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The miR-143/145 Cluster, a Novel Diagnostic Biomarker in Chondrosarcoma, Acts as a Tumor Suppressor and Directly
Joaquin Urdinez1,2, Aleksandar Boro1, Alekhya Mazumdar1,2
1Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland.
Abstract:
Chondrosarcoma is the second most frequent bone sarcoma. Due to the inherent chemotherapy and radiotherapy resistance and absence of known therapeutic targets, clinical management is limited to surgical resection. Consequently, patients with advanced disease face a poor prognosis. Hence, elucidating regulatory networks governing chondrosarcoma pathogenesis is vital for development of effective therapeutic strategies. Here, miRNA and mRNA next generation sequencing of different subtypes of human chondrogenic tumors in combination with in silico bioinformatics tools were performed with the aim to identify key molecular factors. We identified miR-143/145 cluster levels to inversely correlate with tumor grade. This deregulation was echoed in the miRNA plasma levels of patients and we provided the first evidence that circulating miR-145 is a potential noninvasive diagnostic biomarker and can be valuable as an indicator to improve the currently challenging diagnosis of cartilaginous bone tumors. Additionally, artificial upregulation of both miRNAs impelled a potent tumor suppressor effect in vitro and in vivo in an orthotopic xenograft mouse model. A combined in silico/sequencing approach revealed FSCN1 as a direct target of miR-143/145, and its depletion phenotypically resembled miR-143/145 upregulation in vitro. Last, FSCN1 is a malignancy-promoting factor associated with aggressive chondrosarcoma progression. Our findings underscore miR-143/145/FSCN1 as important players in chondrosarcoma and may potentially open new avenues for specific therapeutic intervention options. © 2020 American Society for Bone and Mineral Research.
Insights
MicroRNAs miR-143/145 show tumor suppressor roles in chondrosarcoma, a bone cancer. Circulating miR-145 may serve as a noninvasive biomarker for diagnosis and prognosis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Chondrosarcoma, a common bone sarcoma, exhibits resistance to conventional therapies, necessitating novel treatment strategies.
- Current management relies on surgery, with limited options for advanced disease, highlighting the need for understanding its pathogenesis.
- Elucidating regulatory networks is crucial for developing effective therapeutic interventions for chondrosarcoma.
Purpose of the Study:
- To identify key molecular factors and regulatory networks in chondrosarcoma pathogenesis.
- To investigate the role of miR-143/145 cluster in chondrosarcoma development and progression.
- To explore the diagnostic potential of circulating microRNAs in cartilaginous bone tumors.
Main Methods:
- Next-generation sequencing (miRNA and mRNA) of human chondrogenic tumors.
- In silico bioinformatics analysis to identify molecular interactions.
- In vitro and in vivo (orthotopic xenograft mouse model) experiments to assess miRNA function.
- Correlation analysis of miRNA expression with tumor grade and plasma levels.
Main Results:
- miR-143/145 cluster levels inversely correlate with chondrosarcoma tumor grade.
- Downregulation of miR-143/145 is observed in patient plasma, with miR-145 showing potential as a noninvasive diagnostic biomarker.
- Artificial upregulation of miR-143/145 demonstrated significant tumor suppressor effects in vitro and in vivo.
- FSCN1 identified as a direct target of miR-143/145, with FSCN1 depletion mimicking miRNA upregulation effects.
- FSCN1 acts as a malignancy-promoting factor in aggressive chondrosarcoma progression.
Conclusions:
- The miR-143/145/FSCN1 axis plays a critical role in chondrosarcoma pathogenesis.
- Circulating miR-145 represents a promising noninvasive biomarker for chondrosarcoma diagnosis.
- Targeting the miR-143/145/FSCN1 pathway offers potential therapeutic strategies for chondrosarcoma.
