Overexpression of a secretory leukocyte protease inhibitor in human gastric cancer

Abstract

Complementary DNA microarrays have identified aberrantly expressed genes in patients with gastric cancer. One that encodes secretory leukocyte protease inhibitor (SLPI) is among the aberrantly expressed genes and is associated with metastasis in gastric cancers. We evaluated the potential of SLPI expression as a helpful biomarker for detection of gastric cancer. Tumor tissue and matching noncancerous mucosa were obtained from 60 patients immediately after gastric resection. SLPI expression levels were determined by Northern and Western blot tests and quantitativereverse transcriptase-polymerase chain reaction (Q-RT-PCR). Paraffin-fixed tumor tissues were used for immunohistochemistry study in 119 patients. A consistent result was obtained between all examinations except plasma SLPI. SLPI mRNA transcripts and protein were overexpressed in gastric cancer cells, and the depth of wall invasion was significantly greater in serosa-invading (T3 and T4) cancers compared to the serosa-free (T1 and T2) cancers. These enhanced expressions were significantly associated with lymph node metastasis, and were significantly higher in stages III and IV, and higher than those in stages I and II. Five-year survival of patients with lower expression of the SLPI gene was significantly better than among patients with a higher expression. To better understand the function of SLPI in human gastric cancer cells, isogenic SLPI overexpressing cell lines (AZ521) were prepared. The migratory and invasive abilities were increased 4.4-fold to 6.9-fold, or 3.0-fold to 4.1-fold, respectively, in SLPI-overexpressing cell lines. The results point to SLPI as a potential prognostic marker for gastric cancer and its function in cell invasion. ' 2008 Wiley-Liss, Inc.Key words: gastrointestinal neoplasms; SLPI protein, human; reverse transcriptase polymerase chain reaction; tumor markers Gastric cancer is the second most common cancer in the world. It is the fifth leading cause of cancer-related deaths in Taiwan 1 and, despite a declining incidence, it is similarly serious in Western countries. 2 Surgery is the only cure for gastric cancer; however, curative resection is not feasible for the many patients whose cancer is too far advanced when detected. 3 To improve the poor survival outcome and permit earlier diagnosis, there is a need for new and more sensitive prognostic indicators or tumor markers than those currently available, such as carcinoembryonic antigen and CA19-9. 4 Gastric cancer is divided into 2 histomorphologic types, ''intestinal-differentiated'' and ''diffuse-undifferentiated.'' 5,6 However, similar lesions may differ in biological aggressiveness and response to therapy. 7 The molecular events involved in development and progression of gastric cancer are complex, and involve multiple genes and steps that operate sequentially or in concert. 6 Risk factors for gastric cancer include genetic alterations, chromosomal instability and infection caused by the bacterium Helicobacter pylori. 8,9 Numerous biomarkers have contributed to our kn...

Glucose‐regulated protein 58 modulates cell invasiveness and serves as a prognostic marker for cervical cancer

“…Many of these genes are involved in the processes of tumor invasion and progression. CD24, (38) LAMB3, (39) S100A4, (40,41) S100A10 (42) and SLPI (9) are overexpressed in various types of tumor to augment cell invasiveness. Conversely, IGFBP7 is downregulated in melanoma, colon cancer and thyroid carcinoma, and restoration of IGFBP7 expression reduces the migration ability of cells.…”

“…Western blot analysis was performed as described previously. (9) Grp58-specific first antibody (1:10 000 dilution, Atlas; Sigma-Aldrich, St Louis, MO, USA) and horseradish peroxidase-conjugated, affinity-purified second antibody to rabbit (Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA) were used. The immunocomplexes were visualized by chemiluminescence with an ECL detection kit (Amersham, Piscataway, NJ, USA).…”

“…The migration and invasion activity of cells was examined using the Transwell migration assay (CorningCostar 3494 Transwell, Lowell, MA, USA) as described previously. (9) Xenograft mouse model. HeLa stable cells were harvested and washed twice with PBS.…”

Secretory leukocyte protease inhibitor is associated with MMP-2 and MMP-9 to promote migration and invasion in SNU638 gastric cancer cells

“…Moreover, the blood concentration of SLPI is high in ovarian cancer compared to normal ovaries or benign ovarian tumors, and is particularly high in malignant tumors with a high metastatic potential (22). SLPI mRNA is overexpressed in serosa invading gastric cancer cells, and the cell migration and invasion rate was significantly increased in AZ521 cells, a SLPI overexpressing gastric cancer cell line (16). In the present study, SLPI mRNA and protein expression in SNU638 cells, which have higher metastatic potential than SNU484 cells, was higher than in SNU484 cells.…”

“…The secretion of MMP-2 and MMP-9 in the skin wound tissue of SLPI null mice was higher than that in normal mice (15). The migration and invasion rate in the AZ521 gastric cancer cell line was increased strongly by the overexpression of SLPI (16). MMP-2 and MMP-9 are expressed strongly in gastric cancer tissue compared to normal tissue (17).…”