The miR-143/145 Cluster, a Novel Diagnostic Biomarker in Chondrosarcoma, Acts as a Tumor Suppressor and Directly Inhibits Fascin-1

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.

Fascin actin-bundling protein 1 in human cancer: Promising biomarker or therapeutic target?

“…As shown in Figure 4, miR-145 negatively regulates FSCN1 mRNA levels in many different human cancers, including nasopharyngeal, laryngeal, esophageal, breast, lung, stomach, liver, colon, bladder, cervix, prostate, and cartilage cancers. 72,77,80,82,101,104,109,117,[156][157][158][159] miR-133a/b directly targets FSCN1 in a variety of human cancers and acts as a tumor suppressor. 87,93,158,[160][161][162][163][164] Furthermore, the FSCN1 gene has been identified as a direct target of several miRNAs, such as miR-143 in chondrosarcoma and esophageal carcinoma, 80,165 miR-24 in nasopharyngeal and prostate cancer, 106,131 miR-326 in lung and gastric cancer, 166,167 and so on (summarized in Figure 4).…”

“…72,77,80,82,101,104,109,117,[156][157][158][159] miR-133a/b directly targets FSCN1 in a variety of human cancers and acts as a tumor suppressor. 87,93,158,[160][161][162][163][164] Furthermore, the FSCN1 gene has been identified as a direct target of several miRNAs, such as miR-143 in chondrosarcoma and esophageal carcinoma, 80,165 miR-24 in nasopharyngeal and prostate cancer, 106,131 miR-326 in lung and gastric cancer, 166,167 and so on (summarized in Figure 4). All of the above-mentioned miRNAs were, however, significantly downregulated in corresponding human cancer specimens or cell lines and exerted their anti-tumor functions through a coordinated regulation of FSCN1.…”

Recent trends in targeting miRNAs for cancer therapy

“…[ 138 ] Tanaka et al using microarray technology showed the role of gastric juice‐derived exosomal hsa‐miR‐933 in functional dyspepsia. Urdinez et al [ 139 ] discovered the role of miR‐143/145 in chondrosarcoma as diagnostic biomarker.…”

Exploring the Role of Osteosarcoma-Derived Extracellular Vesicles in Pre-Metastatic Niche Formation and Metastasis in the 143-B Xenograft Mouse Osteosarcoma Model

“…RNA isolation and analysis were performed, as described previously [57]. Briefly, lung tissue from tumor-bearing mice at day 12 (n = 6; T1-T6) and PBS injected control mice at day 12 (n = 4; PBS1-PBS4) were either snap-frozen directly in liquid nitrogen or embedded in OCT (81-0771-00, Biosystems AG, Muttenz, Switzerland) and then snap-frozen on dry ice.…”