The miR-34 family and its clinical significance in ovarian cancer

Abstract

The tumor suppressor miR-34 family is transcriptionally induced by p53. Clinical significance of the various miR-34 family members has not been studied in ovarian cancer. In 228 ovarian cancers and in 19 non-neoplastic fallopian tube samples we analysed miR-34 a/b/c expression in relation to clinicopathological characteristics and clinical outcome. We found significantly lower levels of miR-34 a/b/c in ovarian cancers as compared to control-tissues (P=0.002, P<0.001, P<0.001, respectively). Expression of miR-34 b/c revealed an inverse correlation with BRCA1/2 mRNA-expression (BRCA1: miR34 b/c P=0.002 each; BRCA2: miR-34 b/c P<0.001 each), the same was true for miR-34a and BRCA2 mRNA-expression (P<0.001). The miR-34 family expression was found to be significantly lower in type 2 in comparison to type 1 cancers (P<0.001) and in TP53-mutated compared with TP53-wild-type ovarian cancers (P<0.001, P=0.002, P=0.004, respectively). When low grade serous ovarian cancers were compared with high grade serous cancers the respective miR-34 a/b/c expression was 2.6-, 40.8- and 32.3-fold higher. The expression of each of the miR-34 family members was revealed to be of independent prognostic relevance regarding progression free survival (PFS); miR-34a: HR 0.6, P=0.033; miR-34b: HR 0.2, P=0.001 and miR-34c: HR 0.3, P=0.002, respectively). For overall survival (OS) independency of the prognostic value was confined to miR-34b (HR 0.4, P=0.016) and miR-34c (HR 0.6, P=0.049). The independency of the prognostic value of our identified thresholds was confirmed for PFS for miR-34c in a publicly available dataset (NCBI Gene Expression Omnibus GSE73582). Our findings suggest that downregulation of miR-34 family is a crucial part in ovarian cancer development. Low miR-34 levels are linked to a worse overall survival and progression free survival and may indicate a more aggressive disease.

Keywords: carcinogenesis; miR-34; ovarian cancer; p53; survival.

Figure 1

Correlation analysis in the miR-34 family. Linear regression analysis of (A) miR-34a and miR-34b expression, (B) miR-34a and miR-34c expression, (C) miR-34b and miR-34c expression. mRNA expression values were normalized to TATA box binding protein (TBP) expression.

Figure 2

Correlation analysis of miR-34 a/b/c and BRCA1/2 mRNA expression. MiR-34 expression and (A) BRCA1 mRNA and (B) BRCA2 mRNA expression. mRNA expression values were normalized to TBP expression.

Figure 3

Kaplan Meier survival analysis and miR-34 a/b/c mRNA-expression in 228 OC patients. Progression free survival and (A) miR-34a expression, (B) miR-34b expression, (C) miR-34c expression. Overall survival and (D) miR-34a expression, (E) miR34b expression, (F) miR-34c expression. Cut-off points: miR-34a expression: low/ high: </>60^th percentile; miR-34b expression: low/ high: </>86^th percentile, miR-34c expression: low/ high: </>80^th percentile.