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HMGA2 and high-grade serous ovarian carcinoma

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Abstract

HMGA2, the High Mobility Group A2 gene, plays a very important role in fetal development and carcinogenesis. As an oncofetal gene, it is upregulated in tumors of both epithelial and mesenchymal tissue origin. Chromosomal translocations of HMGA2 are common in mesenchymal tumors, whereas the regulatory mechanisms of HMGA2 in malignant epithelial tumors are much more complex. As an architectural transcription factor, it is involved in multiple biological pathways by targeting different downstream genes in different cancers. HMGA2 is upregulated in both the early and late stages of high-grade serous ovarian carcinoma (HGSOC) and, according to The Cancer Genomic Atlas, is among a signature of genes overexpressed in ovarian cancer. Recent identification of miR-182 as a mediator of BRCA1 and HMGA2 deregulation in ovarian cancer cells may guide us toward a better understanding of the roles of HMGA2 in ovarian carcinogenesis. In this article, we will review recent developments and findings related to HMGA2, including its regulation, oncogenic properties, major functional pathways associated with the tumorigenesis of HGSOC, and its potential role as a biomarker for clinical application.

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References

  1. Fusco A, Fedele M (2007) Roles of HMGA proteins in cancer. Nat Rev Cancer 7:899–910

    Article  PubMed  CAS  Google Scholar 

  2. Young AR, Narita M (2007) Oncogenic HMGA2: short or small? Genes Dev 21:1005–1009

    Article  PubMed  CAS  Google Scholar 

  3. Goodwin G (1998) The high mobility group protein, HMGI-C. Int J Biochem Cell Biol 30:761–766

    Article  PubMed  CAS  Google Scholar 

  4. Reeves R (2001) Molecular biology of HMGA proteins: hubs of nuclear function. Gene 277:63–81

    Article  PubMed  CAS  Google Scholar 

  5. Cleynen I, Van de Ven WJ (2008) The HMGA proteins: a myriad of functions (review). Int J Oncol 32:289–305

    PubMed  CAS  Google Scholar 

  6. Hammond SM, Sharpless NE (2008) HMGA2, microRNAs, and stem cell aging. Cell 135:1013–1016

    Article  PubMed  CAS  Google Scholar 

  7. Giancotti V, Berlingieri MT, DiFiore PP, Fusco A, Vecchio G, Crane-Robinson C (1985) Changes in nuclear proteins on transformation of rat epithelial thyroid cells by a murine sarcoma retrovirus. Cancer Res 45:6051–6057

    PubMed  CAS  Google Scholar 

  8. Fedele M, Visone R, De Martino I, Troncone G, Palmieri D, Battista S, Ciarmiello A, Pallante P, Arra C, Melillo RM et al (2006) HMGA2 induces pituitary tumorigenesis by enhancing E2F1 activity. Cancer Cell 9:459–471

    Article  PubMed  CAS  Google Scholar 

  9. Hauke S, Leopold S, Schlueter C, Flohr AM, Murua Escobar H, Rogalla P, Bullerdiek J (2005) Extensive expression studies revealed a complex alternative splicing pattern of the HMGA2 gene. Biochim Biophys Acta 1729:24–31

    Article  PubMed  CAS  Google Scholar 

  10. Peng Y, Laser J, Shi G, Mittal K, Melamed J, Lee P, Wei JJ (2008) Antiproliferative effects by Let-7 repression of high-mobility group A2 in uterine leiomyoma. Mol Cancer Res 6:663–673

    Article  PubMed  CAS  Google Scholar 

  11. Ashar HR, Chouinard RA Jr, Dokur M, Chada K (2010) In vivo modulation of HMGA2 expression. Biochim Biophys Acta 1799:55–61

    Article  PubMed  CAS  Google Scholar 

  12. Zhou X, Benson KF, Ashar HR, Chada K (1995) Mutation responsible for the mouse pygmy phenotype in the developmentally regulated factor HMGI-C. Nature 376:771–774

