Virchows Archiv

, Volume 471, Issue 1, pp 117–122 | Cite as

HIF-1α, MDM2, CDK4, and p16 expression in ischemic fasciitis, focusing on its ischemic condition

  • Yuichi Yamada
  • Izumi Kinoshita
  • Kenichi Kohashi
  • Hidetaka Yamamoto
  • Yuki Kuma
  • Takamichi Ito
  • Kenji Koda
  • Atsushi Kisanuki
  • Manabu Kurosawa
  • Michiko Yoshimura
  • Masutaka Furue
  • Yoshinao Oda
Original Article

Abstract

Ischemic fasciitis is a benign myofibroblastic lesion, occurring in the sacral region or proximal thigh of elderly or bedridden individuals. The pathogenesis of ischemic fasciitis is thought to be based on ischemic condition; however, it has never been demonstrated. In this study, we examined the expression of ischemia-associated proteins in ischemic fasciitis by immunohistochemical and genetic methods. Specifically, this study aimed to reveal the expression of HIF-1α, MDM2, CDK4, p16, and gene amplification of MDM2 gene. Seven cases of ischemic fasciitis from among the soft-tissue tumors registered at our institution were retrieved. Histopathological findings were as follows: poorly demarcated nodular masses, a proliferation of spindle-shaped fibroblastic or myofibroblastic cells with oval nuclei and eosinophilic or pale cytoplasm, zonal fibrinous deposition, pseudocystic degeneration, granulation-like proliferation of capillary vessels, ganglion-like cells, myxoid or hyalinized stroma, and chronic inflammatory infiltration. Immunohistochemically, the spindle cells were positive for HIF-1α (7/7 cases), MDM2 (4/7 cases), CDK4 (4/7 cases), p16 (7/7 cases), p53 (2/7 case), cyclin D1 (7/7 cases), and alpha-smooth muscle actin (6/7 cases). Neither MDM2 gene amplification nor USP6 gene split signal was detected in any case. Overexpression of the above proteins may be associated with the pathogenic mechanism of ischemic fasciitis. It is noted that the immunohistochemical positivity of MDM2, CDK4, and p16 do not necessarily indicate malignant neoplasm such as dedifferentiated liposarcoma.

Keywords

Ischemic fasciitis Dedifferentiated liposarcoma MDM2 CDK4 p16 

Notes

Acknowledgments

This study was supported by a JSPS KAKENHI Grant (No. 25293088) and by funds from the Scholarship Program of the Takeda Science Foundation. Technical support for the experimental trials was provided by the following laboratory assistants: Motoko Tomita, Mami Nakamizo, Juri Godo, Midori Kinoshita, Hisami Matsumoto, and Noriko Aoki. We also appreciate the technical assistance from The Research Support Center, Kyushu University Graduate School of Medical Sciences.

Author contributions

Yuichi Yamada and Izumi Kinoshita performed the research and wrote the paper. Kenichi Kohashi and Hidetaka Yamamoto contributed to the research design and slide review. Yuki Kuma, Takamichi Ito, and Masutaka Furue contributed to the sample collection and research design. Yoshinao Oda designed the research and gave final approval of the manuscript. All authors critically reviewed and approved the manuscript.

Compliance with ethical standards

This study was approved by the Ethics Committee of Kyushu University (Nos. 25-111, 25-143) and conducted according to the principles embodied in the Declaration of Helsinki. Informed consent was obtained from the subjects or guardians.

Conflict of interest

The authors declare that there are no conflict of interest.

Supplementary material

428_2017_2122_MOESM1_ESM.xlsx (11 kb)
Supplementary Table 1 (XLSX 10 kb).

