J Cancer 2020; 11(6):1446-1456. doi:10.7150/jca.33831

Research Paper

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

Hannah Welponer1, Irina Tsibulak1, Verena Wieser1, Christine Degasper1, Giridhar Shivalingaiah2#, Sören Wenzel2, Susanne Sprung3, Christian Marth1, Hubert Hackl4, Heidelinde Fiegl1*✉, Alain G. Zeimet1*✉

1. Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Tyrol, 6020, Austria
2. Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Tyrol, 6020, Austria.
3. Institute of Pathology, Medical University of Innsbruck, Innsbruck, Tyrol, 6020, Austria.
4. Biocenter, Division of Bioinformatics, Medical University of Innsbruck, Innsbruck, Tyrol, 6020, Austria.
#Present address: Novartis - Global Drug Development Regulatory Affairs CMC, Sandoz GmbH, Langkampfen, Tyrol, 6336, Austria.
* These authors contributed equally to this work

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Welponer H, Tsibulak I, Wieser V, Degasper C, Shivalingaiah G, Wenzel S, Sprung S, Marth C, Hackl H, Fiegl H, Zeimet AG. The miR-34 family and its clinical significance in ovarian cancer. J Cancer 2020; 11(6):1446-1456. doi:10.7150/jca.33831. Available from https://www.jcancer.org/v11p1446.htm

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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: ovarian cancer, miR-34, p53, survival, carcinogenesis