    Article  PubMed  CAS  Google Scholar 

  13. Fedele M, Battista S, Kenyon L, Baldassarre G, Fidanza V, Klein-Szanto AJ, Parlow AF, Visone R, Pierantoni GM, Outwater E et al (2002) Overexpression of the HMGA2 gene in transgenic mice leads to the onset of pituitary adenomas. Oncogene 21:3190–3198

    Article  PubMed  CAS  Google Scholar 

  14. Battista S, Fidanza V, Fedele M, Klein-Szanto AJ, Outwater E, Brunner H, Santoro M, Croce CM, Fusco A (1999) The expression of a truncated HMGI-C gene induces gigantism associated with lipomatosis. Cancer Res 59:4793–4797

    PubMed  CAS  Google Scholar 

  15. Arlotta P, Tai AK, Manfioletti G, Clifford C, Jay G, Ono SJ (2000) Transgenic mice expressing a truncated form of the high mobility group I-C protein develop adiposity and an abnormally high prevalence of lipomas. J Biol Chem 275:14394–14400

    Article  PubMed  CAS  Google Scholar 

  16. Zaidi MR, Okada Y, Chada KK (2006) Misexpression of full-length HMGA2 induces benign mesenchymal tumors in mice. Cancer Res 66:7453–7459

    Article  PubMed  CAS  Google Scholar 

  17. Weedon MN, Lettre G, Freathy RM, Lindgren CM, Voight BF, Perry JR, Elliott KS, Hackett R, Guiducci C, Shields B et al (2007) A common variant of HMGA2 is associated with adult and childhood height in the general population. Nat Genet 39:1245–1250

    Article  PubMed  CAS  Google Scholar 

  18. Wood LJ, Maher JF, Bunton TE, Resar LM (2000) The oncogenic properties of the HMG-I gene family. Cancer Res 60:4256–4261

    PubMed  CAS  Google Scholar 

  19. Di Cello F, Hillion J, Hristov A, Wood LJ, Mukherjee M, Schuldenfrei A, Kowalski J, Bhattacharya R, Ashfaq R, Resar LM (2008) HMGA2 participates in transformation in human lung cancer. Mol Cancer Res 6:743–750

    Article  PubMed  Google Scholar 

  20. Mayr C, Hemann MT, Bartel DP (2007) Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science 315:1576–1579

    Article  PubMed  CAS  Google Scholar 

  21. Wu J, Liu Z, Shao C, Gong Y, Hernando E, Lee P, Narita M, Muller W, Liu J, Wei JJ (2011) HMGA2 overexpression-induced ovarian surface epithelial transformation is mediated through regulation of EMT genes. Cancer Res 71:349–359

    Article  PubMed  CAS  Google Scholar 

  22. Mine N, Kurose K, Konishi H, Araki T, Nagai H, Emi M (2001) Fusion of a sequence from HEI10 (14q11) to the HMGIC gene at 12q15 in a uterine leiomyoma. Jpn J Cancer Res 92:135–139

    Article  PubMed  CAS  Google Scholar 

  23. Takahashi T, Nagai N, Oda H, Ohama K, Kamada N, Miyagawa K (2001) Evidence for RAD51L1/HMGIC fusion in the pathogenesis of uterine leiomyoma. Gene Chromosome Cancer 30:196–201

    Article  CAS  Google Scholar 

  24. Kurose K, Mine N, Doi D, Ota Y, Yoneyama K, Konishi H, Araki T, Emi M (2000) Novel gene fusion of COX6C at 8q22-23 to HMGIC at 12q15 in a uterine leiomyoma. Gene Chromosome Cancer 27:303–307

    Article  CAS  Google Scholar 

  25. Schoenmakers EF, Huysmans C, Van de Ven WJ (1999) Allelic knockout of novel splice variants of human recombination repair gene RAD51B in t(12;14) uterine leiomyomas. Cancer Res 59:19–23

