Perlecan, a candidate gene for the CAPB locus, regulates prostate cancer cell growth via the Sonic Hedgehog pathway.
Perlecan, a candidate gene for the CAPB locus, regulates prostate cancer cell growth via the Sonic Hedgehog pathway.
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DOI：
10.1186/1476-4598-5-9
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发表时间：
2006-03-01
期刊：
影响因子：
37.3
通讯作者：
Datta S
中科院分区：
文献类型：
--
作者：
Datta MW;Hernandez AM;Schlicht MJ;Kahler AJ;DeGueme AM;Dhir R;Shah RB;Farach-Carson C;Barrett A;Datta S
遗传研究将CAPB基因座与脑癌和前列腺癌的家族风险联系起来。我们已经确定HSPG 2（串珠素）作为CAPB的候选基因。以前，我们已经在果蝇中将串珠素与刺猬信号联系起来。最近，我们已经证明了Hedgehog信号在人类晚期前列腺癌中的重要性。在这里，我们展示了串珠素在前列腺癌中的表达，以及其通过Sonic Hedgehog（SHH）信号传导的相互作用和调节在前列腺癌细胞生长中的功能。前列腺癌组织中的串珠素表达与高Gleason评分和快速细胞增殖相关。串珠素在前列腺癌细胞系中高度表达，包括雄激素不敏感细胞系和针对转移特性选择的细胞系。在这些细胞系中抑制串珠素表达会降低细胞生长。在雄激素敏感细胞系LNCaP中同时阻断串珠素表达和雄激素信号传导是相加的，表明这两种途径的独立性。基于Ki-67免疫组织化学，串珠素表达与肿瘤组织微阵列中的SHH和增加的肿瘤细胞增殖相关。在前列腺癌细胞系中通过siRNA抑制串珠素表达降低了SHH信号传导，而下游SHH效应物GLI 1的表达挽救了增殖缺陷。串珠素与增加量的SHH形成复合物，其与前列腺癌细胞系的增加的转移潜力相关。SHH信号传导在转移性更强的细胞系中也增加。转移性前列腺癌细胞系生长在血清饥饿条件下（低雄激素和生长因子）导致串珠素表达的维持。在低雄激素、低生长因子条件下，串珠素表达水平与细胞维持SHH信号传导的能力相关。我们已经证明，串珠素，CAPB基因座的候选基因，是一个新的组成部分，SHH途径在前列腺肿瘤和工作独立的雄激素信号。在转移性肿瘤细胞中，增加的SHH信号传导与串珠素表达和更多串珠素-SHH复合物的维持相关。串珠素是一种蛋白聚糖，其调节细胞外和基质对生长因子如SHH的可及性，从而允许在生长因子限制条件下维持SHH信号传导。这种蛋白聚糖代表了SHH活性的重要中枢调节因子，并为阻断SHH效应提供了理想的药物靶点。
Genetic studies associated the CAPB locus with familial risk of brain and prostate cancers. We have identified HSPG2 (Perlecan) as a candidate gene for CAPB. Previously we have linked Perlecan to Hedgehog signaling in Drosophila. More recently, we have demonstrated the importance of Hedgehog signaling in humans for advanced prostate cancer. Here we demonstrate Perlecan expression in prostate cancer, and its function in prostate cancer cell growth through interaction and modulation of Sonic Hedgehog (SHH) signaling. Perlecan expression in prostate cancer tissues correlates with a high Gleason score and rapid cell proliferation. Perlecan is highly expressed in prostate cancer cell lines, including androgen insensitive cell lines and cell lines selected for metastatic properties. Inhibition of Perlecan expression in these cell lines decreases cell growth. Simultaneous blockade of Perlecan expression and androgen signaling in the androgen-sensitive cell line LNCaP was additive, indicating the independence of these two pathways. Perlecan expression correlates with SHH in tumor tissue microarrays and increased tumor cell proliferation based on Ki-67 immunohistochemistry. Inhibition of Perlecan expression by siRNA in prostate cancer cell lines decreases SHH signaling while expression of the downstream SHH effector GLI1 rescues the proliferation defect. Perlecan forms complexes with increasing amounts of SHH that correlate with increasing metastatic potential of the prostate cancer cell line. SHH signaling also increases in the more metastatic cell lines. Metastatic prostate cancer cell lines grown under serum-starved conditions (low androgen and growth factors) resulted in maintenance of Perlecan expression. Under low androgen, low growth factor conditions, Perlecan expression level correlates with the ability of the cells to maintain SHH signaling. We have demonstrated that Perlecan, a candidate gene for the CAPB locus, is a new component of the SHH pathway in prostate tumors and works independently of androgen signaling. In metastatic tumor cells increased SHH signaling correlates with the maintenance of Perlecan expression and more Perlecan-SHH complexes. Perlecan is a proteoglycan that regulates extracellular and stromal accessibility to growth factors such as SHH, thus allowing for the maintenance of SHH signaling under growth factor limiting conditions. This proteoglycan represents an important central regulator of SHH activity and presents an ideal drug target for blocking SHH effects.
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