Tumor necrosis factor receptor modulator spermatogenesis-associated protein 2 is a novel predictor of outcome in ovarian cancer

Cancer Sci. 2019 Mar;110(3):1117-1126. doi: 10.1111/cas.13955. Epub 2019 Feb 16.

Abstract

Inflammation plays a crucial role in the pathogenesis of cancer with tumor necrosis factor-α (TNF-α) as a key mediator. Recently, spermatogenesis-associated protein 2 (SPATA2) was identified as a TNF receptor modulator which is required for TNF-induced inflammation and apoptosis. The available data on TNF-α in ovarian cancer (OC) are inconsistent, and SPATA2 is completely uncharacterized in tumorigenesis. We analyzed expression of SPATA2 and TNFA by quantitative real-time polymerase chain reaction in tissues of 171 patients with low-grade serous (LGSOC), high-grade serous (HGSOC), endometrioid and clear cell OC compared with 28 non-malignant control tissues. We stimulated OC cells (OVCAR3) with pro-inflammatory (TNF-α, interleukin [IL]-1β) and mitogenic stimuli (IL-6, lysophosphatidic acid) to establish a direct effect between inflammatory signaling and SPATA2. Pro-inflammatory, but not mitogenic stimuli, potently induced SPATA2 expression in OC cells. Expression of TNFA and SPATA2 was higher in OC compared with control tissues (P = 0.010 and P = 0.001, respectively) and correlated with each other (P = 0.034, rs = 0.198). When compared with grade 1 cancers, SPATA2 was expressed higher in grade 2 and 3 tumors (P = 0.011) as well as in HGSOC compared with LGSOC (P = 0.024). Multivariate survival analyses revealed that OC with high SPATA2 expression were associated with reduced progression-free survival (P = 0.048) and overall survival (P < 0.001). In conclusion, SPATA2 expression is regulated by TNF-α and IL-1β and is found to independently affect clinical outcome in OC patients. These data implicate a role of SPATA2 in tumorigenesis which warrants further investigation in gynecological malignancies.

Keywords: inflammation; ovarian cancer; spermatogenesis-associated protein 2; tumor necrosis factor-α; tumorigenesis.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Carcinogenesis / metabolism
  • Female
  • Humans
  • Interleukin-1beta / metabolism
  • Middle Aged
  • Ovarian Neoplasms / metabolism*
  • Progression-Free Survival
  • Proteins / metabolism*
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Spermatogenesis / physiology*
  • Tumor Necrosis Factor-alpha / metabolism
  • Young Adult

Substances

  • Interleukin-1beta
  • Proteins
  • Receptors, Tumor Necrosis Factor
  • SPATA2 protein, human
  • Tumor Necrosis Factor-alpha

Associated data

  • GENBANK/NM_001135773.1