Reduced expression of tissue factor pathway inhibitor-2 contributes to apoptosis and angiogenesis in cervical cancer

Abstract

Background: Tissue factor pathway inhibitor-2 (TFPI-2) is an extracellular matrix associated broad-spectrum Kunitz-type serine proteinase inhibitor. Recently, down regulation of TFPI-2 was suggested to be involved in tumor invasion and metastasis in some cancers.

Methods: This study involved 12 normal cervical squamous epithelia, 48 cervical intraepithelial neoplasia (CIN), and 68 cervical cancer. The expression of TFPI-2, Ki-67 and vascular endothelial growth factor (VEGF) were investigated by immunohistochemistry staining. The apoptolic index(AI) was determined with an in situ end-labeling assay(TUNEL). And the marker of CD34 staining was used as an indicator of microvessel density (MVD).

Results: TFPI-2 expression has a decreasing trend with the progression of cervical cancer and was significantly correlated with FIGO stage, lymph node metastasis and HPV infection. In addition, there were significant positive correlations between the grading of TFPI-2 expression and AI(P=0.004). In contrast, the expression of TFPI-2 and VEGF or MVD was negatively correlated (both p < 0.001). However, we did not establish any significant correlation between Ki-67 and TFPI-2 expression in cervical cancer.

Conclusions: The results suggested that the expression of TFPI-2 had a decreasing trend with tumor progression of cervical cancer. There was a close association between the expression of TFPI-2 and tumor cell apoptosis and angiogenesis in patients with cervical cancer. TFPI-2 may play an inhibitive role during the development of cervical cancer.

Figure 1

The grading of immunohistochemical staining for TFPI-2. Immunohistochemical staining of cervical tissues for TFPI-2 (A-E). The immunostaining intensity was defined as grade 0 (no detectable staining, A), grade1 (weak staining, B), grade 2(clear but not so strong staining, C), grade 3 (more strong staining, D) and grade 4 (stronggest staining, E). The nuclei were counterstained with hematoxylin blue. Image magnifications are 200×.

Figure 2

Immunohistochemical staining of TFPI-2, and Ki-67, TUNEL, VEGF and CD34 in cervical tissues. Immunohistochemical staining of TFPI-2 in cervical tissues (A-D), and Ki-67 (E), TUNEL (F), VEGF (G) and CD34 (H) in ICC. The analysis showed TFPI-2 expression in normal squamous epithelial cells showed strongly positive staining for cytoplasmic(A), clear cytoplasmic staining in CIN I (B), while CIN II and III show potent staining (C), weak staining in tumor cells (D). The nuclei were counterstained with hematoxylin blue. Image magnifications are 200×.