MicroRNA-204 critically regulates carcinogenesis in malignant peripheral nerve sheath tumors

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft tissue sarcomas accounting for 310 of all soft tissue sarcomas. Neurofibromatosis type 1 (NF1) is the most important known risk factor. MPNSTs are often diagnosed at an advanced stage when distant metastases have developed. Although surgical resection remains the main treatment for MPNSTs, complete surgical resection is rarely possible. The prognosis for patients with MPNSTs is poor. There is an urgent need for improved therapies. To this end, we investigated whether microRNA (miR), specifically miR-204, might be implicated in MPNSTs because it is located at a cancer-associated genomic region exhibiting high frequency of loss of heterozygosity in tumors. We show that miR-204 expression is downregulated in NF1 and non-NF1 MPNST tumor tissues and in tumor cell lines. Restoring miR-204 expression in MPNST cell lines STS26T (non-NF1), ST88-14 (NF1), and T265p21 (NF1) significantly reduces cellular proliferation, migration, and invasion in vitro. Restoring miR-204 expression in STS26T decreases tumor growth and malignant progression in vivo. We also report that miR-204 inhibits Ras signaling and expression of high mobility group gene A2. These findings support the hypothesis that miR-204 plays critical roles in MPNST development and tumor progression. miR-204 may represent a novel biomarker for diagnosis and a candidate target with which to develop effective therapies for MPNSTs.

恶性外周神经鞘瘤（MPNST）是极具侵袭性的软组织肉瘤，占所有软组织肉瘤的3 - 10%。1型神经纤维瘤病（NF1）是已知最重要的风险因素。MPNST通常在已发生远处转移的晚期才被诊断出来。尽管手术切除仍是MPNST的主要治疗方法，但完全手术切除很少能够实现。MPNST患者的预后很差。迫切需要改进治疗方法。为此，我们研究了微小RNA（miR），特别是miR - 204是否可能与MPNST有关，因为它位于一个在肿瘤中呈现高频杂合性缺失的癌症相关基因组区域。我们发现miR - 204在NF1和非NF1的MPNST肿瘤组织以及肿瘤细胞系中的表达下调。在MPNST细胞系STS26T（非NF1）、ST88 - 14（NF1）和T265p21（NF1）中恢复miR - 204的表达，可在体外显著降低细胞增殖、迁移和侵袭能力。在STS26T中恢复miR - 204的表达可在体内降低肿瘤生长和恶性进展。我们还报告称miR - 204抑制Ras信号传导以及高迁移率族基因A2的表达。这些发现支持了miR - 204在MPNST发生和肿瘤进展中起关键作用的假设。miR - 204可能代表一种新的诊断生物标志物以及一个开发MPNST有效治疗方法的候选靶点。