骨肉瘤miRNA的研究进展

Research progress of MicroRNAs in Osteosarcoma

骨肉瘤是一种起源于间叶组织的原发性恶性骨肿瘤,好发于青少年,发病率约为百万分之三[1],恶性度高,早期易转移,对化疗易产生耐受性,预后差.目前研究证实肿瘤实质上是一种基因疾病[2],肿瘤的发生发展涉及多个基因的改变,包括正常基因的突变或缺失、癌基因的异常扩增和表达以及多个调节基因的协同作用,加之基因本身多效性和机体免疫因素,最终决定肿瘤表型的表达与否[3].

It＇s all known that tumor is a virtually genetic disease （a consequence of disordered genome function） and has 5 major stages （initiation, promotion, malignant conversion, progression, and metastasis）. A lot of genes abnormal expression and gene deregulation cause tumor＇s occurrence and development, which basically involve balance between 2 major factors： oncogenes that promote cell proliferation and tumorigenesis and tumor suppressor genes that repress cell division and tumor formation. Osteosarcoma is a primary malignant bone tumor with high morbidity in young adults and adolescent. It occurs most often in the bone of the lower extremities and in the humerus of young patients. Due to the rapid and aggressive and chemoresistance nature of the disease, osteosarcoma has worse prognosis than other bone tumors. Now MicroRNAs （MicRNAs） are focused in osteosarcoma＇s research. MicRNAs are a class of 19-24 nucleotides long, philogenetically conserved, non-coding RNAs. MiRNAs are an abundant RNA species constituting 〉2% of the predicted human genes （〉1,000 genes）, which regulate - 30% of protein-coding genes. Today the miRNAs registry accounts for 15,172 miRNAs and involves tumor＇s proliferation, apoptosis, loss of differentiation, metabolism in different cancer-related processes of through regulation of expression of multiple target genes as tumor suppressor or oncogenes with a post-transcriptional mechanism. This article outlines miRNAs＇ role in bone development and mesenchymal stem cells, expression difference （up- or down-regulation） in osteosarcoma, single miRNA＇s biogenesis, targets and function in order to discuss mutual relation between osteosarcoma and miRNAs. MiRNAs play a very important role in skeleton development through Hedgehog, Wnt, fibroblast growth factors （FGF）, bone morphogenetic proteins （BMP） and platelet derived growth factor （PDGF） signal. MiR-214, miR- 196, miR-140 and MiR-133 activate a specific transcriptional program through the above signal. The expression of miRNAs is deregulated in human cancer, with some miRNAs consistently up- or down-regulated in more than 1 type of neoplasm. In 7 cases of osteosarcoma sample from patients, WEI found 28 miRNA genes were up-regulated, and 26 down-regulated, respectively. MiR-38 1, miR-1 8a, miR-586, miR Plus-42780, and miR-377 genes were expressed 2.5-fold higher than in normal tissue, and miR-586 was the most up-regulated gene, 5-fold. MiR-144 was the most down-regulated gene 39-fold. GAO and Angelique found different changes of miRNAs expression in SOSP-9607cell line and osteosarcoma cell after chemotherapy. However different miRNAs play different pole in osteosarcoma pathology. For example miRNA-21 increased ostosarcoma cell invasion and migration as a target of PECK （reversion- inducing- cysteine-rich protein with kazal motifs）, which is a tumor suppressor gene. Through the suppression of DTL （denticleless protein homolog）, miRNA-215 induced a decreased cell proliferation by causing G2-arrest and leading to an increase in chemoresistance to MTX （methotrexate） and TDX （tomudex）. MiR-140 induced p53 and p21 expression accompanied with G1 and G2 phase arrest. Histone deacetylase 4 （HDAC4） was confirmed to be 1 of the important targets of miR-140. The current miRNAs tissues revealed that miRNAs could be useful for cancer classification, prognostic stratification, and drug-response prediction for diagnosis, therapy and follow-up of osteosarcoma, in the next years, miRNAs perhaps would have a great impact in osteosarcoma.