To the Editor: Osteosarcoma (OS), a disease seriously endangering the health of young people, is the eighth most common primary malignant bone tumor affecting children and adolescents. Typically occurring in the metaphysis of long tubular bone, OS develops from mesenchymal cells and accounts for 20% of primary bone tumors. About 70% to 80% of patients are 8 to 9 years, and the annual incident cases are around 1 to 3 million people.[1] Let-7 is a large, highly conserved family of microRNA (miRNA) that plays an important role in mammalian cell differentiation. Recent studies suggest that let-7 is a tumor suppressor gene, as its expression level is decreased to different degrees in various tumor tissues and is closely related to tumor occurrence, invasion, and metastasis. Here, we review the role of let-7 in the invasion and metastasis of OS. miRNAs are non-coding RNAs with highly conserved sequences in plants and animals. miRNAs play an important role in the cellular function of multicellular organisms, through complete or incomplete complementary binding with a target gene that leads to the degradation or translation inhibition of messenger RNA (mRNA) and regulation of target gene expression. Let-7 was originally found in Caenorhabditis elegans (C. elegans) and has a length of 20 to 23 nt; it is a key regulator of the sequential development of nematodes. Its sequences, expression patterns, and regulatory functions are highly conserved among species. At present, 12 let-7 coding genes have been found in the human genome: let-7a-1, let-7a-2, let-7a-3, Let-7b, Let-7c, Let-7d, Let-7e, Let-7f-1, Let-7f-2, Let-7g, Let-7I,a nd Mir-98. There have been a growing number of reports in recent years focusing on the effect of let-7 family members on tumors. Liu et al[2] found that the expression level of let-7 in oral squamous cancer cells decreased, while the expression level of high-mobility protein A2 increased; these findings suggest a negative correlation between the expression levels of let-7 and an activated gene associated with epithelial transformation. In addition, through co-transfection experiments, it was found that let-7 could inhibit the protein with high mobility and inhibit the process of epithelial transformation. As tumor invasion is based on epithelial transformation, these results suggest that let-7 is of great significance in this process. Fas, a type of tumor necrosis factor receptor-α also interacts with let-7, as well as tumor necrosis factor-α, the ligand of Fas. Fas induces apoptosis by binding to the receptor regulating apoptosis on the cell surface. When Geng et al[3] administered let-7 inhibitors to colon cancer patients, Fas was detected at high expression levels and promoted the apoptosis of colon cancer cells. Therefore, activation of Fas can inhibit the biosynthesis process of let-7 whereas let-7 inhibits the transcription of Fas, thus negatively affecting the expression of Fas. In addition, overexpression of let-7 is also able to influence the Fas expression; thus, a two-way feedback regulation pathway exists between the two factors and this affects the apoptosis of tumor cells. Lin28 is a highly conserved RNA-binding protein that inhibits the maturation of let-7. Similar to Fas, lin28 is also a target gene associated with and downstream of let-7, which affects the occurrence, invasion, and metastasis of tumors by affecting the generation of let-7. Let-7 inhibits lin28 translation by binding to the 3′ untranslated region (UTR) of lin28 mRNA, thus forming a two-way negative feedback regulation relationship between the two factors.[4] The lin28-let-7 pathway is involved in a variety of biological functions, including stem cell function and tumorigenesis.[5] In addition, a number of studies[4-8] reported that the let-7 family inhibits the proliferation by affecting the metabolism of OS cells while promoting OS cell apoptosis, and participates in the OS cell invasion and metastasis through regulation of the expression of target genes. Such effects influence patient prognosis. Aurora-B (AURKB) is a serine/threonine kinase involved in the regulation of the progression of mitosis. Its abnormal activity is genetically destabilizing, and this can potentially lead to cancer. Pi[6] reported that let-7a overexpression leads to a decrease in AURKB, and inhibits the invasion, proliferation, and migration ability of OS cells. Conversely, overexpression of AURKB restores the malignant phenotype of OS cells. Therefore, the therapeutic regulation of let-7a and AURKB may be a novel therapeutic strategy for the treatment of OS. It has been reported that epigenetic dysregulation induced by PcG family proteins played an important role in the development of OS. Polycomb repressive complex 1 (PRC1) is a complex composed of PcG protein and chromobox homolog 2 (CBX2), which consists of CBX2/4/6/7/8. Han et al[7] reported that let-7a inhibits the expression of CBX2 mRNA by directly binding to the 3′-UTR of CBX2, whereas overexpression of let-7a inhibits the proliferation of OS cells; conversely, CBX2 overexpression reverses this effect, thus confirming the importance of let-7a/CBX2 axis in the progression of OS. Therefore, CBX2 is likely