et al. (1989) Relationship of cytogenetic subtypes of salivary gland pleomorphic adenomas with patient age and histologic type. Cancer 64: 876–880. doi: 10.1002/1097-0142(19890815)64:4<876::aid-cncr2820640419>3.0.co;2-j
[7]
Schoenmakers EF, Wanschura S, Mols R, Bullerdiek J, Van den Berghe H, et al. (1995) Recurrent rearrangements in the high mobility group protein gene, HMGI-C, in benign mesenchymal tumours. Nat Genet 10: 436–444. doi: 10.1038/ng0895-436
[8]
Van de Ven WJ, Schoenmakers EF, Wanschura S, Kazmierczak B, Kools PF, et al. (1995) Molecular characterization of MAR, a multiple aberration region on human chromosome segment 12q13–q15 implicated in various solid tumors. Genes Chromosomes Cancer 12: 296–303. doi: 10.1002/gcc.2870120410
[9]
Ashar HR, Fejzo MS, Tkachenko A, Zhou X, Fletcher JA, et al. (1995) Disruption of the architectural factor HMGI-C: DNA-binding AT hook motifs fused in lipomas to distinct transcriptional regulatory domains. Cell 82: 57–65. doi: 10.1016/0092-8674(95)90052-7
[10]
Bustin M, Reeves R (1996) High-mobility-group chromosomal proteins: architectural components that facilitate chromatin function. Prog Nucleic Acid Res Mol Biol 54: 35–100. doi: 10.1016/s0079-6603(08)60360-8
[11]
Chiappetta G, Avantaggiato V, Visconti R, Fedele M, Battista S, et al. (1996) High level expression of the HMGI (Y) gene during embryonic development. Oncogene 13: 2439–2446.
[12]
Rogalla P, Drechsler K, Frey G, Hennig Y, Helmke B, et al. (1996) HMGI-C expression patterns in human tissues. Implications for the genesis of frequent mesenchymal tumors. Am J Pathol 149: 775–779.
[13]
Rommel B, Rogalla P, Jox A, Kalle CV, Kazmierczak B, et al. (1997) HMGI-C, a member of the high mobility group family of proteins, is expressed in hematopoietic stem cells and in leukemic cells. Leuk Lymphoma 26: 603–607.
[14]
Hirning-Folz U, Wilda M, Rippe V, Bullerdiek J, Hameister H (1998) The expression pattern of the Hmgic gene during development. Genes Chromosomes Cancer 23: 350–357. doi: 10.1002/(sici)1098-2264(199812)23:4<350::aid-gcc10>3.3.co;2-5
[15]
Li O, Vasudevan D, Davey CA, Dr？ge P (2006) High-level expression of DNA architectural factor HMGA2 and its association with nucleosomes in human embryonic stem cells. Genesis 44: 523–529. doi: 10.1002/dvg.20242
[16]
Markowski DN, Winter N, Meyer F, von Ahsen I, Wenk H, et al. (2011) p14Arf acts as an antagonist of HMGA2 in senescence of mesenchymal stem cells-implications for benign tumorigenesis. Genes Chromosomes Cancer 50: 489–498. doi: 10.1002/gcc.20871
[17]
Kas K, Voz ML, R？ijer E, ？str？m AK, Meyen E, et al. (1997) Promoter swapping between the genes for a novel zinc finger protein and beta-catenin in pleiomorphic adenomas with t(3;8)(p21;q12) translocations. Nat Genet 15: 170–174. doi: 10.1038/ng0297-170
[18]
Kas K, Voz ML, Hensen K, Meyen E, Van de Ven WJ (1998) Transcriptional activation capacity of the novel PLAG family of zinc finger proteins. J Biol Chem 273: 23026–23032. doi: 10.1074/jbc.273.36.23026
[19]
Hibbard MK, Kozakewich HP, Dal Cin P, Sciot R, Tan X, et al. (2000) PLAG1 fusion oncogenes in lipoblastoma. Cancer Res 60: 4869–4872.
