Deletion of 3p13-14 locus spanning FOXP1 to SHQ1 cooperates with PTEN loss in prostate oncogenesis.
Deletion of 3p13-14 locus spanning FOXP1 to SHQ1 cooperates with PTEN loss in prostate oncogenesis.
复制标题
DOI：
10.1038/s41467-017-01198-9
复制
发表时间：
2017-10-20
影响因子：
16.6
通讯作者：
Sawyers CL
中科院分区：
文献类型：
--
作者：
Hieronymus H;Iaquinta PJ;Wongvipat J;Gopalan A;Murali R;Mao N;Carver BS;Sawyers CL
位于3 p13 -14的多基因位点，跨越FOXP 1到SHQ 1，通常在前列腺癌中缺失，并且在一系列癌症中广泛丢失，但对肿瘤发生或预后的意义尚不清楚。在这里，我们报告说，FOXP 1-SHQ 1缺失与PTEN的损失，加速前列腺肿瘤的发生和损失的组成基因与前列腺癌，乳腺癌，头颈癌复发。我们证明，Foxp 1-Shq 1缺失与Pten丢失相结合加速了小鼠的前列腺肿瘤发生，这与在人类癌症中观察到的FOXP 1-SHQ 1和PTEN丢失的相关性一致。合并Foxp 1-Shq 1和Pten缺失的肿瘤显示增殖和间变性去分化增加，以及mTORC 1过度活化和Akt磷酸化减少。Foxp 1-Shq 1缺失恢复Pten缺失肿瘤中受抑制的AR靶基因的表达，绕过PI 3 K介导的雄激素轴抑制。此外，FOXP 1-SHQ 1缺失具有预后相关性，癌症复发与PTEN和FOXP 1-SHQ 1基因的联合缺失相关。尽管3 p13 -14位点在前列腺癌中通常缺失，但潜在驱动基因的身份仍不清楚。在这里，作者使用PTEN丢失驱动的前列腺癌小鼠模型，表明多基因FOXP 1-SHQ 1缺失是具有预后价值的驱动事件。
A multigenic locus at 3p13-14, spanning FOXP1 to SHQ1, is commonly deleted in prostate cancer and lost broadly in a range of cancers but has unknown significance to oncogenesis or prognosis. Here, we report that FOXP1-SHQ1 deletion cooperates with PTEN loss to accelerate prostate oncogenesis and that loss of component genes correlates with prostate, breast, and head and neck cancer recurrence. We demonstrate that Foxp1-Shq1 deletion accelerates prostate tumorigenesis in mice in combination with Pten loss, consistent with the association of FOXP1-SHQ1 and PTEN loss observed in human cancers. Tumors with combined Foxp1-Shq1 and Pten deletion show increased proliferation and anaplastic dedifferentiation, as well as mTORC1 hyperactivation with reduced Akt phosphorylation. Foxp1-Shq1 deletion restores expression of AR target genes repressed in tumors with Pten loss, circumventing PI3K-mediated repression of the androgen axis. Moreover, FOXP1-SHQ1 deletion has prognostic relevance, with cancer recurrence associated with combined loss of PTEN and FOXP1-SHQ1 genes. Although the locus at 3p13-14 is commonly deleted in prostate cancer, the identity of the potential driver genes is still unclear. Here, the authors, using a PTEN loss-driven prostate cancer mouse model, show that a multigenic FOXP1-SHQ1 deletion is a driver event with prognostic value.
登录
查看更多内容
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
2.9
作者：
Halacli SO;Dogan AL
通讯作者：
Dogan AL
影响因子：
64.8
作者：
Cheng, MY;Bullock, CM;Zhou, QY
通讯作者：
Zhou, QY
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network