Pu Youguang, Zhao Fangfang, Li Yinpeng, Cui Mingda, Wang Haiyan, Meng Xianghui, Cai Shanbao
Cancer Epigenetics Program, Anhui Cancer Hospital, West Branch of Anhui Provincial Hospital, Anhui Medical University, Hefei, 230031, Anhui, China.
Xinxiang Medical University, Xinxiang, Henan, 453000, China.
BMC Cancer. 2017 Jan 10;17(1):45. doi: 10.1186/s12885-016-3002-x.
Chemoresistance hinders the curative cancer chemotherapy. MicroRNAs (miRNAs) are key players in diverse biological processes including the chemoresistance of cancers.
A RNA-seq-based miR-omic analysis of osteosarcoma (OS) cells was performed to detect the levels of miR-34a-5p. Bioinformatics analysis revealed that AGTR1 is one of the target genes of miR-34a-5p. The mRNA and protein levels of AGTR1 were detected in both the miR-34a-5p-mimic transfected G-292 and miR-34a-5p-antagomiR transfected SJSA-1 cells. The involvement of AGTR1 with OS chemoresistance was validated by the experiments with siRNA-mediated repression or overexpression of the AGTR1 gene.
We showed that miR-34a-5p promotes the multi- chemoresistance of OS. The angiotensin II type 1 receptor (AGTR1) gene, is one of the targets of miR-34a-5p in OS and thus negatively correlates with OS chemoresistance by systematic investigations of a multi-drug sensitive (G-292) and resistant (SJSA-1) OS cell lines. Down-regulation of the AGTR1 expression by siRNA passivates G-292 cells and suppresses cell apoptosis, while over-expression of AGTR1 sensitizes SJSA-1 cells and thus promotes the drug-triggered cell death.
The miR-34a-5p and its target gene AGTR1 are the potential targets for an effective chemotherapy of OS. Our results also provide novel insights into the effective chemotherapy for OS patients.
化疗耐药阻碍了癌症的治愈性化疗。微小RNA（miRNA）是包括癌症化疗耐药在内的多种生物学过程的关键参与者。
对骨肉瘤（OS）细胞进行基于RNA测序的miR组分析，以检测miR-34a-5p的水平。生物信息学分析显示AGTR1是miR-34a-5p的靶基因之一。在转染了miR-34a-5p模拟物的G-292细胞和转染了miR-34a-5p拮抗剂的SJSA-1细胞中检测AGTR1的mRNA和蛋白质水平。通过siRNA介导的AGTR1基因抑制或过表达实验验证了AGTR1与OS化疗耐药的关系。
我们发现miR-34a-5p促进了OS的多药耐药。通过对多药敏感（G-292）和耐药（SJSA-1）的OS细胞系进行系统研究，血管紧张素II 1型受体（AGTR1）基因是OS中miR-34a-5p的靶基因之一，因此与OS化疗耐药呈负相关。siRNA下调AGTR1表达可使G-292细胞失活并抑制细胞凋亡，而AGTR1过表达可使SJSA-1细胞敏感，从而促进药物触发的细胞死亡。
miR-34a-5p及其靶基因AGTR1是OS有效化疗的潜在靶点。我们的结果也为OS患者的有效化疗提供了新的见解。
