Upregulated Long Noncoding RNA UCA1 Enhances Warburg Effect via miR-203/HK2 Axis in Esophagal Cancer

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.

Involvement of Long Non-Coding RNAs in Glucose Metabolism in Cancer

“…It significantly suppresses the degradation of HK2 by sponging miR-203. Upregulated UCA1 increases the glucose uptake, lactate output and extracellular acidification rate (ECAR) value [ 63 ].…”

Upregulated UCA1 contributes to oxaliplatin resistance of hepatocellular carcinoma through inhibition of miR‐138‐5p and activation of AKT/mTOR signaling pathway

“…Conversely, knockdown of UCA1 expression in HepG2/OXA and SMMC‐7721/OXA cells significantly decreased the expression of p‐AKT and p‐mTOR (Figure 3D‐F). Interestingly, miR‐138‐5p was assumed as a transcriptional suppressor of UCA1 41 . Thereby, we explored whether upregulation of miR‐138‐5p expression could cause the opposite effect on AKT/mTOR pathway activation induced by high UCA1 expression.…”

“…Interestingly, miR-138-5p was assumed as a transcriptional suppressor of UCA1. 41 Thereby, we explored whether upregulation of miR-138-5p expression could cause the opposite effect on AKT/mTOR pathway activation induced by high UCA1 expression. As expected, we found that both UCA1 expression (Figure 2H) and the level of phosphorylated AKT and mTOR in HepG2/OXA and SMMC-7721/OXA cells were greatly descended after transfection with miR-138-5p mimics (p < 0.01 or p < 0.05) (Figure 3G-I).…”

Long Noncoding RNA UCA1 in Gastrointestinal Cancers: Molecular Regulatory Roles and Patterns, Mechanisms, and Interactions

“…Additionally, lncRNA UCA1 also can directly interact with miR-204 to reduce miR-204-mediated Sox4 degradation; thus, Sox4 can exert its biological role as a tumor-promoting protein to stimulate EC progression [38]. Apart from that, overexpressed lncRNA UCA1 could also promote cell proliferation and metastasis by enhancing aerobic glycolysis through Warburg effect [39]. ese happened when lncRNA UCA1 sequestered miR-203, which then increased the levels of hexokinase 2 (HXK2) [39].…”

“…Apart from that, overexpressed lncRNA UCA1 could also promote cell proliferation and metastasis by enhancing aerobic glycolysis through Warburg effect [39]. ese happened when lncRNA UCA1 sequestered miR-203, which then increased the levels of hexokinase 2 (HXK2) [39].…”