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

Ana Pavlič,Kristian Urh,Nina Zidar,Emanuela Boštjančič,Katarina Štajer

doi:10.3389/fonc.2021.662806

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.

Highlights

Significant progress has been made in recent decades in our understanding of cancer development, progression and metastasizing
We analyzed the expression of the miR-200 family, known to be the master regulator of epithelial-mesenchymal transition (EMT), and their target genes, to investigate the role of EMT in CRC invasion and metastasizing
The results of our study suggest the involvement of partial EMT at the invasive tumor front and the involvement of partial mesenchymal-epithelial transition (MET) in both lymph node and liver metastases

Summary

Introduction

Significant progress has been made in recent decades in our understanding of cancer development, progression and metastasizing. During EMT, epithelial cells change from stationary polarized cells to mobile spindle cells In cancer, this transition is assumed to be the basis for progression and metastasis, enabling cells to migrate from the primary tumor [6, 7]. Complete EMT includes a switch in intermediate filament expression, an alteration in intercellular junction composition and a concurrent change of cell morphology [10, 11]. It appears that full EMT rarely occurs in human cancer though it does exist, e.g., in spindle cell carcinoma, which can be regarded as a “positive” control when studying the markers of EMT [12]. Markers of EMT include classical and desmosomal cadherins, intermediate filaments and transcription factors, but their expression patterns can be variable in diseases in which EMT presumably plays an important role [13, 14]

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