15-PGDH inhibits hepatocellular carcinoma growth through 15-keto-PGE2/PPARγ-mediated activation of p21WAF1/Cip1.
15-PGDH inhibits hepatocellular carcinoma growth through 15-keto-PGE2/PPARγ-mediated activation of p21WAF1/Cip1.
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15-羟基前列腺素脱氢酶（15-hydroxyprostaglandin dehydrogenase, 15-PGDH）是前列腺素代谢的关键酶。本研究为15-PGDH通过15-keto-PGE2/PPARγ/p21WAF1/Cip1信号通路抑制肝细胞癌（HCC）生长提供了重要证据。强制过表达15-PGDH抑制HCC细胞的体外生长，而敲低15-PGDH则增强肿瘤生长参数。在SCID小鼠肿瘤异种移植模型中，接种过表达15-PGDH的人HCC细胞（Huh7）可显著抑制肿瘤生长，而敲低15-PGDH可促进肿瘤生长。在将小鼠肝癌细胞（Hepa1-6）接种于同源C57BL/6小鼠的单独肿瘤移植模型中，瘤内注射表达15-PGDH的腺病毒载体（pAd-15-PGDH）可显著抑制异种移植肿瘤的生长。15-PGDH的抗肿瘤作用是通过其酶促产物15-酮- pge2介导的，其作为内源性PPARγ配体。15- pgdh衍生的15-keto-PGE2激活PPARγ增强了PPARγ与p21WAF1/Cip1启动子的关联，增加了p21的表达以及与CDK2、CDK4和PCNA的关联。shRNA缺失p21可逆转15- pgdh诱导的肝癌细胞生长抑制；p21过表达可阻止15-PGDH敲低诱导的肿瘤细胞生长。这些结果表明，关键的15-PGDH/15-keto- pge2介导的PPARγ和p21WAF1/Cip1信号级联激活调节肝癌发生和肿瘤进展。
15-hydroxyprostaglandin dehydrogenase (15-PGDH) is a key enzyme in prostaglandin metabolism. This study provides important evidence for inhibition of hepatocellular carcinoma (HCC) growth by 15-PGDH through the 15-keto-PGE2/PPARγ/p21WAF1/Cip1 signaling pathway. Forced overexpression of 15-PGDH inhibited HCC cell growth in vitro, whereas knockdown of 15-PGDH enhanced tumor growth parameters. In a tumor xenograft model in SCID mice, inoculation of human HCC cells (Huh7) with overexpression of 15-PGDH led to significant inhibition of tumor growth, while knockdown of 15-PGDH enhanced tumor growth. In a separate tumor xenograft model in which mouse HCC cells (Hepa1-6) were inoculated into syngeneic C57BL/6 mice, intratumoral injection of adenovirus vector expressing 15-PGDH (pAd-15-PGDH) significantly inhibited xenograft tumor growth. The anti-tumor effect of 15-PGDH is mediated through its enzymatic product, 15-keto-PGE2, which serves as an endogenous PPARγ ligand. Activation of PPARγ by 15-PGDH-derived 15-keto-PGE2 enhanced the association of PPARγ with the p21WAF1/Cip1 promoter and increased p21 expression and association with CDK2, CDK4 and PCNA. Depletion of p21 by shRNA reversed 15-PGDH-induced inhibition of HCC cell growth; overexpression of p21 prevented 15-PGDH knockdown-induced tumor cell growth. These results demonstrate a key 15-PGDH/15-keto-PGE2-mediated activation of PPARγ and p21WAF1/Cip1 signaling cascade that regulates hepatocarcinogenesis and tumor progression.
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