References

  1. 1.
    Liegl-Atzwanger B (2013) Ischemic fasciitis. In: CDM F, Bridge JA, PCW H, Mertens F (eds) World Health Organization classification of tumours. Pathology and genetics of tumours of soft tissue and bone. IARC Press, Lyon, p 52Google Scholar
  2. 2.
    Lee SH, Wolf PL, Escudero R, Deutsch R, Jamieson SW, Thistlethwaite PA (2000) Early expression of angiogenesis factors in acute myocardial ischemia and infarction. N Engl J Med 342:626–633CrossRefPubMedGoogle Scholar
  3. 3.
    Shyu KG, Wang MT, Wang BW, Chang CC, Leu JG, Kuan P, Chang H (2002) Intramyocardial injection of naked DNA encoding HIF-1alpha/VP16 hybrid to enhance angiogenesis in an acute myocardial infarction model in the rat. Cardiovasc Res 54:576–583CrossRefPubMedGoogle Scholar
  4. 4.
    Marfella R, D’Amico M, Di Filippo C, Piegari E, Nappo F, Esposito K, Berrino L, Rossi F, Giugliano D (2002) Myocardial infarction in diabetic rats: role of hyperglycaemia on infarct size and early expression of hypoxia-inducible factor 1. Diabetologia 45:1172–1181CrossRefPubMedGoogle Scholar
  5. 5.
    Parisi Q, Biondi-Zoccai GG, Abbate A, Santini D, Vasaturo F, Scarpa S, Bussani R, Leone AM, Petrolini A, Silvestri F, Biasucci LM, Baldi A (2005) Hypoxia inducible factor-1 expression mediates myocardial response to ischemia late after acute myocardial infarction. Int J Cardiol 99:337–339CrossRefPubMedGoogle Scholar
  6. 6.
    Blanco Pampín J, García Rivero SA, Otero Cepeda XL, Vázquez Boquete A, Forteza Vila J, Hinojal FR (2006) Immunohistochemical expression of HIF-1alpha in response to early myocardial ischemia. J Forensic Sci 51:120–124CrossRefPubMedGoogle Scholar
  7. 7.
    Bergeron M, Yu AY, Solway KE, Semenza GL, Sharp FR (1999) Induction of hypoxia-inducible factor-1 (HIF-1) and its target genes following focal ischaemia in rat brain. Eur J Neurosci 11:4159–4170CrossRefPubMedGoogle Scholar
  8. 8.
    Sun L, Marti HH, Veltkamp R (2008) Hyperbaric oxygen reduces tissue hypoxia and hypoxia-inducible factor-1 alpha expression in focal cerebral ischemia. Stroke 39:1000–1006CrossRefPubMedGoogle Scholar
  9. 9.
    El Naggar A, Clarkson P, Zhang F, Mathers J, Tognon C, Sorensen PH (2012) Expression and stability of hypoxia inducible factor 1α in osteosarcoma. Pediatr Blood Cancer 59:1215–1222CrossRefPubMedGoogle Scholar
  10. 10.
    Nakayama K, Kanzaki A, Hata K, Katabuchi H, Okamura H, Miyazaki K, Fukumoto M, Takebayashi Y (2002) Hypoxia-inducible factor 1 alpha (HIF-1 alpha) gene expression in human ovarian carcinoma. Cancer Lett 176:215–223CrossRefPubMedGoogle Scholar
  11. 11.
    Giatromanolaki A, Koukourakis MI, Sivridis E, Turley H, Talks K, Pezzella F, Gatter KC, Harris AL (2001) Relation of hypoxia inducible factor 1 alpha and 2 alpha in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival. Br J Cancer 85:881–890CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Büchler P, Reber HA, Büchler M, Shrinkante S, Büchler MW, Friess H, Semenza GL, Hines OJ (2003) Hypoxia-inducible factor 1 regulates vascular endothelial growth factor expression in human pancreatic cancer. Pancreas 26:56–64CrossRefPubMedGoogle Scholar
  13. 13.
    Krishnamachary B, Berg-Dixon S, Kelly B, Agani F, Feldser D, Ferreira G, Iyer N, LaRusch J, Pak B, Taghavi P, Semenza GL (2003) Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res 63:1138–1143PubMedGoogle Scholar
  14. 14.
    Theodoropoulos VE, Lazaris AC, Sofras F, Gerzelis I, Tsoukala V, Ghikonti I, Manikas K, Kastriotis I (2004) Hypoxia-inducible factor 1 alpha expression correlates with angiogenesis and unfavorable prognosis in bladder cancer. Eur Urol 46:200–208CrossRefPubMedGoogle Scholar
  15. 15.
    Kurtkaya-Yapicier O, Scheithauer BW, Hebrink D, James CD (2002) p53 in nonneoplastic central nervous system lesions: an immunohistochemical and genetic sequencing study. Neurosurgery 51:1246–1254CrossRefPubMedGoogle Scholar
  16. 16.
    Love S (2003) Neuronal expression of cell cycle-related proteins after brain ischaemia in man. Neurosci Lett 353:29–32CrossRefPubMedGoogle Scholar
  17. 17.
    Wen Y, Yang S, Liu R, Simpkins JW (2005) Cell-cycle regulators are involved in transient cerebral ischemia induced neuronal apoptosis in female rats. FEBS Lett 579:4591–4599CrossRefPubMedGoogle Scholar
  18. 18.
    Mocanu MM, Yellon DM (2003) p53 down-regulation: a new molecular mechanism involved in ischaemic preconditioning. FEBS Lett 555:302–306CrossRefPubMedGoogle Scholar
  19. 19.
