Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, but there are few effective treatments. Aberrant microRNA (miRNA) biogenesis is correlated with HCC development. We previously demonstrated that peptidyl‐prolyl cis‐trans isomerase NIMA‐interacting 1 (Pin1) participates in miRNA biogenesis and is a potential HCC treatment target. However, how Pin1 modulates miRNA biogenesis remains obscure. Here, we present in vivo evidence that Pin1 overexpression is directly linked to the development of HCC. Administration with the Pin1 inhibitor (API‐1), a specific small molecule targeting Pin1 peptidyl‐prolyl isomerase domain and inhibiting Pin1 cis‐trans isomerizing activity, suppresses in vitro cell proliferation and migration of HCC cells. But API‐1‐induced Pin1 inhibition is insensitive to HCC cells with low Pin1 expression and/or low exportin‐5 (XPO5) phosphorylation. Mechanistically, Pin1 recognizes and isomerizes the phosphorylated serine‐proline motif of phosphorylated XPO5 and passivates phosphorylated XPO5. Pin1 inhibition by API‐1 maintains the active conformation of phosphorylated XPO5 and restores XPO5‐driven precursor miRNA nuclear‐to‐cytoplasm export, activating anticancer miRNA biogenesis and leading to both in vitro HCC suppression and HCC suppression in xenograft mice. Conclusion: Experimental evidence suggests that Pin1 inhibition by API‐1 up‐regulates miRNA biogenesis by retaining active XPO5 conformation and suppresses HCC development, revealing the mechanism of Pin1‐mediated miRNA biogenesis and unequivocally supporting API‐1 as a drug candidate for HCC therapy, especially for Pin1‐overexpressing, extracellular signal–regulated kinase–activated HCC. (Hepatology 2018).

中文翻译：

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通过抑制剂 API-1 靶向 Pin1 调节 microRNA 生物发生并抑制肝细胞癌的发展

肝细胞癌（HCC）是全球癌症死亡的主要原因，但有效的治疗方法很少。异常的微小 RNA (miRNA) 生物发生与 HCC 的发展相关。我们之前证明肽基-脯氨酰顺反异构酶 NIMA 相互作用 1 (Pin1) 参与 miRNA 生物发生并且是潜在的 HCC 治疗靶点。然而，Pin1 如何调节 miRNA 生物发生仍不清楚。在这里，我们提出了体内证据，表明 Pin1 过表达与 HCC 的发展直接相关。Pin1 抑制剂 (API-1) 是一种特异性小分子，靶向 Pin1 肽基-脯氨酰异构酶结构域并抑制 Pin1 顺反异构化活性，可抑制体外细胞增殖和 HCC 细胞迁移。但是 API-1 诱导的 Pin1 抑制对具有低 Pin1 表达和/或低输出蛋白 5 (XPO5) 磷酸化的 HCC 细胞不敏感。在机制上，Pin1 识别磷酸化 XPO5 的磷酸化丝氨酸-脯氨酸基序并使其异构化，并钝化磷酸化 XPO5。API-1 抑制 Pin1 维持磷酸化 XPO5 的活性构象并恢复 XPO5 驱动的前体 miRNA 核向细胞质输出，激活抗癌 miRNA 生物发生并导致体外 HCC 抑制和异种移植小鼠的 HCC 抑制。结论：实验证据表明，API-1 抑制 Pin1 通过保留活性 XPO5 构象上调 miRNA 生物发生并抑制 HCC 发展，揭示了 Pin1 介导的 miRNA 生物发生机制并明确支持 API-1 作为 HCC 治疗的候选药物，特别是对于 Pin1 过表达、细胞外信号调节激酶激活的 HCC。（肝病学 2018）。