    PubMed  CAS  Google Scholar 

  26. Kubo T, Matsui Y, Naka N, Araki N, Goto T, Yukata K, Endo K, Yasui N, Myoui A, Kawabata H et al (2009) Expression of HMGA2-LPP and LPP-HMGA2 fusion genes in lipoma: identification of a novel type of LPP-HMGA2 transcript in four cases. Anticancer Res 29:2357–2360

    PubMed  CAS  Google Scholar 

  27. Pierron A, Fernandez C, Saada E, Keslair F, Hery G, Zattara H, Pedeutour F (2009) HMGA2-NFIB fusion in a pediatric intramuscular lipoma: a novel case of NFIB alteration in a large deep-seated adipocytic tumor. Cancer Genet Cytogenet 195:66–70

    Article  PubMed  CAS  Google Scholar 

  28. Petit MM, Schoenmakers EF, Huysmans C, Geurts JM, Mandahl N, Van de Ven WJ (1999) LHFP, a novel translocation partner gene of HMGIC in a lipoma, is a member of a new family of LHFP-like genes. Genomics 57:438–441

    Article  PubMed  CAS  Google Scholar 

  29. Velagaleti GV, Tonk VS, Hakim NM, Wang X, Zhang H, Erickson-Johnson MR, Medeiros F, Oliveira AM (2010) Fusion of HMGA2 to COG5 in uterine leiomyoma. Cancer Genet Cytogenet 202:11–16

    Article  PubMed  CAS  Google Scholar 

  30. Klemke M, Meyer A, Nezhad MH, Bartnitzke S, Drieschner N, Frantzen C, Schmidt EH, Belge G, Bullerdiek J (2009) Overexpression of HMGA2 in uterine leiomyomas points to its general role for the pathogenesis of the disease. Gene Chromosome Cancer 48:171–178

    Article  CAS  Google Scholar 

  31. Broberg K, Zhang M, Strombeck B, Isaksson M, Nilsson M, Mertens F, Mandahl N, Panagopoulos I (2002) Fusion of RDC1 with HMGA2 in lipomas as the result of chromosome aberrations involving 2q35-37 and 12q13-15. Int J Oncol 21:321–326

    PubMed  CAS  Google Scholar 

  32. Italiano A, Cardot N, Dupre F, Monticelli I, Keslair F, Piche M, Mainguene C, Coindre JM, Pedeutour F (2007) Gains and complex rearrangements of the 12q13-15 chromosomal region in ordinary lipomas: the “missing link” between lipomas and liposarcomas? Int J Cancer 121:308–315

    Article  PubMed  CAS  Google Scholar 

  33. Nucci MR, Weremowicz S, Neskey DM, Sornberger K, Tallini G, Morton CC, Quade BJ (2001) Chromosomal translocation t(8;12) induces aberrant HMGIC expression in aggressive angiomyxoma of the vulva. Gene Chromosome Cancer 32:172–176

    Article  CAS  Google Scholar 

  34. Dreux N, Marty M, Chibon F, Velasco V, Hostein I, Ranchere-Vince D, Terrier P, Coindre JM (2010) Value and limitation of immunohistochemical expression of HMGA2 in mesenchymal tumors: about a series of 1052 cases. Mod Pathol 23:1657–1666

    Article  PubMed  CAS  Google Scholar 

  35. Hristov AC, Cope L, Reyes MD, Singh M, Iacobuzio-Donahue C, Maitra A, Resar LM (2009) HMGA2 protein expression correlates with lymph node metastasis and increased tumor grade in pancreatic ductal adenocarcinoma. Mod Pathol 22:43–49

    Article  PubMed  CAS  Google Scholar 

  36. McMillen BD, Aponte MM, Liu Z, Helenowski IB, Scholtens DM, Buttin BM, Wei JJ (2012) Expression analysis of MIR182 and its associated target genes in advanced ovarian carcinoma. Mod Pathol 25:1644–1653

