Epithelial-Mesenchymal Transition in Colorectal Carcinoma: Comparison Between Primary Tumor, Lymph Node and Liver Metastases

Abstract

There is emerging evidence suggesting that epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) play an important role in colorectal carcinoma (CRC), but their exact role remains controversial. Our aim was to analyze the miR-200 family as EMT markers and their target genes expression at invasive tumor front and in nodal and liver metastases. Sixty-three formalin-fixed paraffin-embedded tissue samples from 19 patients with CRC were included. Using a micropuncture technique, tissue was obtained from central part and invasive front of the primary tumor, and nodal and liver metastases. Expression of the miR-200 family and their target genes CDKN1B, ONECUT2, PTPN13, RND3, SOX2, TGFB2 and ZEB2 was analyzed using real-time PCR. We found miR-200 family down-regulation at invasive front compared to central part, and up-regulation of miRNA-200a/b/c and miR-429 in metastases compared to invasive front. At invasive front, TGFB2 was the only gene with inverse expression to the miR-200 family, whereas in metastases inverse expression was found for ONECUT2 and SOX2. CDKN1B, PTPN13 and ZEB2 were down-regulated at invasive front and up-regulated in metastases. Our results suggest the involvement of partial EMT at invasive tumor front, and partial MET in metastases in CRC, based on miR-200 family and its target genes expression.

Differential Expression of Decorin in Metastasising Colorectal Carcinoma Is Regulated by miR-200c and Long Non-Coding RNAs

“…In contrast, another study showed miR-200c upregulation in primary CRC compared to liver metastases [ 36 ]. However, to the best of our knowledge, this was the first report of miR-200c expression in lymph node metastases of CRC in comparison to primary CRC besides our previous study that focused on the epithelial-mesenchymal transition [ 37 ]. Furthermore, our results suggest that in contrast to a previous bioinformatics analysis [ 19 ], miR-200c has a positive influence on DCN expression in CRC metastases.…”

The Role of Inflammatory Cytokines in the Pathogenesis of Colorectal Carcinoma—Recent Findings and Review

“…Once the cancer cells exit the bloodstream and form micrometastases, a reverse process, called mesenchymal–epithelial transition, enables them to form metastatic lesions [ 45 ]. Tumor-associated macrophages (TAM), myeloid-derived stem cells (MDSC), and lymphocytes Th1/Tc infiltrating the TME influence the epithelial cells undergoing TME through the secretion of IL-1β, IL6, IL8, IL10, IL17, TGF-β, or TNFα [ 46 ].…”

“…Under the influence of IL-1β, IL-8, and TGFβ, which can affect Wnt/β-catenin signaling, cancer cells can gain stem-like qualities and form a subpopulation of cancer stem cells capable of self-renewal and recreation of the entire tumor population [ 47 ]. Simultaneously, the infiltration of suppressive immune cells into the TME increases, and the immunophenotype of local cells changes, leading to the failure of immune surveillance and cancer immune escape [ 36 , 39 , 45 , 47 ]. Hence, tumor-associated signaling is essential in understanding the pathogenesis of CRC and in applying potential therapeutic approaches.…”

Metastatic EMT Phenotype Is Governed by MicroRNA-200-Mediated Competing Endogenous RNA Networks

“…A study on spindle cell carcinoma showed significant miR-141, -200a, -200c, and -429 downregulation in carcinoma tissue compared with normal mucosa [ 15 , 62 ]. Furthermore, downregulation of the miR-200 family showed a significant correlation with loss of E-cadherin, characteristic for EMT progression [ 15 , 63 , 64 , 65 ]. Another study demonstrated that restored levels of miR-200a inhibited tumor growth in vivo [ 66 ].…”