Department of Surgery, University of Heidelberg, Heidelberg, Germany.
Cancer Sci. 2011 Oct;102(10):1799-807. doi: 10.1111/j.1349-7006.2011.02023.x. Epub 2011 Aug 4.
The tumor edge of colorectal cancer and its adjacent peritumoral tissue is characterized by an invasion front-specific expression of genes that contribute to angiogenesis or epithelial-to-mesenchymal transition. Dysregulation of these genes has a strong impact on the invasion behavior of tumor cells. However, the invasion front-specific expression of microRNA (miRNA) still remains unclear. Therefore, the aim of the present study was to investigate miRNA expression patterns at the invasion front of colorectal liver metastases. Laser microdissection of colorectal liver metastases was performed to obtain separate tissue compartments from the tumor center, tumor invasion front, liver invasion front and pure liver parenchyma. Microarray expression analysis revealed 23 miRNA downregulated in samples from the tumor invasion front with respect to the same miRNA in the liver, the liver invasion front or the tumor center. By comparing samples from the liver invasion front with samples from pure liver parenchyma, the tumor invasion front and the tumor center, 13 miRNA were downregulated. By quantitative RT-PCR, we validated the liver invasion front-specific downregulation of miR-19b, miR-194, let-7b and miR-1275 and the tumor invasion front-specific downregulation of miR-143, miR- 145, let-7b and miR-638. Univariate analysis demonstrated that enhanced expression of miR-19b and miR-194 at the liver invasion front, and decreased expression of let-7 at the tumor invasion front, is an adverse prognostic marker of tumor recurrence and overall survival. In conclusion, the present study suggests that invasion front-specific downregulation of miRNA in colorectal liver metastases plays a pivotal role in tumor progression.
结直肠癌肿瘤边缘及其相邻的肿瘤周围组织的特点是浸润前沿特异性表达参与血管生成或上皮间质转化的基因。这些基因的失调对肿瘤细胞的浸润行为有很强的影响。然而，miRNA（microRNA）在浸润前沿的特异性表达仍不清楚。因此，本研究旨在探讨结直肠癌肝转移浸润前沿的 miRNA 表达模式。通过激光显微切割获得结直肠癌肝转移的组织标本，分别从肿瘤中心、肿瘤浸润前沿、肝脏浸润前沿和纯肝实质中获得单独的组织区室。微阵列表达分析显示，与肝脏、肝脏浸润前沿或肿瘤中心相同的 miRNA 相比，在肿瘤浸润前沿的样本中，有 23 个 miRNA 下调。通过比较肝脏浸润前沿与纯肝实质、肿瘤浸润前沿和肿瘤中心的样本，有 13 个 miRNA 下调。通过定量 RT-PCR，我们验证了 miR-19b、miR-194、let-7b 和 miR-1275 在肝脏浸润前沿的特异性下调，以及 miR-143、miR-145、let-7b 和 miR-638 在肿瘤浸润前沿的特异性下调。单因素分析表明，肝脏浸润前沿 miR-19b 和 miR-194 的表达增强，以及肿瘤浸润前沿 let-7 的表达降低，是肿瘤复发和总生存的不良预后标志物。总之，本研究表明，结直肠癌肝转移中 miRNA 的浸润前沿特异性下调在肿瘤进展中起关键作用。