to be a potential target for the treatment of OS. Insulin like growth factor 1 receptor (IGF1R) is a widely expressed cell membrane receptor that is overexpressed in many different types of tumors. Numerous studies have shown that IGF1R is significantly increased in OS tissues as compared with neighboring non-tumor tissues; this suggests that IGF1R overexpression in OS tissues may be related to the occurrence and development of tumors. Zhang et al[4] found that let-7b is one of the regulators of IGF1R in OS tissues, and its overexpression led to down-regulation of IGF1R protein levels. During the t1 to t2 phase of OS cells, let-7b was observed to significantly negatively correlate with IGF1R expression. Let-7b can bind to the 3′-UTR of IGF1R directly, and thus can negatively regulate the expression of IGF1R and inhibit the proliferation and invasion of OS cells. Therefore, let-7b/IGF1R is very likely to be a new target for the treatment of OS. Human apurinic/apyrimidinic endonuclease 1 (APE1) is involved in DNA damage repair and REDOX, and plays a core regulatory role in the radiotherapy resistance of OS. Dai et al[8] confirmed that APE1 can directly affect the expression of miRNAs in OS cells. Bioinformatics analysis showed that APE1 may affect the expression of downstream target genes by regulating miRNA and that it participates in biological processes, such as tumorigenesis, cell survival, proliferation, adhesion, and multiple signaling pathways. It has been suggested that APE1 may regulate the expression of let-7b and let-7i in OS cells by regulating the DNA-binding activity of the nuclear factor-κB (NF-κB). Rhotekin (RTKN) is a small guanosine triphosphate (GTP)-binding protein that regulates cell growth, differentiation, and apoptosis by binding to activated Rho molecules. Previous reports suggest that RTKN is highly expressed in a variety of malignant tumors and is closely related to tumor cell infiltration and metastasis and a poor patient prognosis. miRNA target gene prediction software and double luciferase experiments validated the RTKN gene as a direct target gene of let-7d.[6] Specifically, Rong et al[9] found that overexpression of let-7d led to lower expression of RTKN mRNA in U2OS cells, as compared to control cells, and inhibited the proliferation, migration, and invasion of U2OS cells. Thus, regulation of let-7d and RTKN is a potential new therapeutic approach for the treatment of OS. Chen et al[10] found that an RNA-binding protein (TARBP2) increases the expression of let-7f-5p in OS cells, suggesting that TARBP2 may promote the maturation of pre-let-7f in these cells. TARBP2 is a downstream and functional target of let-7f-5p that regulates the expression of let-7f-5p due to a regulatory feedback loop between let-7f-5p and TARBP2. This is induced by the hypoxia-promoted OS cell malignant phenotype and activation of the Wnt signaling pathway. Zhou et al[11] found that Hsa-let-7g, also a member of the let-7 family, enhances the proliferation of OS in vitro and in vivo; histological analysis confirmed that Hsa-let-7g increased the incidence of OS lung metastasis in nude mice. This study highlighted the fact that the expression of a member of Hox genes (HOXB1) in OS was significantly lower than that of matched adjacent non-nodal disorganized tissues. Because OS is marked by abnormal activation of the NF-κB pathway, Hsa-let-7g could potentially reduce the expression of HOXB1 and thus activate the NF-κB pathway to promote the occurrence of OS. However, further studies are needed to fully delineate the roles of these factors in OS transformation. In conclusion, Let-7 family members are implicated in the proliferation, differentiation, and apoptosis of OS cells and the occurrence, invasiveness, and metastasis of OS, a serious health threat in adolescents and one of the most common malignant bone tumors [Figure 1]. Research, however, on the role of let-7 family in the invasion and metastasis of OS is still preliminary, and let-7 target genes and the underlying mechanism whereby let-7 is involved in these processes are not yet entirely clear. Therefore, further investigation of the clinical potential of targeting let-7 family members and the role of these factors in the regulation of tumor development is needed.Figure 1: The let-7 family regulates the invasion and metastasis of OS. let-7: A large, highly conserved family of miRNA including let-7a, let-7b, let-7f-5p, Has-let-7g, etc. APE1: Human apurinic/apyrimidinic endonuclease 1; AURKB: Aurora-B; CBX2: Chromobox homolog 2; HOXB1: A member of Hox genes; IGFIR: Insulin-like growth factor type 1 receptor; miR-513a-5p: A member of microRNAs; miRNAs: MicroRNA; MMP2: Matrix metallopeptidase 2; MMP9: Matrix metallopeptidase 9; NF-κB: Nuclear factor-κB; OS: Osteosarcoma; TARBP2: An RNA-binding protein; UTR: Untranslated region.Acknowledgements This work was supported by the National Natural Science Foundation of China (Nos. 81860472 and 81560435) and the Natural Science Foundation of Jiangxi Province (No. 20192ACBL21041). Conflicts of interest None.
Search from 250 M+ research papersSearch from 250 M+ research papers
Open Access
Just Published
Apr 30, 2024
Thomaz Talarico Neto + 5