Yoshikawa H, Matsubara K, Qian G S, Jackson P, Groopman J D, Manning J E, Harris C C, Herman J G
The Johns Hopkins University School of Medicine, The Oncology Center, Baltimore, Maryland, USA.
Nat Genet. 2001 May;28(1):29-35. doi: 10.1038/ng0501-29.
Hepatocellular carcinoma (HCC) is a major cause of cancer death, but the molecular mechanism for its development beyond its initiation has not been well characterized. Suppressor of cytokine signaling (SOCS-1; also known as JAB and SSI-1) switches cytokine signaling 'off' by means of its direct interaction with Janus kinase (JAK). We identified aberrant methylation in the CpG island of SOCS-1 that correlated with its transcription silencing in HCC cell lines. The incidence of aberrant methylation was 65% in the 26 human primary HCC tumor samples analyzed. Moreover, the restoration of SOCS-1 suppressed both growth rate and anchorage-independent growth of cells in which SOCS-1 was methylation-silenced and JAK2 was constitutively activated. This growth suppression was caused by apoptosis and was reproduced by AG490, a specific, chemical JAK2 inhibitor that reversed constitutive phosphorylation of STAT3 in SOCS-1 inactivated cells. The high prevalence of the aberrant SOCS-1 methylation and its growth suppression activity demonstrated the importance of the constitutive activation of the JAK/STAT pathway in the development of HCC. Our results also indicate therapeutic strategies for the treatment of HCC including use of SOCS-1 in gene therapy and inhibition of JAK2 by small molecules, such as AG490.
肝细胞癌（HCC）是癌症死亡的主要原因之一，但其起始后发展的分子机制尚未得到充分阐明。细胞因子信号转导抑制因子（SOCS-1；也称为JAB和SSI-1）通过与Janus激酶（JAK）直接相互作用来“关闭”细胞因子信号转导。我们在SOCS-1的CpG岛中发现了异常甲基化，这与其在肝癌细胞系中的转录沉默相关。在所分析的26个人类原发性肝癌肿瘤样本中，异常甲基化的发生率为65%。此外，SOCS-1的恢复抑制了SOCS-1甲基化沉默且JAK2组成性激活的细胞的生长速率和非贴壁依赖性生长。这种生长抑制是由凋亡引起的，并且可被AG490重现，AG490是一种特异性化学JAK2抑制剂，可逆转SOCS-1失活细胞中STAT3的组成性磷酸化。异常SOCS-1甲基化的高发生率及其生长抑制活性表明JAK/STAT通路的组成性激活在HCC发展中的重要性。我们的结果还表明了HCC的治疗策略，包括在基因治疗中使用SOCS-1以及用小分子如AG490抑制JAK2。
