Abstract
Simple SummaryRhabdomyosarcoma (RMS) is a soft tissue sarcoma with embryonal (ERMS) and alveoral (ARMS) features, most frequently found in children. ARMS has the worse prognosis due to the formation of the chimeric PAX3–FOXO1 gene. New therapies are needed for the treatment of ARMS. The aim of this study is to evaluate the anticancer effect of chemically-modified MIR143-3p#12 (CM-MIR143#12) on RMS. The ectopic expression of CM-MIR143#12 induced a cell growth suppression by silencing not only KRAS, AKT, and ERK but also the PAX3–FOXO1 chimeric gene, and KRAS networks could control the expression of chimeric PAX3–FOXO1 in ARMS cells. Moreover, CM-MIR143#12 also silenced NRAS mutant in ERMS RD cells. CM-MIR143#12 can be a new nucleic acid medicine for the treatment of RMS by impairing the RAS networks including PAX3–FOXO1.Rhabdomyosarcoma (RMS) is a soft tissue sarcoma most frequently found in children. In RMS, there are two major subtypes, embryonal RMS (ERMS) and alveolar RMS (ARMS). ARMS has the worse prognosis of the two owing to the formation of the chimeric PAX3–FOXO1 gene. A novel therapeutic method is required for treating ARMS. In our previous study, we found that the ectopic expression of chemically modified MIR143-3p#12 (CM-MIR143#12), which is RNase-resistant and shows the highest anti-proliferation activity among the synthesized MIR143 derivatives that were tested, induces significant cell growth suppression by targeting KRAS, AKT, and ERK in colorectal cancer cells. The expression of MIR143-3p in RMS was dramatically downregulated compared with that of normal tissue. Ectopic expression of CM-MIR143#12 in RMS cells resulted in a significant growth inhibitory effect through the induction of apoptosis and autophagy. Interestingly, we found that CM-MIR143#12 also silenced the expression of chimeric PAX3–FOXO1 directly and, using siR-KRAS or siR-AKT, that KRAS networks regulated the expression of PAX3–FOXO1 in ARMS cells. In ERMS harboring NRAS mutation, CM-MIR143#12 silenced mutated NRAS. These findings indicate that CM-MIR143#12 efficiently perturbed the RAS signaling pathway, including the ARMS-specific KRAS/PAX3–FOXO1 networks.
Highlights
Rhabdomyosarcoma (RMS) is a soft tissue malignant tumor that develops with the highest frequency in childhood
We recently reported that the ectopic expression of the chemically modified MIR143-3p#12 (CM-MIR143#12) induces significant inhibition of cancer cell growth through the targeting of KRAS, AKT, and ERK in colorectal [35], bladder [36], and gastric cancer cells [37]
We found that CM-MIR143#12 silenced the PAX3–FOXO1 chimeric gene, and that KRAS networks could control the expression of chimeric PAX3–FOXO1 in alveolar RMS (ARMS) cells
Summary
Rhabdomyosarcoma (RMS) is a soft tissue malignant tumor that develops with the highest frequency in childhood. Cancers 2020, 12, 3312 t(2;13)(q35;q14) or t(1;13)(q35;q14), which results in the formation of the characteristic chimeric gene through the fusion of PAX3 or PAX7 with FOXO1 that is involved in the pathogenesis of ARMS [3,4,5,6]. It was reported that 40% of clinical ERMS samples have mutations in genes of the FGFR4/RAS pathway [8,9]. It was reported that mutations of RAS were found in 22.4% of fusion-negative RMS cases (NRAS, 11.7%; KRAS, 6.4%; HRAS, 4.3%) [8]. RMS cell lines harboring RAS mutation were strongly dependent on the RAS/RAF/MEK pathway. The phenotype of non-mutated RAS in RMS cells depends on other pathways such as PAX3–FOXO1/FGFR4 [10] and PI3K/AKT/mTOR [11]. A novel therapeutic method that systemically inactivates these pathways is required for the treatment of RMS [12,13]
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