Hexavalent chromium induces malignant transformation of human lung bronchial epithelial cells via ROS-dependent activation of miR-21-PDCD4 signaling.
Hexavalent chromium induces malignant transformation of human lung bronchial epithelial cells via ROS-dependent activation of miR-21-PDCD4 signaling.
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DOI：
10.18632/oncotarget.9967
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发表时间：
2016-08-09
期刊：
影响因子：
--
通讯作者：
Shi X
中科院分区：
文献类型：
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作者：
Pratheeshkumar P;Son YO;Divya SP;Turcios L;Roy RV;Hitron JA;Wang L;Kim D;Dai J;Asha P;Zhang Z;Shi X
六价铬[Cr(VI)]是一种众所周知的与肺癌风险增加有关的人类致癌物。然而，Cr（VI）诱导的致癌机制尚不清楚。MicroRNA-21 （miR-21）是致癌过程的关键调节因子。研究表明，miR-21通过靶向肿瘤抑制基因程序性细胞死亡4 （PDCD4）发挥其致癌活性。本研究探讨了miR-21-PDCD4信号在Cr（VI）诱导的细胞转化和肿瘤发生中的作用。结果表明，Cr（VI）可诱导人支气管上皮细胞（BEAS-2B）产生ROS。慢性暴露于Cr（VI）可引起BEAS-2B细胞的恶性转化。Cr（VI）导致miR-21表达显著增加，并抑制PDCD4表达。值得注意的是，IL-6激活STAT3转录对于Cr（VI）诱导的miR-21升高至关重要。在BEAS-2B细胞中稳定敲低miR-21或过表达PDCD4可显著降低Cr（VI）诱导的细胞转化。此外，Cr（VI）诱导的PDCD4抑制抑制了下游E-cadherin蛋白的表达，但促进了β-catenin/ tcf依赖性uPAR和c-Myc的转录。我们还发现，在慢性Cr（VI）暴露的BEAS-2B细胞产生的异种移植肿瘤中，miR-21水平升高，PDCD4表达降低。此外，miR-21的稳定下调和PDCD4的过表达降低了裸小鼠慢性Cr（VI）暴露的BEAS-2B细胞的致瘤性。综上所述，这些结果表明miR-21-PDCD4信号轴在Cr（VI）诱导的癌变中起重要作用。
Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with an increased risk of lung cancer. However, the mechanisms underlying Cr(VI)-induced carcinogenesis remain unclear. MicroRNA-21 (miR-21) is a key regulator of oncogenic processes. Studies have shown that miR-21 exerts its oncogenic activity by targeting the tumor suppressor gene programmed cell death 4 (PDCD4). The present study examined the role of miR-21-PDCD4 signaling in Cr(VI)-induced cell transformation and tumorigenesis. Results showed that Cr(VI) induces ROS generation in human bronchial epithelial (BEAS-2B) cells. Chronic exposure to Cr(VI) is able to cause malignant transformation in BEAS-2B cells. Cr(VI) caused a significant increase of miR-21 expression associated with an inhibition of PDCD4 expression. Notably, STAT3 transcriptional activation by IL-6 is crucial for the Cr(VI)-induced miR-21 elevation. Stable knockdown of miR-21 or overexpression of PDCD4 in BEAS-2B cells significantly reduced the Cr(VI)-induced cell transformation. Furthermore, the Cr(VI) induced inhibition of PDCD4 suppressed downstream E-cadherin protein expression, but promoted β-catenin/TCF-dependent transcription of uPAR and c-Myc. We also found an increased miR-21 level and decreased PDCD4 expression in xenograft tumors generated with chronic Cr(VI)-exposed BEAS-2B cells. In addition, stable knockdown of miR-21 and overexpression of PDCD4 reduced the tumorogenicity of chronic Cr(VI)-exposed BEAS-2B cells in nude mice. Taken together, these results demonstrate that the miR-21-PDCD4 signaling axis plays an important role in Cr(VI)-induced carcinogenesis.