Abstract
BackgroundThe microRNA-200 (miR-200) family acts as a major suppressor of epithelial-mesenchymal transition (EMT). Impaired miR-200 expression may lead to EMT initiation and eventually cancer dissemination. The presence of tumor budding cells (TBC) is associated with metastasis and poor prognosis, and molecular similarities to EMT indicate that these cells may reflect ongoing EMT. The aim of this study was to investigate the expression of miR-200b in budding cells of colon cancer and the relationship with the EMT-markers E-cadherin, β-catenin and laminin-5γ2.Material & methodsMiR-200b was investigated by in situ hybridization in 58 cases of stage II (n = 36) and III colon (n = 22) cancers with tumor budding. Expression of E-cadherin, β-catenin and laminin-5γ2 was examined by immunohistochemistry. A multiplex fluorescence assay combining miR-200b with cytokeratin and laminin-5γ2 was employed on a subset of 16 samples.ResultsMiR-200b was downregulated in the TBC at the invasive front of 41 out of 58 (71%) cases. The decline was present in both mismatch satellite stable and instable adenocarcinomas. The majority of cases also showed loss of membranous E-cadherin and increased nuclear β-catenin in the TBC, while laminin-5γ2 expression was upregulated at the invasive front and in the tumor buds of approximately half the adenocarcinomas. However, the miR-200b decline was not statistically associated with the expression of any of the EMT-markers. The miR-200b decline was also documented by multiplex fluorescence. Fourteen out of fifteen cases showed a decrease in miR-200b expression in the majority of the TBC, but no obvious relationship between miR-200b and laminin-5γ2 expression was observed. Conclusion: The findings support the assumption of a miR-200b related downregulation in colon cancer budding cells. Whether miR-200b expression may be of clinical significance awaits further studies.
Highlights
Epithelial-mesenchymal transition (EMT) is considered a key event in carcinoma dissemination [1]
Whole tissue slides, stained by IHC, were scored for E-cadherin (n = 56), β-catenin (n = 52) and laminin-5γ2 (n = 58); the missing cases were excluded due to absence of tumor budding in deeper sections of the tissue block
It was noted that five of these were mismatch repair protein deficient cancers (71%), whereas this was the case for only five out of 51 (10%) cancers displaying EMT (p = 0.001). This could be attributed to the expression of β-catenin alone, in that nuclear βcatenin expression was absent in the MSI tumor budding cells (TBC), but present in the mismatch satellite stable (MSS) TBC (p
Summary
Epithelial-mesenchymal transition (EMT) is considered a key event in carcinoma dissemination [1]. The miR-200 family (miR-200a, miR-200b, miR-200c, miR-141, and miR-429) appears to exert an inhibitory effect on EMT in a number of cancers by repressing transcription factors zinc finger E-box binding homeobox 1 (ZEB1) and 2 (ZEB2). This maintains E-cadherin levels and the epithelial phenotype[4, 5]. The aim of this study was to investigate the expression of miR-200b in budding cells of colon cancer and the relationship with the EMT-markers E-cadherin, β-catenin and laminin-5γ2
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