HOXB13 promotes androgen independent growth of LNCaP prostate cancer cells by the activation of E2F signaling.
HOXB13 promotes androgen independent growth of LNCaP prostate cancer cells by the activation of E2F signaling.
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DOI：
10.1186/1476-4598-9-124
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发表时间：
2010-05-27
期刊：
影响因子：
37.3
通讯作者：
Jung C
中科院分区：
文献类型：
--
作者：
Kim YR;Oh KJ;Park RY;Xuan NT;Kang TW;Kwon DD;Choi C;Kim MS;Nam KI;Ahn KY;Jung C
雄激素信号传导在前列腺癌的发生和进展中起着关键作用。然而，激素消融治疗后出现雄激素非依赖性前列腺癌细胞，导致严重的临床问题。我们先前已经证明HOXB 13同源域蛋白通过抑制雄激素介导的信号而作为前列腺癌细胞生长抑制剂发挥作用。然而，HOXB 13在前列腺癌细胞的雄激素非依赖性生长中的作用仍然无法解释。在这份报告中，我们首次证明，HOXB 13是高度过表达的肿瘤相比，不含前列腺特异性抗原的肿瘤，在初始治疗后的复发难治性肿瘤。在功能上，在无雄激素的环境中，LNCaP前列腺癌细胞中HOXB 13的最小诱导达到正常前列腺的水平，显著促进细胞增殖，而抑制抑制细胞增殖。在雄激素不存在的情况下，HOXB 13介导的细胞生长促进似乎主要通过抑制p21 waf肿瘤抑制因子的表达来激活RB-E2 F信号传导来实现。事实上，HOXB 13的强制表达显著降低了p21 waf的表达;这种抑制在很大程度上影响了HOXB 13介导的E2 F信号传导的促进作用。总之，这项研究的结果表明存在一种新的途径，有助于了解前列腺癌细胞的雄激素非依赖性生存。这些发现表明，HOXB 13的上调与前列腺癌细胞在缺乏雄激素或低雄激素浓度下通过调节p21介导的E2 F信号传导的附加生长优势相关。
Androgen signaling plays a critical role in the development of prostate cancer and its progression. However, androgen-independent prostate cancer cells emerge after hormone ablation therapy, resulting in significant clinical problems. We have previously demonstrated that the HOXB13 homeodomain protein functions as a prostate cancer cell growth suppressor by inhibiting androgen-mediated signals. However, the role of the HOXB13 in androgen-independent growth of prostate cancer cells remains unexplained. In this report, we first demonstrated that HOXB13 was highly overexpressed in hormone-refractory tumors compared to tumors without prostate-specific antigen after initial treatment. Functionally, in an androgen-free environment minimal induction of HOXB13 in LNCaP prostate cancer cells, to the level of the normal prostate, markedly promoted cell proliferation while suppression inhibited cell proliferation. The HOXB13-mediated cell growth promotion in the absence of androgen, appears to be mainly accomplished through the activation of RB-E2F signaling by inhibiting the expression of the p21waf tumor suppressor. Indeed, forced expression of HOXB13 dramatically decreased expression of p21waf; this inhibition largely affected HOXB13-mediated promotion of E2F signaling. Taken together, the results of this study demonstrated the presence of a novel pathway that helps understand androgen-independent survival of prostate cancer cells. These findings suggest that upregulation of HOXB13 is associated with an additive growth advantage of prostate cancer cells in the absence of or low androgen concentrations, by the regulation of p21-mediated E2F signaling.
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