[20]
Zatkova A, Rouillard JM, Hartmann W, Lamb BJ, Kuick R, et al. (2004) Amplification and overexpression of the IGF2 regulator PLAG1 in hepatoblastoma. Genes Chromosomes Cancer 39: 126–137. doi: 10.1002/gcc.10307
[21]
Pallasch CP, Patz M, Park YJ, Hagist S, Eggle D, et al. (2009) miRNA deregulation by epigenetic silencing disrupts suppression of the oncogene PLAG1 in chronic lymphocytic leukemia. Blood 114: 3255–3264. doi: 10.1182/blood-2009-06-229898
[22]
Agaram NP, Laquaglia MP, Ustun B, Guo T, Wong GC, et al. (2008) Molecular characterization of pediatric gastrointestinal stromal tumors. Clin Cancer Res 14: 3204–3215. doi: 10.1158/1078-0432.ccr-07-1984
[23]
Voz ML, Agten NS, Van de Ven WJ, Kas K (2000) PLAG1, the main translocation target in pleomorphic adenoma of the salivary glands, is a positive regulator of IGF-II. Cancer Res 60: 106–113.
[24]
Hensen K, Van Valckenborgh IC, Kas K, Van de Ven WJ, Voz ML (2002) The tumorigenic diversity of the three PLAG family members is associated with different DNA binding capacities. Cancer Res 62: 1510–1517.
[25]
Voz ML, Mathys J, Hensen K, Pendeville H, Van Valckenborgh I, et al. (2004) Microarray screening for target genes of the proto-oncogene PLAG1. Oncogene 23: 179–191. doi: 10.1038/sj.onc.1207013
[26]
Nielsen GP, Mandahl N (2002) Lipoma. In: Fletcher CDM, Unni KK, Mertens F, editors: World Health Organization classification of tumours. Pathology and genetics of tumours of soft tissue and bone. Lyon, IARC Press, 20–22.
[27]
Mandahl N, Mertens F (2009) Soft Tissue Tumors. In: Heim S, Mitelman F, editors. Cancer Cytogenetics, 3rd edition. New York, Wiley-Blackwell, 675–711.
[28]
Gisselsson D, Hibbard MK, Dal Cin P, Sciot R, Hsi BL, et al. (2001) PLAG1 alterations in lipoblastoma: involvement in varied mesenchymal cell types and evidence for alternative oncogenic mechanisms. Am J Pathol 159: 955–962. doi: 10.1016/s0002-9440(10)61771-3
[29]
R？pke A, Kalinski T, Kluba U, von Falkenhausen U, Wieacker PF, et al. (2007) PLAG1 activation in lipoblastoma coinciding with low-level amplification of a derivative chromosome 8 with a deletion del(8)(q13q21.2). Cytogenet Genome Res 119: 33–38. doi: 10.1159/000109616
[30]
Bartuma H, Domanski HA, Von Steyern FV, Kullendorff CM, Mandahl N, et al. (2008) Cytogenetic and molecular cytogenetic findings in lipoblastoma. Cancer Genet Cytogenet 183: 60–63. doi: 10.1016/j.cancergencyto.2008.01.017
[31]
Pedeutour F, Deville A, Steyaert H, Ranchere-Vince D, Ambrosetti D, et al. (2012) Rearrangement of HMGA2 in a case of infantile lipoblastoma without Plag1 alteration. Pediatr Blood Cancer 58: 798–800. doi: 10.1002/pbc.23335
[32]
Belge G, Meyer A, Klemke M, Burchardt K, Stern C, et al. (2008) Upregulation of HMGA2 in thyroid carcinomas: a novel molecular marker to distinguish between benign and malignant follicular neoplasias. Genes Chromosomes Cancer 47: 56–63. doi: 10.1002/gcc.20505
[33]
Chiappetta G, Ferraro A, Vuttariello E, Monaco M, Galdiero F, et al. (2008) HMGA2 mRNA expression correlates with the malignant phenotype in human thyroid neoplasias. Eur J Cancer 44: 1015–1021. doi: 10.1016/j.ejca.2008.02.039