    Article  PubMed  CAS  Google Scholar 

  37. Mahajan A, Liu Z, Gellert L, Zou X, Yang G, Lee P, Yang X, Wei JJ (2010) HMGA2: a biomarker significantly overexpressed in high-grade ovarian serous carcinoma. Mod Pathol 23:673–681

    Article  PubMed  CAS  Google Scholar 

  38. Wang X, Liu X, Li AY, Chen L, Lai L, Lin HH, Hu S, Yao L, Peng J, Loera S et al (2011) Overexpression of HMGA2 promotes metastasis and impacts survival of colorectal cancers. Clin Cancer Res 17:2570–2580

    Article  PubMed  CAS  Google Scholar 

  39. Ahmed KM, Tsai CY, Lee WH (2010) Derepression of HMGA2 via removal of ZBRK1/BRCA1/CtIP complex enhances mammary tumorigenesis. J Biol Chem 285:4464–4471

    Article  PubMed  CAS  Google Scholar 

  40. Bagga S, Bracht J, Hunter S, Massirer K, Holtz J, Eachus R, Pasquinelli AE (2005) Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation. Cell 122:553–563

    Article  PubMed  CAS  Google Scholar 

  41. Lee SH, Son MJ, Oh SH, Rho SB, Park K, Kim YJ, Park MS, Lee JH (2005) Thymosin {beta}(10) inhibits angiogenesis and tumor growth by interfering with Ras function. Cancer Res 65:137–148

    PubMed  CAS  Google Scholar 

  42. Pillai RS, Bhattacharyya SN, Artus CG, Zoller T, Cougot N, Basyuk E, Bertrand E, Filipowicz W (2005) Inhibition of translational initiation by Let-7 MicroRNA in human cells. Science 309:1573–1576

    Article  PubMed  CAS  Google Scholar 

  43. Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AE, Horvitz HR, Ruvkun G (2000) The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403:901–906

    Article  PubMed  CAS  Google Scholar 

  44. Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M et al (2004) Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A 101:2999–3004

    Article  PubMed  CAS  Google Scholar 

  45. Shell S, Park SM, Radjabi AR, Schickel R, Kistner EO, Jewell DA, Feig C, Lengyel E, Peter ME (2007) Let-7 expression defines two differentiation stages of cancer. Proc Natl Acad Sci U S A 104:11400–11405

    Article  PubMed  CAS  Google Scholar 

  46. Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, Harano T, Yatabe Y, Nagino M, Nimura Y et al (2004) Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res 64:3753–3756

    Article  PubMed  CAS  Google Scholar 

  47. Wang T, Zhang X, Obijuru L, Laser J, Aris V, Lee P, Mittal K, Soteropoulos P, Wei JJ (2007) A micro-RNA signature associated with race, tumor size, and target gene activity in human uterine leiomyomas. Gene Chromosome Cancer 46:336–347

    Article  CAS  Google Scholar 

  48. Park SM, Shell S, Radjabi AR, Schickel R, Feig C, Boyerinas B, Dinulescu DM, Lengyel E, Peter ME (2007) Let-7 prevents early cancer progression by suppressing expression of the embryonic gene HMGA2. Cell Cycle 6:2585–2590

    Article  PubMed  CAS  Google Scholar 

  49. Lee YS, Dutta A (2007) The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes Dev 21:1025–1030

    Article  PubMed  CAS  Google Scholar 

  50. Moskwa P, Buffa FM, Pan Y, Panchakshari R, Gottipati P, Muschel RJ, Beech J, Kulshrestha R, Abdelmohsen K, Weinstock DM et al (2011) miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors. Mol Cell 41:210–220

    Article  PubMed  CAS  Google Scholar 

  51. Liu Z, Liu J, Segura MF, Shao C, Lee P, Gong Y, Hernando E, Wei JJ (2012) MiR-182 overexpression in tumourigenesis of high-grade serous ovarian carcinoma. J Pathol 228:204–215

    Article  PubMed  CAS  Google Scholar 

  52. Wei JJ, Wu J, Luan C, Yeldandi A, Lee P, Keh P, Liu J (2010) HMGA2: a potential biomarker complement to P53 for detection of early-stage high-grade papillary serous carcinoma in fallopian tubes. Am J Surg Pathol 34:18–26

