Stathmin as a Marker for Malignancy in Pheochromocytomas

Abstract

Pheochromocytomas of the adrenal medulla may be life-threatening catecholamine-producing tumors which are malignant in about 10% of cases. Differential diagnosis between malignant and benign tumors is dependent on the development of metastasis or extensive local invasion. A number of genetic aberrations have been described in pheochromocytomas, but no marker associated to malignancy has been reported. We applied an expression microarray containing 7770 cDNA clones and analysed the expression profiles in eleven tumors compared to normal adrenal medulla. Stathmin (STMN1, Op18) was most conspiciously overexpressed among the differentially expressed genes. RT-PCR analysis further confirmed mRNA overexpression, 6 to 8-fold for benign and malignant tumors, and 16-fold for metastases. Stathmin protein overexpression was observed by immunohistochemistry, and distinct differential protein expression between benign and malignant/metastasis specimens was confirmed by Western blot analysis. The results introduce stathmin as a possible diagnostic marker for malignant pheochromocytomas, and further evaluations are warranted.

benign - microarray - malignant - pheochromocytoma - stathmin - STMN1 - Op18

References

• 1 Astuti D, Douglas F, Lennard TW. et al . Germline SDHD mutation in familial pheochromocytoma.  Lancet. 2001;  357 1181-1182
• 2 Astuti D, Latif F, Dallol A. et al . Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma.  Am J Hum Genet.. 2001;  69 49-54
• 3 Baldassare G, Belleti B, Nicoloso MS. et al . p27(Kip1)-stathmin interaction influences sarcoma cell migration and invasion.  Cancer Cell. 2005;  7 51-63
• 4 Bender BU, Gutsche M, Glasker S. et al . Differential genetic alterations in von Hippel-Lindau syndrome-associated and sporadic pheochromocytomas.  J Clin Endocrinol Metab.. 2000;  85 4568-4574
• 5 Benn DE, Dwight T, Richardson AL. et al . Sporadic and familial pheochromocytomas are associated with loss of at least two discrete intervals on chromosome 1p.  Cancer Res.. 2000;  60 7048-7051
• 6 Bjorklund P, Akerstrom G, Westin G. Accumulation of nonphosphorylated beta-catenin and c-myc in primary and uremic secondary hyperparathyroid tumors.  J Clin Endocrinol Metab.. 2007;  92 338-344
• 7 Cascon A, Ruiz-Llorente S, Rodriguez-Perales S. et al . A novel candidate region linked to development of both pheochromocytoma and head/neck paraganglioma.  Genes Chromosomes Cancer. 2005;  42 260-268
• 8 Curmi PA, Nogues C, Lachkar S. et al . Overexpression of stathmin in breast carcinomas points out to highly proliferative tumours.  Br J Cancer. 2000;  82 142-150
• 9 Dannenberg H, Speel EJ, Zhao J. et al . Losses of chromosomes 1p and 3q are early genetic events in the development of sporadic pheochromocytomas.  Am J Pathol.. 2000;  157 353-359
• 10 Edstrom E, Mahlamaki E, Nord B. et al . Comparative genomic hybridization reveals frequent losses of chromosomes 1p and 3q in pheochromocytomas and abdominal paragangliomas, suggesting a common genetic etiology.  Am J Pathol.. 2000;  156 651-659
• 11 Elkahloun AG, Powers JF, Nyska A. et al . Gene Expression Profiling of Rat Pheochromocytoma.  Ann NY Acad Sci.. 2006;  1073 290-299
• 12 Fryknas M, Wickenberg-Bolin U, Goransson H. et al . Molecular markers for discrimination of benign and malignant follicular thyroid tumors.  Tumour Biol.. 2006;  27 211-220
