Potentiation of inflammatory CXCL8 signalling sustains cell survival in PTEN-deficient prostate carcinoma.
Potentiation of inflammatory CXCL8 signalling sustains cell survival in PTEN-deficient prostate carcinoma.
复制标题
DOI：
10.1016/j.eururo.2012.08.032
复制
发表时间：
2013-08
期刊：
影响因子：
23.4
通讯作者：
Waugh DJ
中科院分区：
文献类型：
--
作者：
Maxwell PJ;Coulter J;Walker SM;McKechnie M;Neisen J;McCabe N;Kennedy RD;Salto-Tellez M;Albanese C;Waugh DJ
炎症和遗传不稳定性是前列腺癌（PCa）的特征。肿瘤抑制基因磷酸酶和张力蛋白同源物（PTEN）的失活在早期PCa中是普遍的。PTEN缺陷与炎症信号传导的关系仍有待研究。确定PTEN功能丧失如何调节PCa中临床相关的促炎趋化因子的表达和功效。实验在建立的基于细胞的PCa模型中进行，由从携带一个PTEN等位基因失活的PTEN杂合（Pten+/−）小鼠收获的前列腺组织中的趋化因子表达的病理分析支持。在正常和缺氧培养条件下测定，使用小干扰RNA（siRNA）或小发夹RNA（shRNA）定向策略来抑制PTEN表达和由此产生的白细胞介素-8（CXCL 8）信号传导。通过实时聚合酶链反应（PCR）、免疫印迹、酶联免疫吸附试验（ELISA）和免疫组化分析PCa细胞和组织中趋化因子表达的变化;通过细胞周期分析、细胞凋亡和存活测定评估趋化因子信号传导对细胞功能的影响。瞬时（siRNA）或延长（shRNA）的PTEN抑制增加了PCa细胞中CXCL 8及其受体、趋化因子（C-X-C基序）受体（CXCR）1和CXCR 2的表达。缺氧诱导的CXCL 8、CXCR 1和CXCR 2表达的增加在PTEN缺失的细胞中在幅度和持续时间上更大。自分泌CXCL 8信号在PTEN缺失的细胞中更有效，诱导缺氧诱导因子-1（HIF-1）和活化B细胞核因子κ轻链增强子（NF-κB）转录，并调节参与存活和血管生成的基因。在Pten+/−鼠前列腺组织中，相对于野生型PTEN（PtenWT）腺体中的正常上皮，在显示非典型细胞学特征的区域中观察到正向趋化因子KC的表达增加。减弱CXCL 8信号通过促进G1期细胞周期阻滞和凋亡降低了携带部分或完全PTEN损失的PCa细胞的活力。目前缺乏临床验证是该研究的局限性。PTEN缺失诱导CXCL 8信号传导的选择性上调，其维持PTEN缺陷型前列腺上皮的生长和存活。
Inflammation and genetic instability are enabling characteristics of prostate carcinoma (PCa). Inactivation of the tumour suppressor gene phosphatase and tensin homolog (PTEN) is prevalent in early PCa. The relationship of PTEN deficiency to inflammatory signalling remains to be characterised. To determine how loss of PTEN functionality modulates expression and efficacy of clinically relevant, proinflammatory chemokines in PCa. Experiments were performed in established cell-based PCa models, supported by pathologic analysis of chemokine expression in prostate tissue harvested from PTEN heterozygous (Pten+/−) mice harbouring inactivation of one PTEN allele. Small interfering RNA (siRNA)–or small hairpin RNA (shRNA)–directed strategies were used to repress PTEN expression and resultant interleukin-8 (CXCL8) signalling, determined under normal and hypoxic culture conditions. Changes in chemokine expression in PCa cells and tissue were analysed by real-time polymerase chain reaction (PCR), immunoblotting, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry; effects of chemokine signalling on cell function were assessed by cell cycle analysis, apoptosis, and survival assays. Transient (siRNA) or prolonged (shRNA) PTEN repression increased expression of CXCL8 and its receptors, chemokine (C-X-C motif) receptor (CXCR) 1 and CXCR2, in PCa cells. Hypoxia-induced increases in CXCL8, CXCR1, and CXCR2 expression were greater in magnitude and duration in PTEN-depleted cells. Autocrine CXCL8 signalling was more efficacious in PTEN-depleted cells, inducing hypoxia-inducible factor-1 (HIF-1) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcription and regulating genes involved in survival and angiogenesis. Increased expression of the orthologous chemokine KC was observed in regions displaying atypical cytologic features in Pten+/− murine prostate tissue relative to normal epithelium in wild-type PTEN (PtenWT) glands. Attenuation of CXCL8 signalling decreased viability of PCa cells harbouring partial or complete PTEN loss through promotion of G1 cell cycle arrest and apoptosis. The current absence of clinical validation is a limitation of the study. PTEN loss induces a selective upregulation of CXCL8 signalling that sustains the growth and survival of PTEN-deficient prostate epithelium.
登录
查看更多内容
影响因子：
6
作者：
Bekes, Erin M.;Schweighofer, Bernhard;Deryugina, Elena I.
通讯作者：
Deryugina, Elena I.
影响因子：
4
作者：
Sun, YX;Wang, JC;Taichman, RS
通讯作者：
Taichman, RS
影响因子：
4.7
作者：
Seaton, Angela;Scullin, Paula;Waugh, David J. J.
通讯作者：
Waugh, David J. J.
影响因子：
--
作者：
Zhong, H;Semenza, GL;De Marzo, AM
通讯作者：
De Marzo, AM
影响因子：
9.2
作者：
Sun, Xueqing;Cheng, Guangcun;Hao, Mingang;Zheng, Jianghua;Zhou, Xiaoming;Zhang, Jian;Taichman, Russell S.;Pienta, Kenneth J.;Wang, Jianhua
通讯作者：
Wang, Jianhua