    Article  PubMed  Google Scholar 

  53. Guttilla IK, White BA (2009) Coordinate regulation of FOXO1 by miR-27a, miR-96, and miR-182 in breast cancer cells. J Biol Chem 284:23204–23216

    Article  PubMed  CAS  Google Scholar 

  54. Wend P, Runke S, Wend K, Anchondo B, Yesayan M, Jardon M, Hardie N, Loddenkemper C, Ulasov I, Lesniak MS et al (2013) WNT10B/beta-catenin signalling induces HMGA2 and proliferation in metastatic triple-negative breast cancer. EMBO Mol Med 5:264–279

    Article  PubMed  CAS  Google Scholar 

  55. Winslow MM, Dayton TL, Verhaak RG, Kim-Kiselak C, Snyder EL, Feldser DM, Hubbard DD, DuPage MJ, Whittaker CA, Hoersch S et al (2011) Suppression of lung adenocarcinoma progression by Nkx2-1. Nature 473:101–104

    Article  PubMed  CAS  Google Scholar 

  56. Winter N, Nimzyk R, Bosche C, Meyer A, Bullerdiek J (2011) Chromatin immunoprecipitation to analyze DNA binding sites of HMGA2. PLoS One 6:e18837

    Article  PubMed  CAS  Google Scholar 

  57. Zha L, Wang Z, Tang W, Zhang N, Liao G, Huang Z (2012) Genome-wide analysis of HMGA2 transcription factor binding sites by ChIP on chip in gastric carcinoma cells. Mol Cell Biochem 364:243–251

    Article  PubMed  CAS  Google Scholar 

  58. Thuault S, Tan EJ, Peinado H, Cano A, Heldin CH, Moustakas A (2008) HMGA2 and Smads co-regulate SNAIL1 expression during induction of epithelial-to-mesenchymal transition. J Biol Chem 283:33437–33446

    Article  PubMed  CAS  Google Scholar 

  59. Thuault S, Valcourt U, Petersen M, Manfioletti G, Heldin CH, Moustakas A (2006) Transforming growth factor-beta employs HMGA2 to elicit epithelial–mesenchymal transition. J Cell Biol 174:175–183

    Article  PubMed  CAS  Google Scholar 

  60. Tan EJ, Thuault S, Caja L, Carletti T, Heldin CH, Moustakas A (2012) Regulation of transcription factor Twist expression by the DNA architectural protein high mobility group A2 during epithelial-to-mesenchymal transition. J Biol Chem 287:7134–7145

    Article  PubMed  CAS  Google Scholar 

  61. Watanabe S, Ueda Y, Akaboshi S, Hino Y, Sekita Y, Nakao M (2009) HMGA2 maintains oncogenic RAS-induced epithelial–mesenchymal transition in human pancreatic cancer cells. Am J Pathol 174:854–868

    Article  PubMed  CAS  Google Scholar 

  62. Zha L, Zhang J, Tang W, Zhang N, He M, Guo Y, Wang Z (2012) HMGA2 elicits EMT by activating the Wnt/beta-catenin pathway in gastric cancer. Dig Dis Sci. doi:10.1007/s10620-012-2399-6

    PubMed  Google Scholar 

  63. Pfannkuche K, Summer H, Li O, Hescheler J, Droge P (2009) The high mobility group protein HMGA2: a co-regulator of chromatin structure and pluripotency in stem cells? Stem Cell Rev 5:224–230

    Article  PubMed  CAS  Google Scholar 

  64. Li O, Li J, Droge P (2007) DNA architectural factor and proto-oncogene HMGA2 regulates key developmental genes in pluripotent human embryonic stem cells. FEBS Lett 581:3533–3537

    Article  PubMed  CAS  Google Scholar 

  65. Li O, Vasudevan D, Davey CA, Droge P (2006) High-level expression of DNA architectural factor HMGA2 and its association with nucleosomes in human embryonic stem cells. Genesis 44:523–529

