Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China.
Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
Acta Pharmacol Sin. 2019 Sep;40(9):1228-1236. doi: 10.1038/s41401-019-0234-8. Epub 2019 Apr 26.
Bufalin, the major active component of the traditional Chinese medicine ChanSu obtained from the skin and parotid venom glands of toads, has long been known as an anticancer agent. Recent studies show that microRNAs (miRs) are involved in the anticancer activities of bufalin, while long non-coding RNAs (lncRNAs) are known to interact with miRNAs to regulate various biological functions. In this paper, we investigated the possible network related to the antimetastatic effect of bufalin in prostate cancer (PCa) cells. We demonstrated that bufalin (0.05-10 µM) dose-dependently suppressed the proliferation of prostate cancer DU145 and PC3 cells with IC values of 0.89 and 1.28 µM, respectively. Furthermore, bufalin treatment significantly suppressed the cell migration and invasion. To explore the role of lncRNAs in the antimetastatic activity of bufalin, we used an lncRNA microarray and found that HOX transcript antisense RNA (HOTAIR) was the most markedly downregulated lncRNA in bufalin-treated PCa cells. Overexpression of HOTAIR counteracted the suppressing effects of bufalin on DU145 and PC3 cells. We then predicted and verified that HOTAIR upregulated FGFR1 expression by sponging miR-520b in PCa cells. In 40 patients with PCa bone metastasis, we used in situ hybridization or immunohistochemical assay to assess the HOTAIR and FGFR1 expression, which revealed that both HOTAIR and FGFR1 expression were significantly higher in bone metastasis tissues than in the primary PCa tissues. In addition, the level of serum HOTAIR was positively associated with the levels of serum bone metabolic markers (CTx, OST, B-ALP and PINP) and may serve as a reasonable biomarker for PCa bone metastasis. Taken together, this is the first study revealing that HOTAIR promotes PCa bone metastasis, and bufalin may be a promising candidate for the treatment of this disease.
蟾酥是从蟾蜍皮肤和腮腺毒液腺中提取的传统中药中的主要活性成分，长期以来一直被认为是一种抗癌剂。最近的研究表明，microRNAs（miRs）参与了蟾酥的抗癌活性，而长链非编码 RNA（lncRNAs）已知与 miRNAs 相互作用以调节各种生物功能。在本文中，我们研究了蟾酥在前列腺癌细胞中的抗转移作用的可能网络。我们证明蟾酥（0.05-10μM）剂量依赖性地抑制前列腺癌 DU145 和 PC3 细胞的增殖，IC 值分别为 0.89 和 1.28μM。此外，蟾酥处理显著抑制细胞迁移和侵袭。为了探讨 lncRNAs 在蟾酥抗转移活性中的作用，我们使用 lncRNA 微阵列发现，HOX 转录反义 RNA（HOTAIR）是蟾酥处理的前列腺癌细胞中下调最明显的 lncRNA。HOTAIR 的过表达抵消了蟾酥对 DU145 和 PC3 细胞的抑制作用。我们随后预测并验证了 HOTAIR 通过海绵 miR-520b 上调前列腺癌细胞中的 FGFR1 表达。在 40 例前列腺癌骨转移患者中，我们使用原位杂交或免疫组织化学检测评估 HOTAIR 和 FGFR1 的表达，结果表明骨转移组织中 HOTAIR 和 FGFR1 的表达均明显高于原发前列腺癌组织。此外，血清 HOTAIR 水平与血清骨代谢标志物（CTX、OST、B-ALP 和 PINP）水平呈正相关，可能作为前列腺癌骨转移的合理生物标志物。总之，这是第一项揭示 HOTAIR 促进前列腺癌骨转移的研究，蟾酥可能是治疗这种疾病的有前途的候选药物。
