Abstract
Esophageal cancer (EC) is one of the most lethal malignancies in humans, and multiple miRNAs have been identified to modulate EC progression by targeting different targets. However, the effect and related mechanism of microRNA-33a-5p (miR-33a-5p) on EC development remain elusive. In this study, we explored the clinical value, function, and possible mechanism of miR-33a-5p in EC. We uncovered that miR-33a-5p and DKK1 are involved in the progression of EC. Significantly, the expression levels of miR-33a-5p were reduced and DKK1 levels were elevated in serum and tissues of clinical EC samples and in EC cell lines. The downregulation of miR-33a-5p and DKK1 upregulation were related to high TNM staging and poor differentiation of patients. The area under the curves (AUCs) of miR-33a-5p and DKK1 for the occurrence of EC were 0.914 and 0.900, respectively. Down-regulation of miR-33a-5p or overexpression of DKK1 indicated a worse prognosis. The miR-33a-5p overexpression or DKK1 depletion induced apoptosis and repressed proliferation, migration, and invasion of EC cells. The repression of miR-33a-5p by inhibitor or DKK1 overexpression presented the conversed effects on EC cells. Mechanically, miR-33a-5p suppressed DKK1 expression, and miR-33a-5p targeted DKK1 to affect the biological behavior of EC through the Wnt/β-catenin pathway. Meanwhile, miR-33a-5p inhibited the tumor growth of EC in vivo. Thus, we concluded that miR-33a-5p inhibited the progression of EC through the DKK1-mediated Wnt/β-catenin pathway. MiR-33a-5p and DKK1 can be used as potential therapeutic targets of EC.
Highlights
Esophageal cancer (EC), which accounts for about 2% of human malignancies, is one of the most lethal malignancies in humans [1]
Further analysis of the relationship between miR-33a-5p, DKK1 and clinical characteristics showed that tumors in most cases were larger than 5cm in size, and were mostly moderately and highly differentiated (Table 3), indicating that miR33a-5p and DKK1 were associated with higher TNM staging and differentiation degree
We found that miR-33a-5p was low expressed in EC, while DKK1 was up-regulated, both of which could be used as potential markers for EC
Summary
Esophageal cancer (EC), which accounts for about 2% of human malignancies, is one of the most lethal malignancies in humans [1]. Among the subtypes of EC, esophageal adenocarcinoma mainly occurs in European and American countries, while in China, esophageal squamous cell carcinoma (ESCC) is the dominant histologic subtype [2]. It often progresses to advanced EC characterized by high invasion and metastasis, high postoperative mortality and poor prognosis [3]. The occurrence and development of EC is a very complex process, involving a variety of carcinogenic signal transduction pathways [4]. Understanding the possible molecular mechanism of the occurrence and progression of EC may contribute to the prevention and treatment of the disease
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