Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea.
Division of Breast Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea.
J Exp Clin Cancer Res. 2021 Jan 25;40(1):43. doi: 10.1186/s13046-021-01839-4.
Prostaglandin is one of the key metabolites for inflammation-related carcinogenesis. Despite the microRNA-155 is implicated in various types of cancers, it's function in prostaglandin metabolism is largely unknown.
A targeted profiling of eicosanoids including prostaglandin, leukotriene and thromboxanes was performed in miR-155 deficient breast tumors and cancer cells. The molecular mechanism of miR-155-mediated prostaglandin reprogramming was investigated in primary and cancer cell lines, by analyzing key enzymes responsible for the prostaglandin production.
We found miR-155-deficient breast tumors, plasma of tumor-bearing mouse and cancer cells show altered prostaglandin level, especially for the prostaglandin E2 (PGE2) and prostaglandin D2 (PGD2). Subsequent analysis in primary cancer cells, 20 triple-negative breast cancer (TNBC) specimens and breast cancer cell lines with miR-155 knockdown consistently showed a positive correlation between miR-155 level and PGE2/PGD2 ratio. Mechanistically, we reveal the miR-155 reprograms the prostaglandin metabolism by up-regulating PGE2-producing enzymes PTGES/PTGES2 while down-regulating PGD2-producing enzyme PTGDS. Further, we show the up-regulation of PTGES2 is driven by miR-155-cMYC axis, whereas PTGES is transactivated by miR-155-KLF4. Thus, miR-155 hires dual-regulatory mode for the metabolic enzyme expression to reprogram the PGE2/PGD2 balance. Lastly, we show the miR-155-driven cellular proliferation is restored by the siRNA of PTGES1/2, of which expression also significantly correlates with breast cancer patients' survival.
Considering clinical trials targeting PGE2 production largely have focused on the inhibition of Cox1 or Cox2 that showed cardiac toxicity, our data suggest an alternative way for suppressing PGE2 production via the inhibition of miR-155. As the antagomiR of miR-155 (MRG-106) underwent a phase-1 clinical trial, its effect should be considered and analyzed in prostaglandin metabolism in tumor.
前列腺素是与炎症相关的致癌作用的关键代谢物之一。尽管 microRNA-155 与多种类型的癌症有关，但它在前列腺素代谢中的功能在很大程度上是未知的。
在 miR-155 缺陷型乳腺癌肿瘤和癌细胞中进行了包括前列腺素、白三烯和血栓素在内的类二十烷酸的靶向分析。通过分析负责前列腺素产生的关键酶，在原代细胞和癌细胞系中研究了 miR-155 介导的前列腺素重编程的分子机制。
我们发现 miR-155 缺陷型乳腺癌肿瘤、荷瘤小鼠的血浆和癌细胞显示出改变的前列腺素水平，特别是前列腺素 E2（PGE2）和前列腺素 D2（PGD2）。在原代癌细胞、20 个三阴性乳腺癌（TNBC）标本和用 miR-155 敲低的乳腺癌细胞系中的后续分析中，miR-155 水平与 PGE2/PGD2 比值之间始终存在正相关。从机制上讲，我们发现 miR-155 通过上调 PGE2 产生酶 PTGES/PTGES2 同时下调 PGD2 产生酶 PTGDS 来重新编程前列腺素代谢。此外，我们表明 PTGES2 的上调是由 miR-155-cMYC 轴驱动的，而 PTGES 则由 miR-155-KLF4 转激活。因此，miR-155 采用双调节模式来表达代谢酶，以重新编程 PGE2/PGD2 平衡。最后，我们表明，通过 PTGES1/2 的 siRNA 可以恢复 miR-155 驱动的细胞增殖，其表达也与乳腺癌患者的生存显著相关。
鉴于靶向 PGE2 产生的临床试验主要集中在抑制 Cox1 或 Cox2，这些抑制剂显示出心脏毒性，我们的数据表明通过抑制 miR-155 来抑制 PGE2 产生的另一种方法。由于 miR-155 的反义寡核苷酸（MRG-106）已进行了 I 期临床试验，因此应考虑并分析其在肿瘤中前列腺素代谢中的作用。
