Deregulated microRNAs in neurofibromatosis type 1 derived malignant peripheral nerve sheath tumors

Abstract

Malignant peripheral nerve sheath tumors (MPNST) are aggressive cancers that occur spontaneously (sporadic MPNST) or from benign plexiform neurofibromas in neurofibromatosis type 1 (NF1) patients. MPNSTs metastasize easily, are therapy resistant and are frequently fatal. The molecular changes underlying the malignant transformation in the NF1 setting are incompletely understood. Here we investigate the involvement of microRNAs in this process. MicroRNA expression profiles were determined from a series of archival, paired samples of plexiform neurofibroma and MPNST. Ninety differentially expressed microRNAs were identified between the paired samples. Three downregulated microRNAs (let-7b-5p, miR-143-3p, miR-145-5p) and two upregulated microRNAs (miR135b-5p and miR-889-3p) in MPNST were selected for functional characterization. In general, their differential expression was validated in a relevant cell line panel but only partly in a series of unpaired, fresh frozen tumor samples. As part of the validation process we also analyzed microRNA expression profiles of sporadic MPNSTs observing that microRNA expression discriminates NF1-associated and sporadic MPNSTs. The role of microRNAs in cancer progression was examined in NF1-derived MPNST cell lines by transiently modulating microRNA levels. Our findings indicate that some microRNAs affect migratory and invasive capabilities and Wnt signaling activity but the effects are distinct in different cell lines. We conclude that miRNAs play essential regulatory roles in MPNST facilitating tumor progression. Neurofibromatosis type 1 (NF1) is a relatively common autosomal dominant disorder which is caused by inherited or sporadic mutations in the NF1 gene 1-3. The NF1 gene encodes the tumor suppressor neurofibromin 1 that functions as a negative regulator of Ras signaling by its GTPase-activating protein (GAP) domain. The partial inactivation of neurofibromin 1 seen in NF1 patients can cause variable symptoms affecting the skin, bone and the nervous system. Moreover, the disease is associated with an increased risk of benign and malignant tumor formation. Almost all NF1 patients develop cutaneous neurofibromas and in many instances also deeper seated plexiform neurofibromas. These benign tumors are believed to originate from the Schwann cell lineage i.e. mature Schwann cells or Schwann cell precursors 4,5 and are characterized by a biallelic inactivation of the NF1 gene 1,6. Approximately 10% of NF1 patients develop malignant peripheral nerve sheath tumors (MPNSTs) usually in the context of pre-existing plexiform neurofibromas. MPNST are highly aggressive tumors that are largely responsible for the reduced life expectancy these patients face 7-9. Early metastasis, poor prognosis, and resistance to therapeutic interventions are common clinical features of this cancer. While patients with non-metastatic disease may benefit from surgical resection and radiation, many patients relapse. These patients, and also those initially

miR-889-3p targeting BMPR2 promotes the development of retinoblastoma via JNK/MAPK/ERK signaling

“…However, according to another study 16 , miR-889-3p functions as an oncogene in osteosarcoma 16 . Furthermore, miR-889-3p promoted the invasive capacity of malignant peripheral nerve sheath tumors 15 . The function of miR-889-3p in Rb currently remains unknown.…”

Pharmacological Approaches in Neurofibromatosis Type 1-Associated Nervous System Tumors

“…Dysregulated miRNAs affect known pathological pathways in cancer such as PTEN, RAS-MAPK, epithelial-mesenchymal transition, and cell cycle progression [145]. Azadeh and colleagues also studied the miRNA expression profile of PN, NF1-MPNSTs, and non-NF1-MPNSTs [146]. They found that the miRNA profile helped to distinguish between NF1-PN, and NF1-MPNST and between NF-1 MPNST and the sporadic form of MPNST.…”

“…They functionally validated six miRNAs among the top 15 differentially expressed miRNAs, including miR-889 which was not reported before. They showed that miR-889 along with miR-135b promote Wnt/B-catenin signaling and contribute to the invasive and migratory capabilities of MPNST cells [146]. The Let7 family is also part of a well-known family that plays a role in cancer.…”

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

“…Neurofibromin 1 (NF1) is derived from neurofibromatosis type I, which is an autosomal dominant genetic disease with the mutation of the NF1 gene. In addition, NF1 is a tumor suppressor gene; NF1 mutation was first demonstrated in the malignant peripheral nerve sheath tumor (MPNST), which is a subtype of STSs ( Amirnasr et al, 2020 ). In addition to that, its mutations were found in other subtypes of STSs.…”