Abstract
Reprogrammed glucose metabolism of enhanced aerobic glycolysis, also known as Warburg effect, which exerts a significant contributor to cancer progression, is regarded as a hallmark of cancer. The roles of long noncoding RNAs (lncRNA) in regulating cancer via metabolic reprogramming are mostly unknown, including esophagal cancer (EC). Here, we showed that how the lncRNA urothelial carcinoma associated 1 (UCA1) exerts pro-oncogene in regulating EC glucose metabolism. Firstly, we found that upregulated UCA1 expression enhances the malignant phenotypes of EC, including poor outcome, larger tumor size, positive lymphatic invasion, and advanced pathological stages. UCA1 silencing could suppress EC cell proliferation and metastasis. Following, bioinformatics analyses revealed that UCA1 regulated the HK2 expression through functioning as a competing endogenous RNA (ceRNA). Mechanistically, UCA1 overexpression could elevate the activation of HK2 oncogenes via inhibition of miR-203 activity, as evidenced by the positive correlation of UCA1 with HK2 and inverse correlation with miR-203 expression. Luciferase activity assay further verified the targeting relationship between UCA1, miR-203, and HK2. Upregulated UCA1 in EC cells significantly suppressed the degradation of HK2 by miR-203. Further research showed that upregulated UCA1 effectively increased the rate of glucose uptake, lactate output, and ECAR value, all of which can be attenuate by HK2 interference and 2-DG, whereas knockdown of UCA1 had the opposite effect. In sum, our findings suggest that the UCA1/miR-203/HK2 axis contributes to EC development by reprogramming tumor glucose metabolism, providing new insight into the management of EC patients.
Highlights
Esophageal cancer (EC) is the eighth most common aggressive malignancies worldwide and ranks sixth most lethal tumor [1, 2]
The chisquared test indicated that urothelial carcinoma associated 1 (UCA1) expression in EC tissues was closely related to tumor size (p 0.033), alcohol status (p 0.004), lymphatic invasion (p < 0.001), distant metastasis (p 0.001), and TNM stage (p < 0.001), whereas no significant differences were found between UCA1 expression and age, gender, smoking status, tumor location, and differentiation (Table 1)
The association of UCA1 expression with the outcome was determined in 110 EC cases. e results showed that higher UCA1 expression indicated unfavorable prognosis using KaplanMeier survival curves and the log-rank test (Figure 1(e)). en, univariate and multivariate analysis were applied using a Cox proportional hazards model to analyze the relationship of UCA1 expression with clinical parameters and patients’ outcomes
Summary
Esophageal cancer (EC) is the eighth most common aggressive malignancies worldwide and ranks sixth most lethal tumor [1, 2]. In China, it is the fourth most frequently diagnosed cancer and ranks as one of the top five deadliest cancers [3]. Even with advances in diagnostic technology, it is difficult to diagnose at early stages for most of the patients, and advanced EC frequently possess an aggressive profile and the clinical manifestations of dysphagia [4, 5]. Accumulating studies has pointed out that dysregulation of lncRNAs was associated with various malignant tumors [13], including urothelial carcinoma associated 1 (UCA1). We investigated the roles and the mechanism undergoing in the EC progress of UCA1. As well as the current study provides the first evidence that UCA1 promotes aerobic glycolysis by suppressing the degradation of HK2 via spongingmiR-203 in EC
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