| Summary: | 博士 === 國立成功大學 === 臨床醫學研究所 === 105 === Esophageal squamous cell carcinoma (ESCC) comprised the majority of esophageal cancer in Taiwan and tends to occur in patients with heavy alcohol consumption. Symptomatic dysphagia caused common patient malnutrition, cachexia and premature treatment termination. In addition, early lymphatic spread and following distant metastasis lead to poor prognosis, even under current multi-modality treatment protocol. Therefore, we aimed to investigate metastasis-related gene alteration in ESCC, not only to be a prognostic indicator but as a potential treatment target.
SLIT2, a secreted glycoprotein, has been found to inactivate Cdc42 GTPase for repulsive axonal guidance, and silenced in some human cancers as a tumor suppressor gene. However, alteration of SLIT2-mediated Cdc42 in terms of migration regulation remains unclear in ESCC. We reported here in ESCC clinical tumor sample, cell and animal models that SLIT2 acts as a migration and metastasis suppressor. Firstly, in clinical ESCC sample, DNA methylation analysis showed an overall 28% (14/50) SLIT2 promoter hypermethylation, responsible for 36% (18/50) low SLIT2 mRNA expression, and 31.8% (49/154) low SLIT2 protein expression, shown in immunohistochemistry study. Further, low SLIT2 protein expression correlated well with poor overall survival and disease-free survival in ESCC patients (p〈0.001, p = 0.004). Secondly, in cell model, knockdown of SLIT2 increased ESCC cell migration, while SLIT2 overexpression reduced cell migration. Further, ESCC cells treated with conditioned media from cells overexpressing SLIT2 also suppressed cell migration. Importantly, silencing of SLIT2 decreased the complex formation between srGAP1 and Cdc42, thus induced Cdc42 activity and promoted membrane localization of focal adhesion kinase and Paxillin. Thirdly, anti-metastatic effect of SLIT2 was confirmed in animal metastasis model with SLIT2 knockdown ESCC cells via tail vein injection. Lastly, because nutritional factors had been proposed to affect DNA methylation, we tried to utilize the ultrathin percutaneous endoscopic gastrostomy (PEG) to improve common malnutrition patient status in locally-advanced ESCC patients. Good PEG successful rate and ceased patient nutritional deterioration were observed in our preliminary data.
In conclusion, our results provide novel evidence that low SLIT2 expression correlates with poor prognosis and promotes migration and metastasis in ESCC, which may be regulated via the Cdc42-mediated pathways.
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