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Unraveling the distinct role of MICAL2 in skeletal muscle physiology and rhabdomyosarcoma tumor progression

ABSTRACT: Rhabdomyosarcoma (RMS) is a prevalent soft tissue sarcoma in pediatric populations, characterized by dysregulated myogenesis and limited treatment options. MICAL2, a protein implicated in cancer progression, has emerged as a potential therapeutic target due to its role in modulating cellular behaviors, including proliferation and migration. However, its involvement in RMS pathogenesis and therapeutic potential remains unclear. In this study, we investigated the role of MICAL2 in RMS progression using in vitro and in vivo models, revealing elevated MICAL2 expression in RMS cell lines compared to healthy counterparts. Knockdown (KD) of MICAL2 using plasmid constructs resulted in reduced proliferation and migration of RMS cells and a significant decrease in metabolic activity in MICAL2-silenced RMS cells was demonstrated. Moreover, in vivo experiments using a TET-ON cassette for silencing MICAL2 in tumor-bearing mice showed that MICAL2 knockdown attenuated primary tumor growth and inhibited metastasis formation, as confirmed by bioluminescence imaging and histological analyses, while also improving ambulation performance. RNA-seq and mass spectrometry analyses further highlighted the molecular changes associated with MICAL2 knockdown, including downregulation of genes involved in proliferation and migration, and upregulation of genes related to muscle function. Taken together, our findings highlight the potential of MICAL2 as a therapeutic target for inhibiting RMS progression. By elucidating the molecular mechanisms underlying MICAL2-mediated effects on proliferation, migration, and metastasis, this study contributes to the understanding of RMS pathogenesis and identifies MICAL2 as a promising candidate for targeted therapy. Further research is foreseen to explore the therapeutic efficacy of MICAL2 inhibition in clinical settings and to elucidate its precise mechanisms of action in RMS.

ORGANISM(S): Mus musculus

PROVIDER: GSE278087 | GEO | 2026/09/24

REPOSITORIES: GEO

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Project description:We have recently reported the down-regulation of pannexin 1 (PANX1) levels in rhabdomyosarcoma (RMS) and that restoration of its expression inhibits the progression of embryonal (eRMS) and alveolar (aRMS) rhabdomyosarcoma in vitro and in vivo. While we have shown that this PANX1-mediated inhibition of RMS progression involves reduction of cell proliferation and migration, as well as induction of apoptosis, the underlining molecular mechanisms at play remained to be elucidated. In the present study, using RNA sequencing (RNA-seq) combined with DAVID analysis, we identified the PANX1 interactome in RMS cells and showed that the Gene Ontology (GO) terms such as apoptosis and migration, and KEGG pathways such as MAPK and Rap1 Signaling pathways were amongst the most highly enriched processes in Rh30 (aRMS) cells expressing ectopic PANX1. We then used a proximity-dependent labeling approach (BioID) to screen for the PANX1 interactors in RMS cells, which was complemented by co-immunoprecipitation (co-IP) coupled to high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) performed using Myc-PANX1-enriched subcellular fractions. STRING protein network analyses of the overlapping hits from these two approaches revealed a PANX1 interactome with plasma membrane and cytoskeleton associated proteins from which ACTB and AHNAK were further validated by co-IP using whole cell lysates followed by Western blotting analysis. Using this new and comprehensive information, we have generated the first online PANX1 transcriptome and interactome databases that allow searching, in a user-friendly manner, for PANX1-regulated genes and PANX1 interactors. Moreover, AHNAK knockdown in PANX1-expressing Rh18 (eRMS) and Rh30 (aRMS) significantly abrogated the PANX1-mediated reduction in cell viability and migration, as well as the PANX1-mediated sensitivity to anoikis. Using a combination of genome-wide unbiased approaches, this study is thus the first to identify the PANX1 transcriptome and interactome, providing the research community with online searchable databases to access the PANX1-regulated genes and PANX1 interacting partners. We have shown that PANX1 interacts with AHNAK and that this interaction is critical to the PANX1-mediated inhibition of RMS cell viability and migration, and induction of apoptosis; thus demonstrating how this new information can be used to identify key members of the PANX1 signaling pathway and their relevance to PANX1 function.

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Unraveling the distinct role of MICAL2 in skeletal muscle physiology and rhabdomyosarcoma tumor progression

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