Kanazawa University, Kanazawa, 920-1192, Japan.
Faculty of Pharmacy, Kindai University, Higashiosaka, Osaka, Japan.
Sci Rep. 2017 Nov 29;7(1):16567. doi: 10.1038/s41598-017-16738-y.
Prostaglandin E (PGE) is associated with proliferation and angiogenesis in colorectal tumours. The role of prostaglandin transporter OATP2A1/SLCO2A1 in colon cancer tumorogenesis is unknown. We evaluated mice of various Slco2a1 genotypes in a murine model of colon cancer, the adenomatous polyposis (APC) mutant (Apc ) model. Median lifespan was significantly extended from 19 weeks in Slco2a1 /Apc mice to 25 weeks in Slco2a1 /Apc mice. Survival was directly related to a reduction in the number of large polyps in the Slco2a1 /Apc compared to the Slco2a1 /Apc or Slco2a1 /Apc mice. The large polyps from the Slco2a1 /Apc mice had significant reductions in microvascular density, consistent with the high expression of Slco2a1 in the tumour-associated vascular endothelial cells. Chemical suppression of OATP2A1 function significantly reduced tube formation and wound-healing activity of PGE in human vascular endothelial cells (HUVECs) although the amount of extracellular PGE was not affected by an OATP2A1 inhibitor. Further an in vivo model of angiogenesis, showed a significant reduction of haemoglobin content (54.2%) in sponges implanted into Slco2a1 , compared to wildtype mice. These studies indicate that OATP2A1 is likely to promote tumorogenesis by PGE uptake into the endothelial cells, suggesting that blockade of OATP2A1 is an additional pharmacologic strategy to improve colon cancer outcomes.
前列腺素 E（PGE）与结直肠肿瘤的增殖和血管生成有关。前列腺素转运蛋白 OATP2A1/SLCO2A1 在结肠癌肿瘤发生中的作用尚不清楚。我们在结直肠腺瘤（APC）突变（Apc）模型的小鼠模型中评估了各种 Slco2a1 基因型的小鼠。中位寿命从 Slco2a1/Apc 小鼠的 19 周显著延长至 Slco2a1/Apc 小鼠的 25 周。存活与 Slco2a1/Apc 小鼠中大型息肉数量的减少直接相关，与 Slco2a1/Apc 或 Slco2a1/Apc 小鼠相比。Slco2a1/Apc 小鼠的大型息肉的微血管密度显著降低，与肿瘤相关的血管内皮细胞中 Slco2a1 的高表达一致。尽管 OATP2A1 抑制剂不影响细胞外 PGE 的量，但 OATP2A1 功能的化学抑制显著降低了人血管内皮细胞（HUVEC）中 PGE 的管形成和伤口愈合活性。此外，在血管生成的体内模型中，与野生型小鼠相比，植入 Slco2a1 的海绵中的血红蛋白含量（54.2%）显著降低。这些研究表明，OATP2A1 可能通过将 PGE 摄取到内皮细胞中促进肿瘤发生，这表明阻断 OATP2A1 是改善结肠癌结局的另一种药理学策略。
