MicroRNAs in the Tumor Biology of Soft Tissue Sarcomas

Abstract

Soft tissue sarcomas represent a rare, heterogeneous group of mesenchymal tumors. In sarcomas, histological classification, prediction of clinical behaviour and prognosis, and targeted treatment is often a challenge. A better understanding of the biology of soft tissue sarcomas is necessary to find reliable diagnostic markers, elucidate prognostic and predictive factors, and improve treatment by finding new targets for therapy. Not much is known about the involvement of microRNAs in soft tissue sarcoma biology. These evolutionarily conserved, small, non proteincoding RNA molecules can target (near-)complementary sequences in the 3’UTR of mRNA molecules, thereby inhibiting their translation into functional proteins. This thesis addresses the role of microRNAs in the tumor biology of soft tissue sarcoma. We showed that microRNAs can discriminate diverse liposarcoma subtype, lipomas and normal fat. We identified that miR-145 and miR-451 have a tumor suppressor-like function, which makes them candidates for future liposarcoma therapies. Myxoid/round cell liposarcomas showed a very distinct microRNA expression profile. Overexpression of miR-497 and miR-30a, which are regulated by the myxoid/round cell specific FUS-CHOP fusion protein, inhibited IGF1R-pathway members and sensitized myxoid liposarcoma cells to doxorubicin therapy. In gastrointestinal stromal tumors miR-17/20a/222 inhibited cell proliferation, affected the cell cycle, induced apoptosis, and inhibited the expression of KIT and ETV1, two essential oncogenes in GIST oncogenesis. This could have great implications for the treatment of (imatinib-resistant) GIST. Furthermore we demonstrated that hypoxia inducible microRNAs, miR-210 and miR-485-5p, fine-tune the expression of HIF3α in hypoxic tumor cells. In summary, we identified microRNAs that can potentially be used as diagnostic, prognostic, or predictive biomarkers in soft tissue sarcomas, or could serve as a target for therapy. These results show that microRNAs hold great potential for future management of soft tissue sarcomas.