Potential microRNA-related Targets for Therapeutic Intervention with Ovarian Cancer Metastasis

Abstract

Treatment of disseminated epithelial ovarian cancer (EOC) is an unmet medical need. Therefore, the identification along with preclinical and clinical validation of new targets is an issue of high importance. In this review we focus on microRNAs that mediate metastasis of EOC. We summarize up-regulated metastasis-promoting and down-regulated metastasis-suppressing microRNAs. We focus on preclinical in vitro and in vivo functions as well as their metastasis-related clinical correlations. Finally, we outline modalities for therapeutic intervention and critical issues of microRNA-based therapeutics in the context of metastatic EOC.

Keywords: Antisense oligonucleotides; ascites fluid; epithelial mesenchymal transition; epithelial ovarian cancer; extracellular matrix; locked nucleic acids; mesothelial cells; peritoneal dissemination; review.

Figure 1. The role of microRNAs -182, -205, -141 and -194 as mediators of migration and metastasis in ovarian carcinoma. Pathways leading to migration and metastasis of ovarian carcinoma activated by individual miRs are indicated. BRCA1, Breast cancer antigen1; EGFR-P, phosphorylated epidermal growth factor; HER2-P, phosphorylated human epidermal growth factor 2; HMGA2, high mobility group AT-hook 2; KLF12, krüppellike factor 12; MMTS1, metastasis suppressor 1; PIP2, phosphatidyl-inositol 4,5 biphosphate; PIP3, phosphatidyl-inositol 3,4,5 triphosphate; PI3K, phosphoinositide-3 kinase; PTEN, phosphatase and tensin homolog; PTPN12, tyrosine phosphatase non-receptor 12; RhoA, ras homolog A; SMAD4, suppressor of mothers against decapentaplegic 4; Sp1, transcription factor Sp1, XIAP, X-linked inhibitor of apoptosis.

Figure 2. miRs -92a, -708 and -6126 inhibit integrin-related pathways of metastases in ovarian cancer. The pathways outlined lead to inhibition of FAK and actin remodeling. a5, Alpha5, integrin subunit; b1, beta1, integrin subunit; FAK-P, phosphorylated fokal adhesion kinase; FN, fibronectin; Rap 1B, ras-related protein-1B.

Figure 3. miRs -138 and -199 are down-regulated in ovarian cancer and target pro-metastatic genes. miR-138 and -199 related pathways leading to invasion and metastasis of ovarian carcinoma are shown. EGFR, Epidermal growth factor receptor; HIF-1α, hypoxia-inducible factor 1α; HIF- 2β, hypoxia-inducible factor 2β; IKKβ, Iĸ kinaseβ; LOX, lysyl-oxidase; MAPK, mitogen-activated protein kinase; MET, MET tyrosine receptor kinase; MyD88, myeloid differentiation factor 88; NFĸB, nuclear factor ĸB; PI3K, phosphoinosite-3-kinase; slug, transcription factor slug; SOX4, SRY-box4; TLR, toll-like receptor.

Figure 4. Mode of action of anti-metastatic miR-145. P70-6SK phosphorylates TTP leading to dissociation of the TTP-DICER complex resulting in processing and activation of miR-145 by DICER. DICER, Microprocessor complex; PI3K, phosphoinosite 3-kinase; p70-S6K, p70 S6 kinase; SOX9, SRY-box 9; TTP-P, phosphorylated tristetraprolin; Twist, transcription factor Twist.

Figure 5. miR-s -214 and -448 inhibit chemokines mediating angiogenesis and invasion of ovarian carcinoma cells. miR-448 inhibits CXCL12. miR-214 down-regulates CCL5 and is decreased in CAFs after their interaction with ovarian cancer cells. CAF, Cancerassociated fibroblast;

Figure 6. Further miRs and their targets involved in modulation of invasion and metastasis of ovarian cancer. The oval circle represents an ovarian carcinoma cell. AXL, Transmembrane tyrosine kinase AXL; EGFR, epidermal growth factor receptor; KPNA2, karyopherin; lncRNA, long non-coding RNA; MMP 7,14, matrix metalloproteinase 7, 14; NFĸB, nuclear factor ĸB; PRKD, protein kinase C delta; RAB 5,22, RAB family GTPase 5,22, S1PR1, shingosine-1-phosphate-receptor; UCA-1, urothelial cancer associated-1; uPA, urokinase plasminogen activator; YAP, yes-associated protein.

Figure 7. Steady-state levels of selected miRs in ovarian cancer. Log2 normalized expression counts as derived by small RNA sequencing from the ovarian carcinoma cohort from TCGA are displayed. This cohort comprises data from 453 tumor patients. No matched normal samples are provided. The red line indicates a count of 100 normalized reads and separates very low from higher expression levels. Data are shown as box plots.