Yonsei Med J.  2018 Jan;59(1):51-56. 10.3349/ymj.2018.59.1.51.

14-3-3ζ Overexpression is Associated with Poor Prognosis in Ovarian Cancer

• Kim HJ
• Sung SH
• Kim CY
• Bae MK
• Cho MS
• Kim YH
• Kim SC
• Ju W

• KMID: 2418848
• DOI: http://doi.org/10.3349/ymj.2018.59.1.51

Abstract

PURPOSE
14-3-3ζ regulates cell signaling, cell cycle progression, and apoptosis, and its overexpression is associated with disease recurrence and poor clinical outcomes in some solid tumors. However, its clinicopathological role in ovarian cancer is unknown. Our goal was to investigate whether 14-3-3ζ is associated with ovarian cancer prognosis.
MATERIALS AND METHODS
We examined 14-3-3ζ expression by immunohistochemistry in ovarian cancer tissues obtained from 88 ovarian cancer patients. The examined tissues were of various histologies and stages. 14-3-3ζ expression was also analyzed by western blot in seven ovarian cancer cell lines and a primary ovary epithelial cell line. Cell viability was measured using an MTS-based assay following cisplatin treatment.
RESULTS
Among the ovarian cancer samples, 53.4% (47/88) showed high 14-3-3ζ expression, and 14-3-3ζ overexpression was positively correlated with more advanced pathologic stages and grades. 14-3-3ζ overexpression was also significantly associated with poor disease-free survival (DFS) and overall survival (OS) of ovarian cancer patients. Median DFS and OS were 1088 and 3905 days, respectively, in the high 14-3-3ζ expression group, but not reached in the low 14-3-3ζ expression group (p=0.004 and p=0.033, log-rank test, respectively). Downregulating 14-3-3ζ by RNA interference in ovarian cancer cells led to enhanced sensitivity to cisplatin-induced cell death.
CONCLUSION
14-3-3ζ overexpression might be a potential prognostic biomarker for ovarian cancer, and the inhibition of 14-3-3ζ could be a therapeutic option that enhances the antitumor activity of cisplatin.

Keyword

Ovarian cancer; 14-3-3ζ; prognostic biomarker; recurrence; cisplatin

MeSH Terms

14-3-3 Proteins/*metabolism
Adult
Aged
Cell Line, Tumor
Cisplatin/therapeutic use
Disease-Free Survival
Down-Regulation
Female
Gene Knockdown Techniques
Gene Silencing
Humans
Immunohistochemistry
Middle Aged
Ovarian Neoplasms/drug therapy/*metabolism/pathology
Prognosis
Young Adult
14-3-3 Proteins
Cisplatin

Figure

• 

  Fig. 1 High 14-3-3ζ expression in ovarian cancer cell lines and tumor tissues. (A) Western blot analysis of 14-3-3ζ expression in primary ovary epithelial (HOSE2) cells and ovarian cancer cell lines. A2780-CisR and TOV21G-CisR cells are cell lines with acquired cisplatin resistance. (B) Western blot analysis of 14-3-3ζ expression in five benign ovarian tumors and nine ovarian cancer tissues. β-actin (Actin) was used as the loading control.

• 

  Fig. 2 14-3-3ζ overexpression is associated with poor DFS and OS in ovarian cancer patients. (A) Representative 14-3-3ζ immunohistochemistry staining in ovarian cancer specimens (n=88). Tumors were classified as negative (0), weakly positive (1), moderately positive (2), and strongly positive (3) for 14-3-3ζ expression (magnification, ×100). (B and C) DFS (B) and OS (C) rates of ovarian cancer patients with low (0, 1, 2) versus high (3) 14-3-3ζ expression. p-values for B and C were determined by log-rank analysis. DFS, disease-free survival; OS, overall survival.

• 

  Fig. 3 Silencing 14-3-3ζ enhances the sensitivity of ovarian cancer cells to cisplatin. (A) Establishing the stable TOV21G cell line with 14-3-3ζ knockdown. Western blot analysis of 14-3-3ζ protein levels in the indicated stable cell lines and non-infected TOV21G cells. β-actin (Actin) was used as the internal loading control; n.s. indicates a non-specific band. (B) Effects of 14-3-3ζ knockdown on cell survival in ovarian cancer cells treated with cisplatin for 72 h. Viable cells were measured using an MTS-based assay. Columns represent means of six replicate experiments; bars±standard deviation; *p<0.001.

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