Altered Expressions of NF1 and NF1-Related microRNAs as Biomarkers in the Diagnosis of Undifferentiated Pleomorphic Sarcoma

Abstract

Objective: Undifferentiated pleomorphic sarcoma (UPS) is a highly malignant, aggressive, and pleomorphic subtype of soft tissue sarcoma in adults. However, UPS is difficult to be diagnosed due to the lack of specific morphological and immunophenotypic features. Here, we aimed to identify new biomarkers for the diagnosis of UPS.Methods: The mRNA and protein expression of neurofibromin 1 (NF1) in 68 pairs of UPS and adjacent normal tissues were detected by qRT-PCR and immunohistochemistry, and the correlation between the NF1 protein expression and clinicopathological characteristics was analyzed. Then, differentially expressed microRNAs (DE miRNAs) were identified between the UPS tumor tissue and matched adjacent normal tissue using Hisep sequencing, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG). The DE miRNAs of the regulating NF1 gene were also identified using the TargetScan and miRanda databases and validated by qRT-PCR.Results: Compared with the adjacent normal tissue, both mRNA and protein expressions of NF1 in the UPS tumor tissue were significantly decreased, and the positive rate of NF1 protein was associated with the tumor size, metastasis, and recurrence. A total of 125 known DE miRNAs were identified from the screened miRNAs based on | log2(Fold Change) ≥5 and p-value < 0.05 (A total of 82 upregulated and 43 downregulated DE miRNAs in the UPS tissue). Target genes regulated by the DE miRNAs were enriched in pathways of metabolisms, RNA degradation, PI3K-Akt, and Rap1 pathway. In total, 11 miRNAs which were predicted to regulate the NF1 gene were screened. After verification, the relative expressions of hsa-miR-199a-3p and hsa-miR-34a-5p were increased and decreased in the UPS tumor tissue compared with those in the adjacent normal tissue, respectively.Conclusion: NF1 and NF1-related microRNAs including hsa-miR-199a-3p and hsa-miR-34a-5p may be novel biomarkers in the diagnosis of undifferentiated pleomorphic sarcoma (UPS).

Recurrent mucinous carcinoma with sarcomatoid and sarcomatous mural nodules: a case report and literature review

“…A comprehensive genomic analysis has reported that the NF1 gene is one of the most frequently altered genes in soft tissue sarcomas (STS) ( 27 ). Studies have demonstrated that individuals with NF1 mutations are predisposed to developing STS ( 28 ). In vitro experiments, NF1 promotes the initiation and progression of UPS by inhibiting the PI3K-Akt-mTOR-S6 pathway ( 28 ).…”

“…Studies have demonstrated that individuals with NF1 mutations are predisposed to developing STS ( 28 ). In vitro experiments, NF1 promotes the initiation and progression of UPS by inhibiting the PI3K-Akt-mTOR-S6 pathway ( 28 ). PI3K pathway is frequently upregulated in epithelial ovarian cancers and plays an important role in cell survival.…”

Association between microRNA 671 polymorphisms and the susceptibility to soft tissue sarcomas in a Chinese population

“…Many miRNAs have also been abnormally expressed in STSs, and the knowledge of miRNA expression patterns in STSs could identify specific signatures for the histological subtypes (5,6). Furthermore, the different profiling of miRNA expression in tumor tissue of STSs compared with adjacent tissue may provide a clue for the diagnosis of STSs (7)(8)(9). Many studies recently have demonstrated that the altered expression of miRNAs is associated with the occurrence of numerous diseases, which may have a significant possibility of being used as biomarkers and targets of treatment for human illnesses.…”

Image_1.tif

“…A comprehensive genomic analysis has reported that the NF1 gene is one of the most frequently altered genes in soft tissue sarcomas (STS) (27). Studies have demonstrated that individuals with NF1 mutations are predisposed to developing STS (28). In vitro experiments, NF1 promotes the initiation and progression of UPS by inhibiting the PI3K-Akt-mTOR-S6 pathway (28).…”

“…Studies have demonstrated that individuals with NF1 mutations are predisposed to developing STS (28). In vitro experiments, NF1 promotes the initiation and progression of UPS by inhibiting the PI3K-Akt-mTOR-S6 pathway (28). PI3K pathway is frequently upregulated in epithelial ovarian cancers and plays an important role in cell survival.…”