Serine Protease Inhibitor Kazal Type 1 (SPINK1) Drives Proliferation and Anoikis Resistance in a Subset of Ovarian Cancers

Oncotarget. 2015 Nov 3;6(34):35737-54. doi: 10.18632/oncotarget.5927.

Abstract

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.

Keywords: EGFR; SPINK1; anoikis; ovarian cancer; serine protease inhibitor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • ErbB Receptors / metabolism*
  • Female
  • Humans
  • Middle Aged
  • Molecular Targeted Therapy
  • Ovarian Neoplasms / diagnosis*
  • Ovarian Neoplasms / mortality
  • Prognosis
  • RNA, Small Interfering / genetics
  • Signal Transduction / genetics
  • Survival Analysis
  • Trypsin Inhibitor, Kazal Pancreatic
  • Young Adult

Substances

  • Biomarkers, Tumor
  • Carrier Proteins
  • RNA, Small Interfering
  • SPINK1 protein, human
  • Trypsin Inhibitor, Kazal Pancreatic
  • EGFR protein, human
  • ErbB Receptors