Down-Regulation of the miRNA-200 Family at the Invasive Front of Colorectal Cancers with Degraded Basement Membrane Indicates EMT Is Involved in Cancer Progression

Abstract

Cancer progression is a complex series of events thought to incorporate the reversible developmental process of epithelial-to-mesenchymal transition (EMT). In vitro, the microRNA-200 family maintains the epithelial phenotype by posttranscriptionally inhibiting the E-cadherin repressors, ZEB1 and ZEB2. Here, we used in situ hybridization and immunohistochemistry to assess expression of miR-200 and EMT biomarkers in formalin-fixed paraffin-embedded human colorectal adenocarcinomas. In addition, laser capture microdissection and quantitative real-time polymerase chain reaction were employed to quantify levels of miR-200 in the normal epithelium, tumor core, invasive front, and stroma. We find that miR-200 is downregulated at the invasive front of colorectal adenocarcinomas that have destroyed and invaded beyond the basement membrane. However, regional lymph node metastases and vascular carcinoma deposits show strong expression of miR-200, suggesting this family of miRNAs is involved in the recapitulation of the primary tumor phenotype at metastatic sites. In contrast, adenomas and adenocarcinomas with intact basement membranes showed uniform miR-200 expression from the tumor core to the tumor-host interface. Taken together, these data support the involvement of EMT and mesenchymal-to-epithelial transition (MET) in the metastasis cascade and show that miR-200 is downregulated in the initial stages of stromal invasion but is restored at metastatic sites.

Specificity Protein 1 (Sp1) Maintains Basal Epithelial Expression of the miR-200 Family

“…We investigated miR-200 expression in relation to Sp1 and Zeb1 expression is several tissues from E13.5 mouse embryos and found Sp1 and miR-200 expression were coincident in all tissues tested, whereas miR-200 was lost in Zeb1-expressing cells. The inverse correlation of miR-200 and Zeb1 are consistent with the observations made in olfactory (39), palate (54), and inner ear (55) tissues as well as at the invasive front of colorectal cancer (56). Thus, we propose that Sp1 maintains basal expression of miR-200 in most cell types, and the absence of miR-200 is primarily triggered by the expression of ZEB and/or other repressing factors.…”

miR-200–containing extracellular vesicles promote breast cancer cell metastasis

“…A biphasic role of miR-200 is also supported by other studies that show that primary cancer cells downregulate miR-200 expression at the invasive front where they undergo EMT and upregulate miR-200s in the resulting metastasis where MET facilitates colonization of a distant tissue (9,26,27). Given the observed transfer of miR-200s from aggressive to less-aggressive cancer cells, it is possible that cancer cells within the primary tumor may initially release miR-200s in EVs to activate an EMT program for invasion and dissemination and then reacquire these EVs or reexpress miR-200 at the metastatic site to undergo MET for colonization.…”

Downregulation of miR‐638 promotes invasion and proliferation by regulating SOX2 and induces EMT in NSCLC

“…Decreased E-cadherin and elevated Vimentin and Snail expression is one hallmark of EMT which is a key element in the cancer invasion [33]. Many studies established functional associations between noncoding microRNAs and key effectors of EMT occurring in the context of carcinogenesis and embryonic development, such as miR-200 [34] and miR-10b [35]. In addition to cancer progression, EMT contributes to chronic epithelial injury [36], leading to tissue fibrosis and organ failure.…”