    Article  PubMed  CAS  Google Scholar 

  66. Morshedi A, Ren Z, Li J, Droge P (2012) Probing into the biological processes influenced by ESC factor and oncoprotein HMGA2 using iPSCs. Stem Cell Rev. doi:10.1007/s12015-012-9373-8

    Google Scholar 

  67. Henriksen J, Stabell M, Meza-Zepeda LA, Lauvrak SA, Kassem M, Myklebost O (2010) Identification of target genes for wild type and truncated HMGA2 in mesenchymal stem-like cells. BMC Cancer 10:329

    Article  PubMed  CAS  Google Scholar 

  68. Nishino J, Kim I, Chada K, Morrison SJ (2008) Hmga2 promotes neural stem cell self-renewal in young but not old mice by reducing p16Ink4a and p19Arf Expression. Cell 135:227–239

    Article  PubMed  CAS  Google Scholar 

  69. Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C, Huang Y, Hu X, Su F, Lieberman J et al (2007) let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 131:1109–1123

    Article  PubMed  CAS  Google Scholar 

  70. Fedele M, Pierantoni GM, Visone R, Fusco A (2006) Critical role of the HMGA2 gene in pituitary adenomas. Cell Cycle 5:2045–2048

    Article  PubMed  CAS  Google Scholar 

  71. De Martino I, Visone R, Wierinckx A, Palmieri D, Ferraro A, Cappabianca P, Chiappetta G, Forzati F, Lombardi G, Colao A et al (2009) HMGA proteins up-regulate CCNB2 gene in mouse and human pituitary adenomas. Cancer Res 69:1844–1850

    Article  PubMed  CAS  Google Scholar 

  72. Tessari MA, Gostissa M, Altamura S, Sgarra R, Rustighi A, Salvagno C, Caretti G, Imbriano C, Mantovani R, Del Sal G et al (2003) Transcriptional activation of the cyclin A gene by the architectural transcription factor HMGA2. Mol Cell Biol 23:9104–9116

    Article  PubMed  CAS  Google Scholar 

  73. Zhu S, Deng S, Ma Q, Zhang T, Jia C, Zhuo D, Yang F, Wei J, Wang L, Dykxhoorn DM et al (2012) microRNA-10A* and microRNA-21 modulate endothelial progenitor cell senescence via suppressing Hmga2. Circ Res. doi:10.1161/CIRCRESAHA.112.280016

    Google Scholar 

  74. Markowski DN, Winter N, Meyer F, von Ahsen I, Wenk H, Nolte I, Bullerdiek J (2011) p14Arf acts as an antagonist of HMGA2 in senescence of mesenchymal stem cells-implications for benign tumorigenesis. Gene Chromosome Cancer 50:489–498

    Article  CAS  Google Scholar 

  75. Venkatesan N, Krishnakumar S, Deepa PR, Deepa M, Khetan V, Reddy MA (2012) Molecular deregulation induced by silencing of the high mobility group protein A2 gene in retinoblastoma cells. Mol Vis 18:2420–2437

    PubMed  CAS  Google Scholar 

  76. Li AY, Boo LM, Wang SY, Lin HH, Wang CC, Yen Y, Chen BP, Chen DJ, Ann DK (2009) Suppression of nonhomologous end joining repair by overexpression of HMGA2. Cancer Res 69:5699–5706

    Article  PubMed  CAS  Google Scholar 

  77. Borrmann L, Schwanbeck R, Heyduk T, Seebeck B, Rogalla P, Bullerdiek J, Wisniewski JR (2003) High mobility group A2 protein and its derivatives bind a specific region of the promoter of DNA repair gene ERCC1 and modulate its activity. Nucleic Acids Res 31:6841–6851

    Article  PubMed  CAS  Google Scholar 

  78. Natarajan S, Hombach-Klonisch S, Droge P, Klonisch T (2013) HMGA2 inhibits apoptosis through interaction with ATR-CHK1 signaling complex in human cancer cells. Neoplasia 15:263–280

