Expression of ADAM9 in CIN3 lesions and squamous cell carcinomas of the cervix

ADAM9 is a member of the ADAM family which is involved in cellular processes like cell adhesion, migration and signalling [M.L. Moss, J.M. White, M.H. Lambert, R.C. Andrews, TACE and other ADAM proteases as targets for drug discovery. Drug Discov. Today 2001; 6:417-426., G. Murphy, The ADAMS: signalling scissors in the tumour microenvironment. Nat. Cancer Rev. 2008; 8:929-941.]. ADAM9 overexpression has been described in many of solid tumours including prostate, renal, pancreas, lung and gastric cancer [R.J. Grutzmann, J. Luttges, B. Sipos, O. Ammerpohl, F. Dobrowolski, I. Alldinger, et al., ADAM9 expression in pancreatic cancer is associated with tumour type and is a prognostic factor in ductal adenocarcinoma. Br. J. Cancer 2004; 90:1053-1058., C.A. Iacobuzio-Donahue, A. Maitra, M. Olsen, A.W. Lowe, N.T. van Heek, C. Rosty, et al., Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays. Am. J. Pathol. 2003; 162: 1151-1162., Y. Shintani, S. Higashiyama, M. Ohta, H. Hirabayashi, S. Yamamoto,T. Yoshimasu, et al., Overexpression of ADAM9 in non-small cell lung cancer correlates with brain metastasis. Cancer Res. 2004; 64:4190-4196., S. Carl-McGrath, U. Lendeckel, M. Ebert, A. Roessner, C. Rocken, The disintegrin-metalloproteinases ADAM9, ADAM12, and ADAM15 are upregulated in gastric cancer. Int. J. Oncol. 2005; 26:17-24., F.R. Fritzsche, K. Wassermann, M. Jung, A. Tölle, I. Kristiansen, M. Lein, et al., ADAM9 is highly expressed in renal cell cancer and is associated with tumour progression. BMC Cancer 2008; 8:179.]. The involvement of this protease in cervical carcinogenesis has not been yet investigated. The aim of this study was to evaluate the expression of ADAM9 in normal epithelium, CIN3 lesions and squamous cell carcinomas (SCC) of the uterine cervix.

Archived paraffin-embedded tissue blocks from biopsy or surgery specimens obtained from 50 subjects with CIN3 and squamous cancer of the cervix were studied by immunohistochemistry using heat-induced epitope retrieval for ADAM9 expression.

Weak expression of ADAM9 was found in the normal cervical epithelium with weak cytoplasmatic staining but also membrane immunoreactivity. Evident staining for ADAM9 was detected in 31 out of 36 (86%) CIN3 lesions and in 13 out of 14 (93%) squamous cell carcinomas of the uterine cervix. Staining was stronger in SCC compared to CIN3 lesions. Moderate staining was detected in 64% (9/14) of SCC and in 36% (13/36) CIN3 lesions. Weak staining was observed in 50% (18/36) of CIN3 lesions and in 29% (4/14) of SCC. The difference in the ADAM9 protein expression between cervical squamous carcinomas and normal epithelium was highly significant. Statistical significance was also found for the increased expression observed in CIN3 lesions versus normal squamous epithelium.

Our results show for the first time, that ADAM9 expression is low in the squamous epithelium of the cervix, but is increased in CIN3 lesions as well as SCCs being the increase in both cases statistically significant.