Upregulation of miR181a/miR212 Improves Myogenic Commitment in Murine Fusion-Negative Rhabdomyosarcoma.

Enrico Pozzo,Maurilio Sampaolesi,Theo Killian,Chao-Chi Wang,Vittoria Marini,Flavio Ronzoni,Nefele Giarratana,Gabriele Sassi,Merve Elmastas,Jason Yustein,Anne Uyttebroeck

doi:10.3389/fphys.2021.701354

Abstract

Fusion-negative rhabdomyosarcoma (FN-RMS) is the most common soft tissue sarcoma of childhood arising from undifferentiated skeletal muscle cells from uncertain origin. Currently used therapies are poorly tumor-specific and fail to tackle the molecular machinery underlying the tumorigenicity and uncontrolled proliferation of FN-RMS. We and other groups recently found that microRNAs (miRNA) network contributes to myogenic epigenetic memory and can influence pluripotent stem cell commitments. Here, we used the previously identified promyogenic miRNAs and tailored it to the murine FN-RMS. Subsequently, we addressed the effects of miRNAs in vivo by performing syngeneic transplant of pre-treated FN-RMS cell line in C57Bl/6 mice. miRNA pre-treatment affects murine FN-RMS cell proliferation in vivo as showed by bioluminescence imaging analysis, resulting in better muscle performances as highlighted by treadmill exhaustion tests. In conclusion, in our study we identified a novel miRNA combination tackling the anti-myogenic features of FN-RMS by reducing proliferation and described novel antitumorigenic therapeutic targets that can be further explored for future pre-clinical applications.

Highlights

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma occurring in the pediatric population, accounting for ∼5% of all pediatric malignancies, and the overall event-free survival is less than 20% in patients with metastatic disease (Chen et al, 2019)
80% of alveolar RMS (ARMS) present the chimeric proteins encoded from the fusion of PAX3 or PAX7 with FOXO1, while 20% are similar to embryonal RMS (ERMS) in terms of clinical outcome (Skapek et al, 2019)
The discrepancy with respect to the number of genes shown to be downregulated compared to the upregulated ones can be sought in the hypermethylation status that characterizes Fusion-negative rhabdomyosarcoma (FN-RMS), as previously described (Mahoney et al, 2012), which leads to the chromatin closure and subsequent reduced expression of several genes

Summary

Introduction

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma occurring in the pediatric population, accounting for ∼5% of all pediatric malignancies, and the overall event-free survival is less than 20% in patients with metastatic disease (Chen et al, 2019). 80% of ARMS present the chimeric proteins encoded from the fusion of PAX3 or PAX7 with FOXO1, while 20% are similar to ERMS in terms of clinical outcome (Skapek et al, 2019). Current treatment regimens include multimodality therapy involving surgery, high-dose chemotherapy and radiotherapy to resect the tumor, achieve remission and guarantee local control (Koscielniak et al, 1999). These therapeutic approaches fail to restore the myogenic propensity of FN-RMS and the persistence of chemoresistant cancer cells in the tumor are pushing research for the development of new therapies including the use of microRNAs (miRNAs). Growing evidence is suggesting that miRNA loss-of-function can cause the progression of cancer, miRNA replacement therapies have emerged as promising treatment strategies for malignant neoplasms (Bonci et al, 2008; Esposito et al, 2014)

Methods

Results

Conclusion