    PubMed  CAS  Google Scholar 

  79. Bullerdiek J, Rommel B (2010) Comment re: HMGA2 is a negative regulator of DNA-PK pathway. Cancer Res 70:1742

    Article  PubMed  CAS  Google Scholar 

  80. Farley J, Ozbun LL, Birrer MJ (2008) Genomic analysis of epithelial ovarian cancer. Cell Res 18:538–548

    Article  PubMed  CAS  Google Scholar 

  81. Bast RC Jr, Hennessy B, Mills GB (2009) The biology of ovarian cancer: new opportunities for translation. Nat Rev Cancer 9:415–428

    Article  PubMed  CAS  Google Scholar 

  82. Vaughan S, Coward JI, Bast RC Jr, Berchuck A, Berek JS, Brenton JD, Coukos G, Crum CC, Drapkin R, Etemadmoghadam D et al (2011) Rethinking ovarian cancer: recommendations for improving outcomes. Nat Rev Cancer 11:719–725

    Article  PubMed  CAS  Google Scholar 

  83. The Cancer Genome Atlas Research Network (2011) Integrated genomic analyses of ovarian carcinoma. Nature 474: 609–615. doi:10.1038/nature10166

    Google Scholar 

  84. Hetland TE, Holth A, Kaern J, Florenes VA, Trope CG, Davidson B (2012) HMGA2 protein expression in ovarian serous carcinoma effusions, primary tumors, and solid metastases. Virchows Arch 460:505–513

    Article  PubMed  CAS  Google Scholar 

  85. Malek A, Bakhidze E, Noske A, Sers C, Aigner A, Schafer R, Tchernitsa O (2008) HMGA2 gene is a promising target for ovarian cancer silencing therapy. Int J Cancer 123:348–356

    Article  PubMed  CAS  Google Scholar 

  86. Meyer B, Loeschke S, Schultze A, Weigel T, Sandkamp M, Goldmann T, Vollmer E, Bullerdiek J (2007) HMGA2 overexpression in non-small cell lung cancer. Mol Carcinog 46:503–511

    Article  PubMed  CAS  Google Scholar 

  87. Aman P (1999) Fusion genes in solid tumors. Semin Cancer Biol 9:303–318

    Article  PubMed  CAS  Google Scholar 

  88. Tallini G, Dal Cin P (1999) HMGI(Y) and HMGI-C dysregulation: a common occurrence in human tumors. Adv Anat Pathol 6:237–246

    Article  PubMed  CAS  Google Scholar 

  89. Welsh JB, Zarrinkar PP, Sapinoso LM, Kern SG, Behling CA, Monk BJ, Lockhart DJ, Burger RA, Hampton GM (2001) Analysis of gene expression profiles in normal and neoplastic ovarian tissue samples identifies candidate molecular markers of epithelial ovarian cancer. Proc Natl Acad Sci U S A 98:1176–1181

    Article  PubMed  CAS  Google Scholar 

  90. Salani R, Kurman RJ, Giuntoli R 2nd, Gardner G, Bristow R, Wang TL, Shih IM (2008) Assessment of TP53 mutation using purified tissue samples of ovarian serous carcinomas reveals a higher mutation rate than previously reported and does not correlate with drug resistance. Int J Gynecol Cancer 18:487–491

    Article  PubMed  CAS  Google Scholar 

  91. Bowtell DD (2010) The genesis and evolution of high-grade serous ovarian cancer. Nat Rev Cancer 10:803–808

    Article  PubMed  CAS  Google Scholar 

  92. Medeiros F, Muto MG, Lee Y, Elvin JA, Callahan MJ, Feltmate C, Garber JE, Cramer DW, Crum CP (2006) The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am J Surg Pathol 30:230–236

    Article  PubMed  Google Scholar 

  93. Levanon K, Crum C, Drapkin R (2008) New insights into the pathogenesis of serous ovarian cancer and its clinical impact. J Clin Oncol 26:5284–5293

