Ji Yanlei, Han Zhen, Shao Limei, Zhao Yuehuan
Department of Special Diagnosis, Shandong Cancer Hospital affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, China.
Department of Internal Medicine, Jinan Second People's Hospital, Jinan, China.
Cancer Med. 2016 Sep;5(9):2534-43. doi: 10.1002/cam4.840. Epub 2016 Jul 27.
MicroRNAs (miRNAs), as a novel class of small noncoding RNAs, have been identified as important transcriptional and posttranscriptional inhibitors of gene expression. Ultrasound-targeted microbubble destruction (UTMD) is a noninvasive method for microRNA delivery. We aimed to investigate the effect of UTMD of miR-133a on breast cancer treatment. It has been reported that miRNA-133a is involved in various cancers. miR-133a was lowly expressed in breast cancer tissues and breast cancer cell lines MCF-7 and MDA-MB-231. The miR-133a expression was significantly upregulated under exogenous miRNA-133a treatment in MCF-7 and MDA-MB-231 cells analyzed by qRT-PCR. Exogenous miR-133a promoted the cell proliferation as determined by diphenyl tetrazolium bromide (MTT) assay and 5-ethynyl-2'-deoxyuridine (EdU) staining. Epidermal growth factor receptor (EGFR) expression and Akt phosphorylation were significantly suppressed after miR-133a transfection by western blot detection. We prepared the miR-133a-microbubble and injected it into breast cancer xenografts. The miR-133a-microbubble injection prolonged miR-133a circulatory time by detecting the amount of miRNA-133a in the plasma. No significant toxicity was observed on alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels at liver and albumin, blood urea nitrogen, or creatine kinase levels at kidney after miR-133a-microbubble injection. The tumor size of miR-133a-microbubble-injected mice was smaller than that of the control group. Furthermore, the delivery efficiency of miR-133a with low frequency was higher than that with common frequency. miR-133a suppressed cell proliferation by suppressing the expression of EGFR and the phosphorylation of Akt. UTMD of miR-133a inhibited the tumor growth and improved the survival rate in breast cancer mice. Our study provides new evidence that UTMD of miRNA is a promising platform for breast cancer therapy.
微小RNA（miRNA）作为一类新型的小非编码RNA，已被确定为基因表达重要的转录和转录后抑制剂。超声靶向微泡破坏（UTMD）是一种用于递送miRNA的非侵入性方法。我们旨在研究miR-133a的UTMD对乳腺癌治疗的影响。据报道，miRNA-133a参与多种癌症。miR-133a在乳腺癌组织以及乳腺癌细胞系MCF-7和MDA-MB-231中低表达。通过qRT-PCR分析，在MCF-7和MDA-MB-231细胞中外源miRNA-133a处理后，miR-133a表达显著上调。通过溴化四氮唑蓝（MTT）法和5-乙炔基-2'-脱氧尿苷（EdU）染色测定，外源性miR-133a促进细胞增殖。通过蛋白质免疫印迹检测，miR-133a转染后表皮生长因子受体（EGFR）表达和Akt磷酸化显著受到抑制。我们制备了miR-133a微泡并将其注入乳腺癌异种移植瘤中。通过检测血浆中miRNA-133a的量，miR-133a微泡注射延长了miR-133a的循环时间。miR-133a微泡注射后，未观察到肝脏中丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）水平以及肾脏中白蛋白、血尿素氮或肌酸激酶水平有明显毒性。注射miR-133a微泡的小鼠的肿瘤大小小于对照组。此外，低频递送miR-133a的效率高于常用频率。miR-133a通过抑制EGFR表达和Akt磷酸化来抑制细胞增殖。miR-133a的UTMD抑制了乳腺癌小鼠的肿瘤生长并提高了存活率。我们的研究提供了新的证据，表明miRNA的UTMD是一种有前景的乳腺癌治疗平台。
