Serine protease inhibitor Kazal type 1 (SPINK1) drives proliferation and anoikis resistance in a subset of ovarian cancers

Ovarian cancer represents the most lethal tumor type among malignancies of the female reproductive system. Overall survival rates remain low. In this study, we identify the serine protease inhibitor Kazal type 1 (SPINK1) as a potential therapeutic target for a subset of ovarian cancers. We show that...

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Bibliographic Details
Published in:Oncotarget 2015-11, Vol.6 (34), p.35737-35754
Main Authors: Mehner, Christine, Oberg, Ann L, Kalli, Kimberly R, Nassar, Aziza, Hockla, Alexandra, Pendlebury, Devon, Cichon, Magdalena A, Goergen, Krista M, Maurer, Matthew J, Goode, Ellen L, Keeney, Gary L, Jatoi, Aminah, Sahin-Tóth, Miklós, Copland, John A, Radisky, Derek C, Radisky, Evette S
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Anoikis - genetics
Biomarkers, Tumor - metabolism
Carcinoma, Endometrioid - diagnosis
Carcinoma, Endometrioid - mortality
Carrier Proteins - genetics
Carrier Proteins - metabolism
Cell Line, Tumor
Cell Proliferation - genetics
Female
Humans
Middle Aged
Molecular Targeted Therapy
Ovarian Neoplasms - diagnosis
Ovarian Neoplasms - mortality
Prognosis
Receptor, Epidermal Growth Factor - metabolism
Research Paper
RNA, Small Interfering - genetics
Signal Transduction - genetics
Survival Analysis
Trypsin Inhibitor, Kazal Pancreatic
Young Adult
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Summary:Ovarian cancer represents the most lethal tumor type among malignancies of the female reproductive system. Overall survival rates remain low. In this study, we identify the serine protease inhibitor Kazal type 1 (SPINK1) as a potential therapeutic target for a subset of ovarian cancers. We show that SPINK1 drives ovarian cancer cell proliferation through activation of epidermal growth factor receptor (EGFR) signaling, and that SPINK1 promotes resistance to anoikis through a distinct mechanism involving protease inhibition. In analyses of ovarian tumor specimens from a Mayo Clinic cohort of 490 patients, we further find that SPINK1 immunostaining represents an independent prognostic factor for poor survival, with the strongest association in patients with nonserous histological tumor subtypes (endometrioid, clear cell, and mucinous). This study provides novel insight into the fundamental processes underlying ovarian cancer progression, and also suggests new avenues for development of molecularly targeted therapies.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.5927