Goto Akiteru, Dobashi Yoh, Tsubochi Hiroyoshi, Maeda Daichi, Ooi Akishi
Department of Cellular and Organ Pathology, Graduate School of Medicine, Akita University, Akita, Akita 010-8543, Japan.
Department of Pathology, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan.
Hum Pathol. 2016 Oct;56:1-10. doi: 10.1016/j.humpath.2016.04.011. Epub 2016 May 14.
MicroRNA (miRNA) expression profiles were examined in 3 groups of lung carcinomas that had been stratified by increases in AKT1 or AKT2 gene number. Microarray analysis using 2000 probes revealed 87 miRNAs that were up-regulated and 32 down-regulated miRNAs in carcinomas harboring amplification or high-level polysomy of the AKT1 (AKT1+), as well as 123 up-regulated and 83 down-regulated miRNAs in those of the AKT2 genes (AKT2+), in comparison with carcinomas harboring disomy of both (AKTd/d). In total, 182 miRNAs were up-regulated in AKT1+ or AKT2+, compared with AKTd/d. Among these, 28 miRNAs were up-regulated in both the AKT1+ and AKT2+ groups, with a log2 ratio between 1.02 and 3.71 relative to AKTd/d group, including all miR-200 family members. Quantitative real-time polymerase chain reaction showed that carcinomas exhibiting lymph vessel invasion had significantly lower expression of miR-200a (P=.0230) and miR-200b (P=.0168), regardless of the status of the AKT genes. Moreover, a detailed statistical analysis revealed that, in adenocarcinoma and in the early stage of carcinomas (pathologic stage I/II), expression of miR-200a was higher in the AKT2+ group compared with the AKT1+ group, and these differences were statistically significant (P=.0334 and P=.0239, respectively). However, the expression of miR-200a was not significantly correlated with the expression of its target, the zinc finger E-box-binding homeobox 1 (ZEB1; P=.3801) or E-cadherin (P=.2840), a marker of the epithelial-mesenchymal transition. These results suggest that AKT2 can regulate miR-200a in a histology- or stage-specific manner and that this regulation is independent of subsequent involvement of miR-200a in epithelial-mesenchymal transition.
在3组已根据AKT1或AKT2基因数量增加进行分层的肺癌中检测了微小RNA（miRNA）表达谱。使用2000个探针的微阵列分析显示，与同时具有双体性的癌（AKTd/d）相比，在具有AKT1扩增或高水平多体性的癌（AKT1+）中，有87个miRNA上调，32个miRNA下调；在具有AKT2基因扩增或高水平多体性的癌（AKT2+）中，有123个miRNA上调，83个miRNA下调。与AKTd/d相比，在AKT1+或AKT2+中共有182个miRNA上调。其中，28个miRNA在AKT1+和AKT2+组中均上调，相对于AKTd/d组的log2比值在1.02至3.71之间，包括所有miR-200家族成员。定量实时聚合酶链反应显示，无论AKT基因状态如何，表现出淋巴管浸润的癌中miR-200a（P=0.0230）和miR-200b（P=0.0168）的表达均显著降低。此外，详细的统计分析显示，在腺癌和癌的早期阶段（病理分期I/II），AKT2+组中miR-200a的表达高于AKT1+组，且这些差异具有统计学意义（分别为P=0.0334和P=0.0239）。然而，miR-200a的表达与其靶标锌指E盒结合同源框1（ZEB1；P=0.3801）或上皮-间质转化标志物E-钙黏蛋白（P=0.2840）的表达无显著相关性。这些结果表明，AKT2可以以组织学或阶段特异性方式调节miR-200a，且这种调节独立于miR-200a随后参与上皮-间质转化的过程。
