E3 ubiquitin ligase Hakai regulates cell growth and invasion, and increases the chemosensitivity to cisplatin in non-small-cell lung cancer cells
E3 ubiquitin ligase Hakai regulates cell growth and invasion, and increases the chemosensitivity to cisplatin in non-small-cell lung cancer cells
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DOI：
10.3892/ijmm.2018.3683
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发表时间：
2018-08-01
影响因子：
5.4
通讯作者：
Ma, Liang
中科院分区：
文献类型：
--
作者：
Liu, Zi;Wu, Yuqing;Ma, Liang
Hakai最初被认为是e -钙粘蛋白复合物的E3泛素连接酶，与细胞粘附和侵袭有关。最近，新出现的证据强烈表明Hakai在某些肿瘤的发生中起着关键作用。然而，Hakai在非小细胞肺癌（NSCLC）中的作用及其潜在的分子机制尚不清楚。本研究发现，与人正常支气管上皮细胞相比，Hakai在NSCLC细胞系中高表达，转染Hakai小干扰RNA可显著抑制A549和NCI-H460 NSCLC细胞的生长。此外，Hakai的抑制作用通过上调E-cadherin和下调N-cadherin来抑制NSCLC细胞的迁移和侵袭。值得注意的是，Hakai基因的下调可导致磷酸化AKT （Ser(473)）的表达降低，Hakai基因的抑制可显著增强小鼠对顺铂的化学敏感性。综上所述，本研究首次证实Hakai基因的下调抑制了NSCLC细胞的增殖、迁移和侵袭，并使NSCLC细胞对顺铂敏感。因此，Hakai可能作为治疗NSCLC的潜在治疗靶点。
Hakai was originally identified as an E3 ubiquitin ligase of the E-cadherin complex implicated in cell adhesion and invasion. Recently, emerging evidence has strongly suggested that Hakai serves a pivotal role in the tumorigenesis of certain tumors. However, the role of Hakai in non-small-cell lung cancer (NSCLC) and its underlying molecular mechanism have not been clarified. In the present study, it was observed that Hakai was highly expressed in NSCLC cell lines compared with human normal bronchial epithelial cells, and transfection with Hakai small interfering RNA significantly inhibited the growth of A549 and NCI-H460 NSCLC cells. In addition, the inhibition of Hakai suppressed NSCLC cell migration and invasion through upregulation of E-cadherin and downregulation of N-cadherin. Notably, it was also revealed that knockdown of Hakai led to a decrease in the expression of phosphorylated AKT (Ser(473)), and a significant enhancement of chemosensitivity to cisplatin was observed following Hakai suppression. In conclusion, the present study demonstrated for the first time that knockdown of Hakai inhibited the proliferation, migration and invasion of NSCLC cells, and sensitized NSCLC cells to cisplatin. Thus, Hakai may serve as a potential therapeutic target for the treatment of NSCLC.