PBK promotes aggressive phenotypes of cervical cancer through ERK/c-Myc signaling pathway
PBK promotes aggressive phenotypes of cervical cancer through ERK/c-Myc signaling pathway
复制标题
PBK通过ERK/c-Myc信号通路促进宫颈癌侵袭表型
DOI：
10.1002/jcp.30134
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发表时间：
2020-11-13
影响因子：
5.6
通讯作者：
Kong, Beihua
中科院分区：
文献类型：
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作者：
Ma, Hanlin;Han, Fang;Kong, Beihua
宫颈癌是全球第四大最常见的女性癌症。PDZ结合激酶(PBK)可促进多种肿瘤的恶性行为。然而，它在宫颈癌中的功能作用和致癌机制尚不清楚。在本研究中，我们报道了PBK在宫颈癌组织中的高表达。PBK可促进宫颈癌细胞的增殖、转移和顺铂耐药。特异性PBK抑制剂OTS514在体外和异种移植模型中均能显著抑制宫颈癌细胞的增殖和转移。此外，OTS514还可增强宫颈癌细胞对顺铂的化疗敏感性。机制上，PBK通过磷酸化ERK1/2促进c-Myc的表达和稳定，OTS514抑制ERK1/2的磷酸化和c-Myc的转录活性。此外，U0126对ERK信号通路的抑制可逆转PBK过表达引起的细胞增殖和转移增加。C-Myc的外源性表达可拮抗PBK基因敲除引起的细胞增殖和转移能力的下降。结论：PBK通过ERK/c-Myc信号通路促进宫颈癌的恶性进展。PBK可能是治疗宫颈癌的一个有前途的分子靶点。
Cervical cancer is the fourth most frequent cancer in women worldwide. PDZ-binding kinase (PBK) is proven to promote the malignant behaviors of various carcinomas. However, its functional roles and oncogenic mechanisms in cervical cancer are poorly understood. In this study, we reported that PBK was highly expressed in cervical cancer tissues. PBK promoted the proliferation, metastasis, and cisplatin resistance of cervical cancer cells. OTS514, a specific PBK inhibitor, could significantly suppress proliferation and metastasis of cervical cancer cells in vitro and in a xenograft model. Besides, OTS514 could enhance cisplatin-based chemosensitivity in cervical cancer cells. Mechanistically, PBK promoted the expression and stabilization of c-Myc through phosphorylating ERK1/2. OTS514 suppressed the phosphorylation of ERK1/2 and the transcriptional activity of c-Myc. Furthermore, inhibition of the ERK signal pathway by U0126 reversed the increased proliferation and metastasis induced by overexpression of PBK. Exogenous expression of c-Myc counteracted the decreased proliferation and metastasis evoked by knockdown of PBK. In conclusion, PBK promoted the malignant progression of cervical cancer through ERK/c-Myc signal pathway. PBK might be a promising molecular target for cervical cancer treatment.