Abstract
BackgroundThe extracellular matrix has been critically associated with the tumorigenesis and progression of Ewing sarcoma (ES). However, the regulatory and prognostic roles of tenascin-C (TNC) in ES remain unclear.MethodsTNC expression was examined in specimens by immunohistochemistry, and the association of TNC expression with ES patient survival was also analysed. TNC-knockout cell lines were constructed using CRISPR/Cas9 methods. In vitro experiments and in vivo bioluminescent imaging using BALB/c nude mice were conducted to evaluate the effect of TNC on ES tumour progression. RNA sequencing was performed, and the underlying mechanism of TNC was further explored.ResultsTNC was overexpressed in ES tissue and cell lines, and TNC overexpression was associated with poor survival in ES patients. TNC enhanced cell proliferation, migration and angiogenesis in vitro and promoted ES metastasis in vivo. The oncoprotein EWS-FLI1 profoundly increased TNC expression by directly binding to the TNC promoter region. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) upregulation induced by Yes-associated protein (YAP) activation was responsible for TNC-regulated ES tumour progression. Activated integrin α5β1 signalling might be correlated with YAP dephosphorylation and nuclear translocation.ConclusionsTNC may promote ES tumour progression by targeting MALAT1 through integrin α5β1-mediated YAP activation.
Highlights
The extracellular matrix has been critically associated with the tumorigenesis and progression of Ewing sarcoma (ES)
We discovered the following: (1) the expression of TNC in ES tumour tissue and cells, (2) the prognostic role of TNC in predicting ES patient survival, (3) the pro-tumorigenic role of TNC in ES cell lines and nude mice, (4) the transcriptional role of the EWS-FLI1 oncoprotein in promoting TNC expression, (5) the expression of Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in ES specimens, and (6) the connection between TNC and MALAT1 and their underlying mechanism in promoting ES tumour progression
TNC overexpression in specimens is associated with ES patient survival TNC overexpression was observed in clinical ES tissues (×10 and ×40) and compare to that in adjacent normal tissue via IHC staining (Fig. 1a)
Summary
Ewing sarcoma (ES), the second most common malignant paediatric tumour of bone and soft tissue, shows a high metastatic incidence and can occur at any age but peaks in individuals at 10–20 years old.[1,2] Despite advanced multidisciplinary treatments for ES, the estimated 2-year survival rate for all patients has remained approximately 52.4%.3 Notably, ES is identified by chromosomal translocations that encode members of the EWS-. Increasing evidence demonstrates that TNC and MALAT1 function in tumour behaviours, their connection and underlying mechanisms in regulating ES tumour progression remain to be elucidated. We discovered the following: (1) the expression of TNC in ES tumour tissue and cells, (2) the prognostic role of TNC in predicting ES patient survival, (3) the pro-tumorigenic role of TNC in ES cell lines (in vitro) and nude mice (in vivo), (4) the transcriptional role of the EWS-FLI1 oncoprotein in promoting TNC expression, (5) the expression of MALAT1 in ES specimens, and (6) the connection between TNC and MALAT1 and their underlying mechanism in promoting ES tumour progression. 1234567890();,: MALAT1 through integrin α5β1-mediated YAP activation These findings reveal that TNC may serve as a prognostic and therapeutic candidate in ES
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