TY - JOUR
T1 - Paracrine SLPI secretion upregulates MMP-9 transcription and secretion in ovarian cancer cells
AU - Hoskins, Ebony
AU - Rodriguez-Canales, Jaime
AU - Hewitt, Stephen M.
AU - Elmasri, Wafic
AU - Han, Jasmine
AU - Han, Shing
AU - Davidson, Ben
AU - Kohn, Elise C.
N1 - Funding Information:
The authors thank Mr. Tim Clair for his guidance and collaboration. This research was supported by the Intramural Research Program of the NIH , National Cancer Institute , Center for Cancer Research , and by grants from the Norwegian Cancer Society and the Health Region of South-Eastern Norway (BD) .
PY - 2011/9
Y1 - 2011/9
N2 - Objectives: Secretory leukocyte protease inhibitor (SLPI) is amplified in serous ovarian cancer. We have dissected its function, showing it is a survival factor for ovarian cancer and promotes tumorigenesis and paclitaxel-resistance. We hypothesized that the protease inhibitory function was responsible for modulating SLPI's invasive capacity. Methods: Stable HEYA8 ovarian cancer transfectants expressing vector, wild type SLPI, and protease inhibitor null (F-)SLPI were examined in vitro and in xenografts. Invasion, enzyme activity, and MMP production and function assays were applied. SLPI and MMP immunoexpression was graded on tissue microarray and clinical samples. Statistical comparisons used unpaired t test and ANOVA, where appropriate. Results: SLPI and F-SLPI cells caused greater parenchymal and peritoneal dissemination over control cells in xenografts and invasion assays (p < 0.001). MMP-9 protease activity was increased in SLPI and F-SLPI cells over control. SLPI, but not F-SLPI, inhibited plasmin activity, necessary for MMP-9 activation and release, and inhibited activation of MMP-9. However, paradoxically, both induced quantitative MMP-9 transcription (p < 0.05) and protein (p < 0.008), yielding an increased net MMP-9 activity in the face of plasmin inhibition. SLPI and MMP-9 expression were strongly correlated in serous ovarian cancers (r2 = 0.986) and a set of ovarian cancers (p < 0.02). SLPI expression was greater in serous than endometrioid ovarian cancers (p = 0.04). Conclusions: SLPI stimulates ovarian cancer invasion, modulated in part by its serine protease inhibitory activity attenuating MMP-9 release. However, SLPI induction of MMP-9, independent of protease inhibition activity, is greater yielding a net pro-invasive behavior. These findings further support SLPI as a molecular target for ovarian cancer.
AB - Objectives: Secretory leukocyte protease inhibitor (SLPI) is amplified in serous ovarian cancer. We have dissected its function, showing it is a survival factor for ovarian cancer and promotes tumorigenesis and paclitaxel-resistance. We hypothesized that the protease inhibitory function was responsible for modulating SLPI's invasive capacity. Methods: Stable HEYA8 ovarian cancer transfectants expressing vector, wild type SLPI, and protease inhibitor null (F-)SLPI were examined in vitro and in xenografts. Invasion, enzyme activity, and MMP production and function assays were applied. SLPI and MMP immunoexpression was graded on tissue microarray and clinical samples. Statistical comparisons used unpaired t test and ANOVA, where appropriate. Results: SLPI and F-SLPI cells caused greater parenchymal and peritoneal dissemination over control cells in xenografts and invasion assays (p < 0.001). MMP-9 protease activity was increased in SLPI and F-SLPI cells over control. SLPI, but not F-SLPI, inhibited plasmin activity, necessary for MMP-9 activation and release, and inhibited activation of MMP-9. However, paradoxically, both induced quantitative MMP-9 transcription (p < 0.05) and protein (p < 0.008), yielding an increased net MMP-9 activity in the face of plasmin inhibition. SLPI and MMP-9 expression were strongly correlated in serous ovarian cancers (r2 = 0.986) and a set of ovarian cancers (p < 0.02). SLPI expression was greater in serous than endometrioid ovarian cancers (p = 0.04). Conclusions: SLPI stimulates ovarian cancer invasion, modulated in part by its serine protease inhibitory activity attenuating MMP-9 release. However, SLPI induction of MMP-9, independent of protease inhibition activity, is greater yielding a net pro-invasive behavior. These findings further support SLPI as a molecular target for ovarian cancer.
KW - MMP-9
KW - Metalloproteinase
KW - Ovarian cancer
KW - SLPI
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U2 - 10.1016/j.ygyno.2011.04.052
DO - 10.1016/j.ygyno.2011.04.052
M3 - Article
C2 - 21676452
AN - SCOPUS:80051548874
SN - 0090-8258
VL - 122
SP - 656
EP - 662
JO - Gynecologic oncology
JF - Gynecologic oncology
IS - 3
ER -