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 (<i>P</i>=0.002, <i>P</i><0.001, <i>P</i><0.001, respectively). Expression of miR-34 b/c revealed an inverse correlation with <i>BRCA1/2</i> mRNA-expression (BRCA1: miR34 b/c <i>P</i>=0.002 each; BRCA2: miR-34 b/c P<0.001 each), the same was true for miR-34a and <i>BRCA2</i> mRNA-expression (<i>P</i><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 <i>TP53</i>-mutated compared with <i>TP53</i>-wild-type ovarian cancers (<i>P</i><0.001, <i>P</i>=0.002, <i>P</i>=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, <i>P</i>=0.033; miR-34b: HR 0.2, <i>P</i>=0.001 and miR-34c: HR 0.3, <i>P</i>=0.002, respectively). For overall survival (OS) independency of the prognostic value was confined to miR-34b (HR 0.4, <i>P</i>=0.016) and miR-34c (HR 0.6, <i>P</i>=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.