Background

Pheochromocytoma (PCC) is a catecholamine-producing and neuroendocrine tumor with the 5-year overall survival of advanced stage PCC lower than 40%. Increasing evidence has shown that aberrant expression of microRNAs (miRNAs) plays important roles in the development and chemotherapy resistance of cancers including PCC.

Objective

The tumor-suppressive function of miR-184 has been identified in several types of cancers. The aim of this study is to explore the function and the underlying mechanism of miR-184 in the chemo-resistance of PCC.

Results

miR-184 expression was significantly lower in doxorubicin (Dox)-resistant pheochromocytoma-12 (PC-12) cells and PCC patients. Consistently, in vitro analysis showed that overexpression of miR-184 obviously improved the sensitivity of PC-12/Dox cells, while knockdown of miR-184 sensitised PC-12/Dox cells to chemotherapeutics. To further understand the possible functional mechanism of miR184 in the chemo-resistance of PCC, the targets of miR-184 were predicted. The results of miRDB database suggested A disintegrin and metalloproteinase 22 (ADAM22) carrying the potential complementary binding sites of miR-184 within its 3′-untranslated region (UTR). Further experiments confirmed that miR-184 bound the 3′-UTR of ADAM22 mRNA and down-regulated the expression of ADAM22 in PC-12/Dox cells. Moreover, ADAM22 was overexpressed in Dox-resistant PC-12 cells and PCC patients. Additionally, overexpression of ADAM22 attenuated miR-184-mediated chemo-sensitivity of PC-12/Dox cells.

Conclusion

miR-184 played a role in the chemo-sensitivity of PC-12/Dox cells at least partially via negatively regulating ADAM22. These results suggested miR-184 as a possible novel target to attenuate the chemo-resistance of PCC.

中文翻译：

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microRNA-184通过靶向ADAM22增强嗜铬细胞瘤12细胞对阿霉素的敏感性

背景

嗜铬细胞瘤（PCC）是一种产生儿茶酚胺的神经内分泌肿瘤，晚期PCC的5年总生存率低于40％。越来越多的证据表明，microRNA（miRNA）的异常表达在包括PCC在内的癌症的发生和化疗耐药中起着重要作用。

目的

已在几种类型的癌症中鉴定了miR-184的肿瘤抑制功能。这项研究的目的是探索miR-184在PCC耐药性中的功能和潜在机制。

结果

在抗阿霉素（Dox）的嗜铬细胞瘤12（PC-12）细胞和PCC患者中，miR-184表达显着降低。一致地，体外分析表明，miR-184的过表达明显改善了PC-12 / Dox细胞的敏感性，而敲低miR-184致敏的PC-12 / Dox细胞对化学疗法的敏感性。为了进一步了解miR184在PCC的化学耐药性中可能的功能机制，预测了miR-184的靶标。miRDB数据库的结果表明，整合素和金属蛋白酶22（ADAM22）在其3'-非翻译区（UTR）内带有miR-184的潜在互补结合位点。进一步的实验证实，miR-184结合ADAM22 mRNA的3'-UTR并下调PC-12 / Dox细胞中ADAM22的表达。此外，ADAM22在耐Dox的PC-12细胞和PCC患者中过表达。此外，ADAM22的过表达减弱了miR-184介导的PC-12 / Dox细胞的化学敏感性。

结论

miR-184至少部分通过负调控ADAM22在PC-12 / Dox细胞的化学敏感性中起作用。这些结果表明，miR-184是减轻PCC的化学耐药性的可能新靶标。