Increased Local Testosterone Levels Alter Human Fallopian Tube mRNA Profile and Signaling.
Increased Local Testosterone Levels Alter Human Fallopian Tube mRNA Profile and Signaling.
复制标题
作者：
睾丸激素的增加与卵巢癌的风险增加有关。高级别浆液性卵巢癌（High Grade Serous Ovarian cancer， HGSOC）多起源于输卵管上皮（FTE），但其致瘤性转化过程中发生的分步事件尚不清楚。输卵管癌早期病变模型刺激卵巢产生更多雄激素，支持高水平睾酮可能促进HGSOC早期发展的假设。然而，雄激素在卵巢癌中的作用尚未被研究。本研究探讨了雄激素在原发性人卵巢卵巢栓塞早期发展中的作用。我们的研究结果表明，睾酮升高改变了hFTE的mRNA谱，增加了WNT4和LGR6的表达，增加了输卵管上皮细胞的迁移能力。输卵管上皮（FTE）在生殖中起着关键作用，可能是高级别浆液性卵巢癌（HGSOC）的起源部位。致瘤性输卵管细胞相当于人类输卵管分泌上皮细胞（FTSEC），当与卵巢共培养时，卵巢分泌睾酮增加，表明睾酮是卵巢与FTSEC之间信号轴的一部分。此外，睾酮促进输卵管细胞的增殖。口服避孕药、输卵管结扎和输卵管切除术都可以预防卵巢癌，但也会降低循环中的雄激素水平。在本研究中，我们研究了睾酮升高对FTE的影响，发现睾酮上调无翼型MMTV整合家族成员4 (WNT4)，诱导永生人输卵管细胞的迁移和侵袭。我们通过RNA测序分析了在微流控系统SOLO-microfluidic platform - (MFP)中生长的原代人输卵管组织，发现p53及其下游靶基因，如配对盒基因2 （PAX2）、细胞周期蛋白依赖性激酶抑制剂1A （CDK1A或p21）和分化簇82 （CD82或KAI1）在睾酮治疗下下调。预测-多器官系统（PREDICT-MOS）是一个微流控平台，旨在支持通过Matrigel研究癌细胞迁移和侵袭的插入技术。使用该系统，我们发现睾酮可以增强FTE的迁移和侵袭，而雄激素受体（AR）拮抗剂比卡鲁胺可以逆转这一过程。睾酮还能增强FTSEC对小鼠卵巢基质的粘附。总的来说，这些结果表明，人类原代输卵管组织和永生化的FTSEC对睾酮有反应，从而改变了调节入侵的基因表达，同时利用了一种新的策略来研究动态流体存在下的迁移。
Increased testosterone has been associated with increased risk of ovarian cancer. High Grade Serous Ovarian Carcinoma (HGSOC) mostly originates from the fallopian tube epithelium (FTE), however, the stepwise events that occur during its tumorigenic transformation are unknown. Early lesion models of fallopian tube cancer stimulate the ovary to produce more androgen, supporting the hypothesis that high levels of testosterone may contribute to HGSOC early development. Nevertheless, the role of androgens in ovarian cancer has not been investigated. This study addresses the role of androgen in the early development of ovarian cancer from primary human FTE. Our results show that increased testosterone alters mRNA profile of hFTE, increasing WNT4 and LGR6 expression as well as increasing the migratory ability of fallopian tube epithelial cells. Fallopian tube epithelium (FTE) plays a critical role in reproduction and can be the site where High Grade Serous Ovarian Carcinoma (HGSOC) originates. Tumorigenic oviductal cells, which are the murine equivalent of human fallopian tube secretory epithelial cells (FTSEC), enhance testosterone secretion by the ovary when co-cultured with the ovary, suggesting that testosterone is part of the signaling axis between the ovary and FTSEC. Furthermore, testosterone promotes proliferation of oviductal cells. Oral contraceptives, tubal ligation, and salpingectomy, which are all protective against developing ovarian cancer, also decrease circulating levels of androgen. In the current study, we investigated the effect of increased testosterone on FTE and found that testosterone upregulates wingless-type MMTV integration family, member 4 (WNT4) and induces migration and invasion of immortalized human fallopian tube cells. We profiled primary human fallopian tissues grown in the microfluidic system SOLO-microfluidic platform –(MFP) by RNA sequencing and found that p53 and its downstream target genes, such as paired box gene 2 (PAX2), cyclin-dependent kinase inhibitor 1A (CDK1A or p21), and cluster of differentiation 82 (CD82 or KAI1) were downregulated in response to testosterone treatment. A microfluidic platform, the PREDICT-Multi Organ System (PREDICT-MOS) was engineered to support insert technology that allowed for the study of cancer cell migration and invasion through Matrigel. Using this system, we found that testosterone enhanced FTE migration and invasion, which was reversed by the androgen receptor (AR) antagonist, bicalutamide. Testosterone also enhanced FTSEC adhesion to the ovarian stroma using murine ovaries. Overall, these results indicate that primary human fallopian tube tissue and immortalized FTSEC respond to testosterone to shift expression of genes that regulate invasion, while leveraging a new strategy to study migration in the presence of dynamic fluid flow.
登录
查看更多内容
影响因子：
3.9
作者：
King SM;Hilliard TS;Wu LY;Jaffe RC;Fazleabas AT;Burdette JE
通讯作者：
Burdette JE
Nanog与雄激素受体信号轴的相互作用诱导卵巢癌干细胞调节：基于CRISPR/Cas9系统的研究
影响因子：
4
作者：
Ling K;Jiang L;Liang S;Kwong J;Yang L;Li Y;PingYin;Deng Q;Liang Z
通讯作者：
Liang Z
影响因子：
2.9
作者：
GASPARD, UJ;ROMUS, MA;FRANCHIMONT, P
通讯作者：
FRANCHIMONT, P
影响因子：
5.8
作者：
Cermik, D;Selam, B;Taylor, HS
通讯作者：
Taylor, HS
影响因子：
4.7
作者：
Dean, Matthew;Jin, Vivian;Burdette, Joanna E.
通讯作者：
Burdette, Joanna E.