GDF15 promotes the proliferation of cervical cancer cells by phosphorylating AKT1 and Erk1/2 through the receptor ErbB2.
GDF15 promotes the proliferation of cervical cancer cells by phosphorylating AKT1 and Erk1/2 through the receptor ErbB2.
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DOI：
10.1186/s13046-018-0744-0
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发表时间：
2018-04-10
期刊：
影响因子：
--
通讯作者：
Zhang P
中科院分区：
文献类型：
--
作者：
Li S;Ma YM;Zheng PS;Zhang P
生长分化因子15（GDF 15）是TGF-β超家族的成员，并且有证据表明在各种人类癌症中分泌大量的GDF 15，例如卵巢癌、前列腺癌和乳腺癌等。然而，GDF 15在宫颈癌中的功能尚未有报道。采用免疫组化法检测GDF 15在正常宫颈和不同宫颈癌组织中的表达。采用细胞生长曲线、MTT法、成瘤实验和流式细胞术观察GDF 15异位表达对宫颈癌细胞增殖和细胞周期的影响。采用Real-time PCR、Western blotting和免疫沉淀法检测细胞周期相关基因、PI 3 K/AKT和MAPK/ERK信号通路相关基因的表达。进行染色质免疫沉淀测定以确认C-myc是否结合GDF 15启动子的特定区域。采用抑制剂处理和免疫沉淀测定来鉴定GDF 15和ErbB 2之间的关联。GDF 15在宫颈癌发生发展过程中表达逐渐增加。GDF 15通过外源性rhGDF 15处理或利用基因编辑技术在体内外均能促进宫颈癌细胞增殖，并显著加速细胞周期由G 0/G1期向S期的转变。rhGDF 15处理组p-ErbB 2、p-AKT 1、p-Erk 1/2、CyclinD 1和CyclinE 1表达上调，p21表达下调。C-myc通过与GDF 15启动子中的E-box基序结合反式激活GDF 15表达，并促成GDF 15/C-myc/GDF 15的正反馈。此外，GDF 15在宫颈癌细胞中以蛋白复合物的形式与ErbB 2结合。我们的数据表明，GDF 15通过与ErbB 2复合的PI 3 K/AKT和MAPK/ERK信号通路上调CyclinD 1和CyclinE 1以及下调p21来促进宫颈癌细胞的增殖。本文的在线版本（10.1186/s13046-018-0744-0）包含补充材料，可供授权用户使用。
Growth differentiation factor 15 (GDF15) is a member of the TGF-β superfamily, and evidence suggests that a substantial amount of GDF15 is secreted in various human cancers, such as ovarian cancer, prostate cancer, and breast cancer, among others. However, the function of GDF15 in cervical cancer has not yet been reported. Immunohistochemistry was used to detect GDF15 expression in normal cervix and in different cervical cancer lesions. Cell growth curves, MTT, tumor formation assays and flow cytometry were utilized to observe the effects of ectopic GDF15 expression on the proliferation and cell cycle of cervical cancer cells. Real-time PCR, western blotting and immunoprecipitation assays were conducted to measure the expression of genes related to the cell cycle and the PI3K/AKT and MAPK/ERK signaling pathways. A chromatin immunoprecipitation assay was performed to confirm whether C-myc bound to a specific region of the GDF15 promoter. Inhibitor treatment and immunoprecipitation assays were employed to identify the association between GDF15 and ErbB2. GDF15 expression gradually increased during the progression of cervical carcinogenesis. GDF15 promoted cervical cancer cell proliferation via exogenous rhGDF15 treatment or the use of gene editing technology in vitro and in vivo and significantly accelerated the cell cycle transition from G0/G1 to S phase. The expression of p-ErbB2, p-AKT1, p-Erk1/2, CyclinD1 and CyclinE1 was up-regulated and the expression of p21 was down-regulated in GDF15-overexpressing and rhGDF15-treated cervical cancer cells. C-myc trans-activated GDF15 expression by binding to the E-box motifs in the promoter of GDF15 and contributed to the positive feedback of GDF15/C-myc/GDF15. Furthermore, GDF15 bound to ErbB2 in a protein complex in cervical cancer cells. Our data demonstrated that GDF15 promoted the proliferation of cervical cancer cells via the up-regulation of CyclinD1 and CyclinE1 and the down-regulation of p21 through both the PI3K/AKT and MAPK/ERK signaling pathways in a complex with ErbB2. The online version of this article (10.1186/s13046-018-0744-0) contains supplementary material, which is available to authorized users.
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