PI3K/AKT pathway activation in bladder carcinogenesis
PI3K/AKT pathway activation in bladder carcinogenesis
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DOI：
10.1002/ijc.28518
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发表时间：
2014-04-15
影响因子：
6.4
通讯作者：
Allory, Yves
中科院分区：
文献类型：
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作者：
Calderaro, Julien;Rebouissou, Sandra;Allory, Yves
PI 3 K/AKT通路被认为在膀胱癌发生中起主要作用，但其与在膀胱癌中观察到的其他分子改变的关系仍然未知。我们根据PTEN表达、PTEN缺失和FGFR 3、PIK 3CA、KRAS、HRAS、NRAS和TP 53基因突变研究了一系列人膀胱尿路上皮癌（UC）中PI 3 K/AKT通路的激活。该系列包括6个正常膀胱尿路上皮样品和129个UC（Ta n = 25，T1 n = 34，T2-T3-T4 n = 70）。通过反相蛋白阵列评估磷酸化AKT（pAKT）、磷酸化S6-核糖体蛋白（pS 6）（PI 3 K/AKT通路的下游效应物）和PTEN的表达。还评估了已知调节PTEN表达的miR-21、miR-19 a和miR-222的表达。pAKT在肿瘤中的表达水平高于正常尿路上皮（p < 0.01），与分期无关，并且与pS 6呈弱正相关（斯皮尔曼系数R-S = 0.26; p = 0.002）。未观察到pAKT或pS 6表达与所研究的基因突变之间的关联。在PTEN缺失的肿瘤中，PTEN表达降低，在T1（p = 0.0089）和T2-T3-T4（p < 0.001）与Ta肿瘤相比;它也与miR-19 a呈负相关。（R-S = -0.50; p = 0.0088）和miR-222（R-S = -0.48; p = 0.0132），但不是miR-21（R-S = -0.27; p = 0.18）表达。pAKT和PTEN表达不呈负相关，相反，在Ta（R-S = 0.54; p = 0.0056）和T1（R-S = 0.56; p = 0.0006）肿瘤中观察到正相关和中度相关。我们的研究表明，PI 3 K/AKT通路激活发生在整个膀胱UC谱中，无论分期或已知最常见的分子改变如何，并且独立于低PTEN表达。
The PI3K/AKT pathway is considered to play a major role in bladder carcinogenesis, but its relationships with other molecular alterations observed in bladder cancer remain unknown. We investigated PI3K/AKT pathway activation in a series of human bladder urothelial carcinomas (UC) according to PTEN expression, PTEN deletions and FGFR3, PIK3CA, KRAS, HRAS, NRAS and TP53 gene mutations. The series included 6 normal bladder urothelial samples and 129 UC (Ta n = 25, T1 n = 34, T2-T3-T4 n = 70). Expression of phospho-AKT (pAKT), phospho-S6-Ribosomal Protein (pS6) (one downstream effector of PI3K/AKT pathway) and PTEN was evaluated by reverse phase protein Array. Expression of miR-21, miR-19a and miR-222, known to regulate PTEN expression, was also evaluated. pAKT expression levels were higher in tumors than in normal urothelium (p < 0.01), regardless of stage and showed a weak and positive correlation with pS6 (Spearman coefficient R-S = 0.26; p = 0.002). No association was observed between pAKT or pS6 expression and the gene mutations studied. PTEN expression was decreased in PTEN-deleted tumors, and in T1 (p = 0.0089) and T2-T3-T4 (p < 0.001) tumors compared to Ta tumors; it was also negatively correlated with miR-19a (R-S = -0.50; p = 0.0088) and miR-222 (R-S = -0.48; p = 0.0132), but not miR-21 (R-S = -0.27; p = 0.18) expression. pAKT and PTEN expressions were not negatively correlated, and, on the opposite, a positive and moderate correlation was observed in Ta (R-S = 0.54; p = 0.0056) and T1 (R-S = 0.56; p = 0.0006) tumors. Our study suggests that PI3K/AKT pathway activation occurs in the entire spectrum of bladder UC regardless of stage or known most frequent molecular alterations, and independently of low PTEN expression.