• 13 Geli J, Nord B, Frisk T. et al . Deletions and altered expression of the RIZ1 tumour suppressor gene in 1p36 in pheochromocytoma and abdominal paragangliomas.  Int J Oncol.. 2005;  26 1385-1391
• 14 Goldstein RE, O’Neill  Jr  JA, Holcomb 3rd  GW. et al . Clinical experience over 48 years with pheochromocytoma.  Ann Surg.. 1999;  229 755-764
• 15 Gunawan B, Schlomm T, Schulten HJ. et al . Cytogenetic characterization of 5 pheochromocytomas.  Cancer Genet. Cytogenet.. 2004;  154 163-166
• 16 Hergovich A, Lisztwan J, Barry R. et al . Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL.  Nat Cell Biol.. 2003;  5 64-70
• 17 Holmfeldt P, Brannstrom K, Stenmark S. et al . Aneugenic activity of Op18/stathmin is potentiated by the somatic Q18-->e mutation in leukemic cells.  Mol Biol Cell. 2006;  17 2921-2930
• 18 Kouzu Y, Uzawa K, Koike H. et al . Overexpression of stathmin in oral squamous-cell carcinoma: correlation with tumour progression and poor prognosis.  Br J Cancer. 2006;  94 717-723
• 19 Lemeta S, Salmenkivi K, Pylkkanen L. et al . Frequent loss of heterozygosity at 6q in pheochromocytoma.  Hum Pathol.. 2006;  37 749-754
• 20 Mannelli M, Ianni L, Cilotti A. et al . Pheochromocytoma in Italy: a multicentric retrospective study.  Eur J Endocrinol.. 1999;  141 619-624
• 21 Melhem RF, Strahler JR, Hailat N. et al . Involvement of OP18 in cell proliferation.  Biochem Biophys Res Commun.. 1991;  179 1649-1655
• 22 Melhem R, Hailat N, Kuick R. et al . Quantitative analysis of Op18 phosphorylation in childhood acute leukemia.  Leukemia.. 1997;  11 1690-1695
• 23 Misek DE, Chang CL, Kuick R. et al . Transforming properties of a Q18-->E mutation of the microtubule regulator Op18.  Cancer Cell. 2002;  2 217-228
• 24 Neumann HP, Bausch B, MacWhinney SR. et al . Germ-line mutations in nonsyndromic pheochromocytoma.  N Engl J Med.. 2002;  346 1459-1466
• 25 Neumann HP, Hoegerle S, Manz T. et al . How many pathways to pheochromocytoma?.  Semin Nephrol.. 2002;  22 89-99
• 26 Ohta S, Lai EW, Pang AL. et al . Downregulation of metastasis suppressor genes in malignant pheochromocytoma.  Int J Cancer. 2005;  114 139-143
• 27 Pawlu C, Bausch B, Reisch N. et al . Genetic testing for pheochromocytoma-associated syndromes.  Ann Endocrinol. (Paris). 2005;  66 178-185
• 28 Price DK, Ball JR, Bahrani-Mostafavi Z. et al . The phosphoprotein Op18/stathmin is differentially expressed in ovarian cancer.  Cancer Invest.. 2000;  18 722-730
• 29 Roos G, Brattsand G, Landberg G. et al . Expression of oncoprotein 18 in human leukemias and lymphomas.  Leukemia.. 1993;  7 1538-1546
• 30 Rubin CI, Atweh GF. The role of stathmin in the regulation of the cell cycle.  J. Cell. Biochem.. 2004;  93 242-250
• 31 Takekoshi K, Nomura F, Isobe K. et al . Identification and initial characterization of stathmin by the differential display method in nerve growth factor-treated PC12 cells.  Eur J Endocrinol.. 1998;  138 707-712
• 32 Thompson LD. Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases.  Am J Surg Pathol.. 2002;  26 551-566
• 33 Yuan RH, Jeng YM, Chen HL. et al . Stathmin overexpression cooperates with p53 mutation and osteopontin overexpression, and is associated with tumour progression, early recurrence, and poor prognosis in hepatocellular carcinoma.  J Pathol.. 2006;  209 549-558

1 These authors contributed equally to this work

Correspondence