    Article  PubMed  Google Scholar 

  94. Lee Y, Miron A, Drapkin R, Nucci MR, Medeiros F, Saleemuddin A, Garber J, Birch C, Mou H, Gordon RW et al (2007) A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J Pathol 211:26–35

    Article  PubMed  CAS  Google Scholar 

  95. Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Fan I, Tang J, Li S, Zhang S, Shaw PA et al (2006) Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J Natl Cancer Inst 98:1694–1706

    Article  PubMed  CAS  Google Scholar 

  96. Zhang S, Royer R, Li S, McLaughlin JR, Rosen B, Risch HA, Fan I, Bradley L, Shaw PA, Narod SA (2011) Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. doi:S0090-8258(11)00062-X

  97. Press JZ, De Luca A, Boyd N, Young S, Troussard A, Ridge Y, Kaurah P, Kalloger SE, Blood KA, Smith M et al (2008) Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities. BMC Cancer 8:17

    Article  PubMed  CAS  Google Scholar 

  98. Suzuki HI, Yamagata K, Sugimoto K, Iwamoto T, Kato S, Miyazono K (2009) Modulation of microRNA processing by p53. Nature 460:529–533

    Article  PubMed  CAS  Google Scholar 

  99. Tarasov V, Jung P, Verdoodt B, Lodygin D, Epanchintsev A, Menssen A, Meister G, Hermeking H (2007) Differential regulation of microRNAs by p53 revealed by massively parallel sequencing: miR-34a is a p53 target that induces apoptosis and G1-arrest. Cell Cycle 6:1586–1593

    Article  PubMed  CAS  Google Scholar 

  100. Chang TC, Wentzel EA, Kent OA, Ramachandran K, Mullendore M, Lee KH, Feldmann G, Yamakuchi M, Ferlito M, Lowenstein CJ et al (2007) Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell 26:745–752

    Article  PubMed  CAS  Google Scholar 

  101. Myatt SS, Wang J, Monteiro LJ, Christian M, Ho KK, Fusi L, Dina RE, Brosens JJ, Ghaem-Maghami S, Lam EW (2010) Definition of microRNAs that repress expression of the tumor suppressor gene FOXO1 in endometrial cancer. Cancer Res 70:367–377

    Article  PubMed  CAS  Google Scholar 

  102. Segura MF, Hanniford D, Menendez S, Reavie L, Zou X, Alvarez-Diaz S, Zakrzewski J, Blochin E, Rose A, Bogunovic D et al (2009) Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor. Proc Natl Acad Sci U S A 106:1814–1819

    Article  PubMed  CAS  Google Scholar 

  103. Wu J, Lu LY, Yu X (2010) The role of BRCA1 in DNA damage response. Protein Cell 1:117–123

    Article  PubMed  CAS  Google Scholar 

  104. Tsai WB, Chung YM, Takahashi Y, Xu Z, Hu MC (2008) Functional interaction between FOXO3a and ATM regulates DNA damage response. Nat Cell Biol 10:460–467

    Article  PubMed  CAS  Google Scholar 

  105. Levanon K, Ng V, Piao HY, Zhang Y, Chang MC, Roh MH, Kindelberger DW, Hirsch MS, Crum CP, Marto JA et al (2010) Primary ex vivo cultures of human fallopian tube epithelium as a model for serous ovarian carcinogenesis. Oncogene 29:1103–1113

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work is partially supported by awards from the Dixon Translation Research Fund and the Marsha Rivkin Ovarian Cancer Center Fund.

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No potential conflicts of interest were disclosed.

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Correspondence to Jian-Jun Wei.

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Wu, J., Wei, JJ. HMGA2 and high-grade serous ovarian carcinoma. J Mol Med 91, 1155–1165 (2013). https://doi.org/10.1007/s00109-013-1055-8

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  • DOI: https://doi.org/10.1007/s00109-013-1055-8

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