[34]
Lappinga PJ, Kip NS, Jin L, Lloyd RV, Henry MR, et al. (2010) HMGA2 gene expression analysis performed on cytologic smears to distinguish benign from malignant thyroid nodules. Cancer Cytopathol 118: 287–297. doi: 10.1002/cncy.20095
[35]
Jin L, Lloyd RV, Nassar A, Lappinga PJ, Sebo TJ, et al. (2011) HMGA2 expression analysis in cytological and paraffin-embedded tissue specimens of thyroid tumors by relative quantitative RT-PCR. Diagn Mol Pathol 20: 71–80. doi: 10.1097/pdm.0b013e3181ed784d
[36]
Prasad NB, Somervell H, Tufano RP, Dackiw AP, Marohn MR, et al. (2008) Identification of genes differentially expressed in benign versus malignant thyroid tumors. Clin Cancer Res 14: 3327–3337. doi: 10.1158/1078-0432.ccr-07-4495
[37]
Baldassarre G, Battista S, Belletti B, Thakur S, Pentimalli F, et al. (2003) Negative regulation of BRCA1 gene expression by HMGA1 proteins accounts for the reduced BRCA1 protein levels in sporadic breast carcinoma. Mol Cell Biol 23: 2225–2238. doi: 10.1128/mcb.23.7.2225-2238.2003
[38]
Mussnich P, D’Angelo D, Leone V, Croce CM, Fusco A (2013) The High Mobility Group A proteins contribute to thyroid cell transformation by regulating miR-603 and miR-10b expression. Mol Oncol 7: 531–542. doi: 10.1016/j.molonc.2013.01.002
[39]
Klemke M, Meyer A, Nezhad MH, Bartnitzke S, Drieschner N, et al. (2009) Overexpression of HMGA2 in uterine leiomyomas points to its general role for the pathogenesis of the disease. Genes Chromosomes Cancer 48: 171–178. doi: 10.1002/gcc.20627
[40]
Markowski DN, Bartnitzke S, Belge G, Drieschner N, Helmke BM, et al. (2010) Cell culture and senescence in uterine fibroids. Cancer Genet Cytogenet 202: 53–57. doi: 10.1016/j.cancergencyto.2010.06.010
[41]
Markowski DN, Helmke BM, Radtke A, Froeb J, Belge G, et al. (2012) Fibroid explants reveal a higher sensitivity against MDM2-inhibitor nutlin-3 than matching myometrium. BMC Womens Health 12: 2. doi: 10.1186/1472-6874-12-2
[42]
Schaffer LG, Slovak ML, Campbell LJ, editors (2009) ISCN 2009: an international system for human cytogenetic nomenclature. Basel, S. Karger.
[43]
Fedele M, Berlingieri MT, Scala S, Chiariotti L, Viglietto G, et al. (1998) Truncated and chimeric HMGI-C genes induce neoplastic transformation of NIH3T3 murine fibroblasts. Oncogene 17: 413–418. doi: 10.1038/sj.onc.1201952
[44]
Brants JR, Ayoubi TA, Chada K, Marchal K, Van de Ven WJ, et al. (2004) Differential regulation of the insulin-like growth factor II mRNA-binding protein genes by architectural transcription factor HMGA2. FEBS Lett 569: 277–283. doi: 10.1016/j.febslet.2004.05.075
[45]
Cleynen I, Brants JR, Peeters K, Deckers R, Debiec-Rychter M, et al. (2007) HMGA2 regulates transcription of the Imp2 gene via an intronic regulatory element in cooperation with nuclear factor-κB. Mol Cancer Res 5: 363–372. doi: 10.1158/1541-7786.mcr-06-0331
[46]
Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects. World Medical Association. Available from: http://www.wma.net/en/30publications/10p？olicies/b3/(accessed on June 22, 2012).