    Tu Y, Hou ST, Huang Z, Robertson GS, MacManus JP (1998) Increased Mdm2 expression in rat brain after transient middle cerebral artery occlusion. J Cereb Blood Flow Metab 18:658–669CrossRefPubMedGoogle Scholar
  20. 20.
    Zhu Y, Mao XO, Sun Y, Xia Z, Greenberg DA (2002) p38 mitogen-activated protein kinase mediates hypoxic regulation of Mdm2 and p53 in neurons. J Biol Chem 277:22909–22914CrossRefPubMedGoogle Scholar
  21. 21.
    Saito A, Hayashi T, Okuno S, Nishi T, Chan PH (2005) Modulation of p53 degradation via MDM2-mediated ubiquitylation and the ubiquitin-proteasome system during reperfusion after stroke: role of oxidative stress. J Cereb Blood Flow Metab 25:267–280CrossRefPubMedGoogle Scholar
  22. 22.
    Toth A, Nickson P, Qin LL, Erhardt P (2006) Differential regulation of cardiomyocyte survival and hypertrophy by MDM2, an E3 ubiquitin ligase. J Biol Chem 281:3679–3689CrossRefPubMedGoogle Scholar
  23. 23.
    Li Y, Chopp M, Powers C, Jiang N (1997) Immunoreactivity of cyclin D1/cdk4 in neurons and oligodendrocytes after focal cerebral ischemia in rat. J Cereb Blood Flow Metab 17:846–856CrossRefPubMedGoogle Scholar
  24. 24.
    Sakurai M, Hayashi T, Abe K, Itoyama Y, Tabayashi K, Rosenblum WI (2000) Cyclin D1 and Cdk4 protein induction in motor neurons after transient spinal cord ischemia in rabbits. Stroke 31:200–207CrossRefPubMedGoogle Scholar
  25. 25.
    Leker RR, Aharonowiz M, Greig NH, Ovadia H (2004) The role of p53-induced apoptosis in cerebral ischemia: effects of the p53 inhibitor pifithrin alpha. Exp Neurol 187:478–486CrossRefPubMedGoogle Scholar
  26. 26.
    Aleixo PB, Hartmann AA, Menezes IC, Meurer RT, Oliveira AM (2009) Can MDM2 and CDK4 make the diagnosis of well differentiated/dedifferentiated liposarcoma? An immunohistochemical study on 129 soft tissue tumours. AMJ Clin Pathol 62:1127–1135CrossRefGoogle Scholar
  27. 27.
    Le Guellec S, Chibon F, Ouali M, Perot G, Decouvelaere AV, Robin YM, Larousserie F, Terrier P, Coindre JM, Neuville A (2014) Are peripheral purely undifferentiated pleomorphic sarcomas with MDM2 amplification dedifferentiated liposarcomas? Am J Surg Pathol 38:293–304CrossRefPubMedGoogle Scholar
  28. 28.
    Weaver J, Downs-Kelly E, Goldblum JR, Turner S, Kulkarni S, Tubbs RR, Rubin BP, Skacel M (2008) Fluorescence in situ hybridization for MDM2 gene amplification as a diagnostic tool in lipomatous neoplasms. Mod Pathol 21:943–949CrossRefPubMedGoogle Scholar
  29. 29.
    Sirvent N, Coindre JM, Maire G, Hostein I, Keslair F, Guillou L, Ranchere-Vince D, Terrier P, Pedeutour F (2007) Detection of MDM2-CDK4 amplification by fluorescence in situ hybridization in 200 paraffin-embedded tumor samples: utility in diagnosing adipocytic lesions and comparison with immunohistochemistry and real-time PCR. Am J Surg Pathol 31:1476–1489CrossRefPubMedGoogle Scholar
  30. 30.
    Binh MB, Sastre-Garau X, Guillou L, de Pinieux G, Terrier P, Lagacé R, Aurias A, Hostein I, Coindre JM (2005) MDM2 and CDK4 immunostainings are useful adjuncts in diagnosing well-differentiated and dedifferentiated liposarcoma subtypes: a comparative analysis of 559 soft tissue neoplasms with genetic data. Am J Surg Pathol 29:1340–1347CrossRefPubMedGoogle Scholar
  31. 31.
    Liegl B, Fletcher CD (2008) Ischemic fasciitis: analysis of 44 cases indicating an inconsistent association with immobility or debilitation. Am J Surg Pathol 32:1546–1552CrossRefPubMedGoogle Scholar
  32. 32.
    Erickson-Johnson MR, Chou MM, Evers BR, Roth CW, Seys AR, Jin L, Ye Y, Lau AW, Wang X, Oliveira AM (2011) Nodular fasciitis: a novel model of transient neoplasia induced by MYH9-USP6 gene fusion. Lab Investig 91:1427–1433CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Yuichi Yamada
    • 1
  • Izumi Kinoshita
    • 1
  • Kenichi Kohashi
    • 1
  • Hidetaka Yamamoto
    • 1
  • Yuki Kuma
    • 1
  • Takamichi Ito
    • 1
  • Kenji Koda
    • 2
  • Atsushi Kisanuki
    • 3
  • Manabu Kurosawa
    • 4
  • Michiko Yoshimura
    • 5
  • Masutaka Furue
    • 6
  • Yoshinao Oda
    • 1
  1. 1.Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical SciencesKyushu UniversityFukuoka-shiJapan
  2. 2.Department of PathologyFujieda Municipal General HospitalFujieda-shiJapan
  3. 3.Department of PathologyNichinan Prefectural Miyazaki HospitalNichinan-shiJapan
  4. 4.Department of PathologyNagahama City HospitalNagahama-shiJapan
  5. 5.Department of PathologyBelland HospitalSakai-shiJapan
  6. 6.Department of Dermatology, Graduate School of Medical ScienceKyushu UniversityFukuoka-shiJapan

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