Activation of the hedgehog pathway in advanced prostate cancer
Activation of the hedgehog pathway in advanced prostate cancer
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DOI：
10.1186/1476-4598-3-29
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发表时间：
2004-01-01
期刊：
影响因子：
37.3
通讯作者：
Xie, Jingwu
中科院分区：
文献类型：
--
作者：
Sheng, Tao;Li, Chengxin;Xie, Jingwu
背景：hedgehog通路在前列腺的发育中起着关键作用。然而，刺猬通路在前列腺癌中的作用尚不清楚。前列腺癌是美国男性癌症死亡的第二大常见原因。因此，识别前列腺癌的新的治疗靶点具有显着的临床意义。结果：在这里，我们报告，激活刺猬通路经常发生在晚期人类前列腺癌。我们发现，在超过70%的Gleason评分为8-10的前列腺肿瘤中检测到高水平的hedgehog靶基因PTCH 1和hedgehog相互作用蛋白（HIP），但在Gleason评分为3-6的肿瘤中仅检测到22%。此外，四种可用的转移性肿瘤均具有PTCH 1和HIP的高表达。为了确定刺猬信号激活的机制，我们研究了Su（Fu）蛋白的表达，Su（Fu）蛋白是刺猬信号通路的负调节因子。我们发现，在27例PTCH 1阳性肿瘤中，有11例未检测到Su（Fu）蛋白，其中2例含有Su（Fu）的体细胞功能丧失突变。此外，在大多数PTCH 1阳性肿瘤中检测到音刺猬蛋白的表达（27个中的24个）。在四种前列腺癌细胞系（大津、DU 145、LN-Cap和PC 3）中也检测到高水平的hedgehog靶基因。我们证明，通过smoothened拮抗剂环巴胺抑制hedgehog信号传导，抑制hedgehog信号传导，下调细胞侵袭力并诱导细胞凋亡。此外，在CMV启动子下表达Gli 1的癌细胞对环巴胺介导的细胞凋亡具有抗性。所有这些数据表明，刺猬通路的前列腺癌cells.Conclusion的细胞功能的一个显着的作用：我们的数据表明，刺猬通路的激活，通过损失苏（Fu）或超表达的音刺猬，可能涉及肿瘤的进展和前列腺癌的转移。因此，hedgehog信号传导的靶向抑制可能对前列腺癌治疗具有重要意义。
Background: The hedgehog pathway plays a critical role in the development of prostate. However, the role of the hedgehog pathway in prostate cancer is not clear. Prostate cancer is the second most prevalent cause of cancer death in American men. Therefore, identification of novel therapeutic targets for prostate cancer has significant clinical implications.Results: Here we report that activation of the hedgehog pathway occurs frequently in advanced human prostate cancer. We find that high levels of hedgehog target genes, PTCH1 and hedgehoginteracting protein (HIP), are detected in over 70% of prostate tumors with Gleason scores 8-10, but in only 22% of tumors with Gleason scores 3-6. Furthermore, four available metastatic tumors all have high expression of PTCH1 and HIP. To identify the mechanism of the hedgehog signaling activation, we examine expression of Su(Fu) protein, a negative regulator of the hedgehog pathway. We find that Su(Fu) protein is undetectable in 11 of 27 PTCH1 positive tumors, two of them contain somatic loss-of-function mutations of Su(Fu). Furthermore, expression of sonic hedgehog protein is detected in majority of PTCH1 positive tumors (24 out of 27). High levels of hedgehog target genes are also detected in four prostate cancer cell lines (TSU, DU145, LN-Cap and PC3). We demonstrate that inhibition of hedgehog signaling by smoothened antagonist, cyclopamine, suppresses hedgehog signaling, down-regulates cell invasiveness and induces apoptosis. In addition, cancer cells expressing Gli1 under the CMV promoter are resistant to cyclopamine-mediated apoptosis. All these data suggest a significant role of the hedgehog pathway for cellular functions of prostate cancer cells.Conclusion: Our data indicate that activation of the hedgehog pathway, through loss of Su(Fu) or overexpression of sonic hedgehog, may involve tumor progression and metastases of prostate cancer. Thus, targeted inhibition of hedgehog signaling may have significant implications of prostate cancer therapeutics.