Abstract
Reelin (RELN), which is a glycoprotein secreted by Cajal-Retzius cells of the developing cerebral cortex, plays an important role in neuronal migration, but its role in cell migration and cancer metastasis is largely unclear. Here, we showed that cell motility was significantly increased in KYSE-510 cells by TGF-β1 treatment. Moreover, TGF-β1 decreased RELN mRNA expression and overexpression of Reelin at least partly reversed TGF-β1-induced cell migration in KYSE-30 cells. Furthermore, this negative regulation of Reelin expression by TGF-β1 was through Snail, one transcription factor which was induced by TGF-β1 in KYSE-510 cells. RELN promoter activity was reduced in parallel with the induction of Snail after TGF-β1 treatment and Snail suppressed both RELN promoter activity and expression through binding to E-box sequences in the RELN promoter region in ESCC cells. Knockdown of RELN induced cell migration in KYSE-510 cells, together with the increase of mesenchymal markers expression. Taken together, Reelin is an essential negative regulator in the TGF-β1-induced cell migration process, and is suppressed by TGF-β pathway at the transcriptional level through Snail regulation. Therefore, the correlation of Reelin and TGF-β pathway was critical in cancer metastasis, and Reelin could be one potential anti-metastasis target in future clinical practice.
Highlights
Reelin was known as a large glycoprotein secreted from CajalRetzius cells of developing cerebral cortex, and acts as a critical regulator of neuronal migration and layer formation during brain development [1,2]
Our results provide the first evidence that Reelin was involved in transforming growth factor-b (TGF-b) signal pathway, which contributes to cancer metastasis and could be useful for anti-cancer strategies
Since the role of TGF-b in esophageal carcinogenesis is not yet understood, we investigated whether TGF-b1 treatment induced esophageal squamous cell carcinoma (ESCC) cells to mesenchymal transition and further elucidated the underlying mechanism responsible for the process
Summary
Reelin was known as a large glycoprotein secreted from CajalRetzius cells of developing cerebral cortex, and acts as a critical regulator of neuronal migration and layer formation during brain development [1,2]. The physiological function of Reelin was intensively studied in brain, recently, RELN was found to be epigenetically silenced in different cancers including pancreatic [5], gastric [6] and breast cancer [7]. The decreased expression of RELN was associated with increased migratory ability, reduced survival and poor prognosis, reduced expression of Reelin is associated with high recurrence rate of hepatocellular carcinoma [8]. Esophageal cancer is the sixth leading cause of cancer death worldwide and, interestingly, the least studied type of tumor [10]. There is an exceedingly high incidence of esophageal squamous cell carcinoma (ESCC) in Asian countries, especially in north and central China [11]. The role of TGF-b in esophageal carcinogenesis and its signaling pathway in EMT process are not yet understood
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