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Cellular migration and invasion uncoupled: increased migration is not an inexorable consequence of epithelial-to-mesenchymal transition.

ABSTRACT: Metastatic dissemination requires carcinoma cells to detach from the primary tumor and invade through the basement membrane. To acquire these characteristics, epithelial tumor cells undergo epithelial-to-mesenchymal transitions (EMT), whereby cells lose polarity and E-cadherin-mediated cell-cell adhesion. Post-EMT cells have also been shown, or assumed, to be more migratory; however, there have been contradictory reports on an immortalized human mammary epithelial cell line (HMLE) that underwent EMT. In the context of carcinoma-associated EMT, it is not yet clear whether the change in migration and invasion must be positively correlated during EMT or whether enhanced migration is a necessary consequence of having undergone EMT. Here, we report that pre-EMT rat prostate cancer (PC) and HMLE cells are more migratory than their post-EMT counterparts. To determine a mechanism for increased epithelial cell migration, gene expression analysis was performed and revealed an increase in epidermal growth factor receptor (EGFR) expression in pre-EMT cells. Indeed, inhibition of EGFR in PC epithelial cells slowed migration. Importantly, while post-EMT PC and HMLE cell lines are less migratory, both remain invasive in vitro and, for PC cells, in vivo. Our study demonstrates that enhanced migration is not a phenotypic requirement of EMT, and migration and invasion can be uncoupled during carcinoma-associated EMT.

SUBMITTER: Schaeffer D

PROVIDER: S-EPMC4135620 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Cellular migration and invasion uncoupled: increased migration is not an inexorable consequence of epithelial-to-mesenchymal transition.

Schaeffer Daneen D Somarelli Jason A JA Hanna Gabi G Palmer Gregory M GM Garcia-Blanco Mariano A MA

Molecular and cellular biology 20140707 18

Metastatic dissemination requires carcinoma cells to detach from the primary tumor and invade through the basement membrane. To acquire these characteristics, epithelial tumor cells undergo epithelial-to-mesenchymal transitions (EMT), whereby cells lose polarity and E-cadherin-mediated cell-cell adhesion. Post-EMT cells have also been shown, or assumed, to be more migratory; however, there have been contradictory reports on an immortalized human mammary epithelial cell line (HMLE) that underwent ...[more]

PMID: 25002532

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Project description:BackgroundOur previous studies revealed that Jagged 2 (JAG2) is involved in the regulation of migration and invasion of colon cancer cells without affecting cell proliferation. This study further explored the specific mechanism by which JAG2 promotes migration and invasion of colorectal cancer cells.MethodsJAG2 mRNA expression in different clinical stages of colorectal cancer and normal intestinal tissues was detected by quantitative PCR (QPCR). QPCR and Western Blot were used to analyze the differential expression of JAG2 mRNA and protein between normal human colon tissue cells and various colorectal cancer cells. Co-expression status of JAG2 and epithelial-mesenchymal transition (EMT) markers in colon cancer tissues and cells was analyzed. The difference between TGF-β-induced EMT model and the JAG2 overexpression model were compared in promoting migration and invasion of HT29 cells. HT29 cells were treated with EMT pathway inhibitors (LY2157299 and Slug siRNA) to identify a cross-talk between the JAG2 effect and the Notch pathway. Co-expressed genes of JAG2 in colorectal cancer cells were identified using siRNA and transcriptome microarray technology. The mutual regulation of JAG2 and the co-expressed gene PRAF2 and the regulation of the paracrine effect of exosomes were analyzed.ResultsJAG2 was abnormally expressed in colorectal cancer tissues and directly related to clinical stages. Similar to the findings in tissues, the expression of both JAG2 mRNA and protein was significantly increased in the colorectal cancer cell lines compared with that of normal colorectal cell line CCD18-Co. It was shown in our cell model that JAG2 was involved in the regulation of migration and invasion independent of the canonical Notch signaling pathway. More interestingly, JAG2 also promoted the migration and invasion of colon cancer cells in a non-EMT pathway. Further analysis revealed the co-expression of JAG2 with PRAF2 in colorectal cancer cells. JAG2-rich exosomes were released from colorectal cancer cells in a PRAF2-dependent way, while these exosomes regulated the metastasis of colorectal cancer cells in a paracrine manner.ConclusionsThis is the evidence supporting the biological function of JAG2 through non-canonical Notch and non-EMT-dependent pathways and also the first demonstration of the functions of PRAF2 in colorectal cancer cells. These findings also provide theoretical basis for the development of small molecules or biological agents for therapeutic intervention targeting JAG2/PRAF2.

Dataset Information

Cellular migration and invasion uncoupled: increased migration is not an inexorable consequence of epithelial-to-mesenchymal transition.

Publications

Cellular migration and invasion uncoupled: increased migration is not an inexorable consequence of epithelial-to-mesenchymal transition.

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