[47]
German National Ethics Council. 2004. Opinion: Biobanks for research. Available from http://www.ethikrat.org/_english/publica？tions/Opinion_Biobanks-for-research.pdf (accessed on June 22, 2012).
[48]
Klemke M, Drieschner N, Belge G, Burchardt K, Junker K, et al. (2012) Detection of PAX8-PPARG fusion transcripts in archival thyroid carcinoma samples by conventional RT-PCR. Genes Chromosomes Cancer 51: 402–408. doi: 10.1002/gcc.21925
[49]
Ayoubi TA, Jansen E, Meulemans SM, Van de Ven WJ (1999) Regulation of HMGIC expression: an architectural transcription factor involved in growth control and development. Oncogene 18: 5076–5087. doi: 10.1038/sj.onc.1202881
[50]
？str？m AK, Voz ML, Kas K, R？ijer E, Wedell B, et al. (1999) Conserved mechanism of PLAG1 activation in salivary gland tumors with and without chromosome 8q12 abnormalities: identification of SII as a new fusion partner gene. Cancer Res 59: 918–923.
[51]
Enlund F, Nordkvist A, Sahlin P, Mark J, Stenman G (2002) Expression of PLAG1 and HMGIC proteins and fusion transcripts in radiation-associated pleomorphic adenomas. Int J Oncol 20: 713–716. doi: 10.3892/ijo.20.4.713
[52]
Tallini G, Vanni R, Manfioletti G, Kazmierczak B, Faa G, et al. (2000) HMGI-C and HMGI(Y) immunoreactivity correlates with cytogenetic abnormalities in lipomas, pulmonary chondroid hamartomas, endometrial polyps, and uterine leiomyomas and is compatible with rearrangement of the HMGI-C and HMGI(Y) genes. Lab Invest 80: 359–369. doi: 10.1038/labinvest.3780040
[53]
Prasad NB, Kowalski J, Tsai HL, Talbot K, Somervell H, et al. (2012) Three-gene molecular diagnostic model for thyroid cancer. Thyroid 22: 275–284. doi: 10.1089/thy.2011.0169
[54]
Hennig Y, Wanschura S, Deichert U, Bartnitzke S, Bullerdiek J (1996) Rearrangements of the high mobility group protein family genes and the molecular genetic origin of uterine leiomyomas and endometrial polyps. Mol Hum Reprod 2: 277–283. doi: 10.1093/molehr/2.4.277
[55]
Hennig Y, Deichert U, Bonk U, Thode B, Bartnitzke S, et al. (1999) Chromosomal translocations affecting 12q14–15 but not deletions of the long arm of chromosome 7 associated with a growth advantage of uterine smooth muscle cells. Mol Hum Reprod 5: 1150–1154. doi: 10.1093/molehr/5.12.1150
[56]
Gross KL, Neskey DM, Manchanda N, Weremowicz S, Kleinman MS, et al. (2003) HMGA2 expression in uterine leiomyomata and myometrium: quantitative analysis and tissue culture studies. Genes Chromosomes Cancer 38: 68–79. doi: 10.1002/gcc.10240
[57]
Asp J, Persson F, Kost-Alimova M, Stenman G (2006) CHCHD7-PLAG1 and TCEA1-PLAG1 gene fusions resulting from cryptic, intrachromosomal 8q rearrangements in pleomorphic salivary gland adenomas. Genes Chromosomes Cancer 45: 820–828. doi: 10.1002/gcc.20346
[58]
Mantovani F, Covaceuszach S, Rustighi A, Sgarra R, Heath C, et al. (1998) NF-κB mediated transcriptional activation is enhanced by the architectural factor HMGI-C. Nucleic Acids Res 26: 1433–1439. doi: 10.1093/nar/26.6.1433
[59]
Noro B, Licheri B, Sgarra R, Rustighi A, Tessari MA, et al. (2003) Molecular dissection of the architectural transcription factor HMGA2. Biochemistry 42: 4569–4577. doi: 10.1021/bi026605k
