Singsuksawat Ekapot, Thuwajit Chanitra, Charngkaew Komgrid, Thuwajit Peti
1Graduate Program in Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wang Lang Road, Bangkok Noi, Bangkok, 10700 Thailand.
2Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wang Lang Road, Bangkok Noi, Bangkok, 10700 Thailand.
Cancer Cell Int. 2018 Feb 20;18:25. doi: 10.1186/s12935-018-0525-z. eCollection 2018.
Cholangiocarcinoma (CCA) is one of the worst prognosis cancer. The survival time of CCA patients is related to serum estrogen levels and estrogen has been found to enhance the proliferation and invasiveness of CCA cells in vitro. This has led to the suggestion that estrogen may play an important role in the progression of CCA. This study tests the relevance of the previous in vitro findings in vivo using a mouse xenograft model of CCA, and investigates possible signaling mechanisms involved.
KKU-213 and KKU-139 CCA cell lines were used in the experiments, xenografted to nude mice and treated with a potent estrogenic agent, 17β-estradiol (E2), and/or with tamoxifen (TAM), an estrogen antagonist.
The results demonstrated that E2 could accelerate growth of the xenograft-tumor and the effect was inhibited by TAM. PCR array screening of E2 responsive genes suggested ETV4 as a promising candidate intracellular mediator. ETV4-knockdown CCA cells were generated and these showed a diminished responsiveness to E2 in both cell and spheroid proliferation assays, and in invasion tests. These results point to ETV4 as a possible mediator of E2-activated CCA progression and as a potential target of TAM-mediated inhibition.
Finally, TAM may be suggested as an adjunctive treatment of CCA to improve the conventional cytotoxic method with more patient toleration.
胆管癌（CCA）是预后最差的癌症之一。CCA患者的生存时间与血清雌激素水平相关，并且已发现雌激素可在体外增强CCA细胞的增殖和侵袭性。这表明雌激素可能在CCA的进展中起重要作用。本研究使用CCA的小鼠异种移植模型在体内测试先前体外研究结果的相关性，并研究其中可能涉及的信号传导机制。
实验使用KKU-213和KKU-139 CCA细胞系，将其异种移植到裸鼠体内，并用强效雌激素药物17β-雌二醇（E2）和/或雌激素拮抗剂他莫昔芬（TAM）进行治疗。
结果表明，E2可加速异种移植肿瘤的生长，而TAM可抑制该作用。对E2反应基因进行PCR阵列筛选表明，ETV4是一个有前景的细胞内介质候选基因。构建了ETV4基因敲低的CCA细胞，这些细胞在细胞和球体增殖试验以及侵袭试验中对E2的反应性均降低。这些结果表明，ETV4可能是E2激活的CCA进展的介质，也是TAM介导的抑制作用的潜在靶点。
最后，他莫昔芬可作为CCA的辅助治疗药物，以改进传统的细胞毒性方法，提高患者耐受性。
