TGF-β1 Upregulates the Expression of LncRNA UCA1 and Its Downstream HXK2 to Promote the Growth of Hepatocellular Carcinoma

Objective: TGF-β1 plays pivotal roles in the development of various malignancies such as hepatocellular carcinoma, while the mechanism of the TGF-β1 function in hepatocellular carcinoma remains unclear. Our study aimed to investigate the molecular mechanisms of the TGF-β1 function in hepatocellular carcinoma.

Patients And Methods: Tumor tissues and adjacent healthy tissues were collected from hepatocellular carcinoma. Blood samples were collected from both hepatocellular carcinoma patients and healthy controls. Expression of TGF-β1, long non-coding RNA (lncRNA) UCA1 and hexokinase 2 (HXK2) in those tissues was detected by qRT-PCR. All patients were followed up for 5 years, and prognostic values of serum HOTAIR for hepatocellular carcinoma were investigated by survival curve analysis. TGF-β1, UCA1, and HXK2 overexpression hepatocellular carcinoma cell lines were established, and the effects on cell proliferation were detected by the CCK-8 assay. Interactions between TGF-β1, UCA1, and HXK2 were explored by Western blot. Effects of TGF-β1 on lactate production, glucose uptake, and ATP production were detected by lactate assay, glucose uptake assay, and ATP assay.

Results: TGF-β1, UCA1, and HXK2 expression levels were upregulated in tumor tissues comparing with adjacent healthy tissues. Serum levels of TGF-β1, UCA1, and HXK2 increased with the increases of primary tumor stage. Patients that have high serum levels of TGF-β1, UCA1, and HXK2 showed lower overall survival rate compared with patients with low serum levels of TGF-β1, UCA1, and HXK2. TGF-β1, UCA1, and HXK2 overexpression promoted proliferation of hepatocellular carcinoma cell. TGF-β1 is a positive upstream regulator of UCA1, which is a positive upstream regulator of HXK2. TGF-β1 overexpression increased lactate production, glucose uptake and ATP production in hepatocellular carcinoma.

Conclusions: TGF-β1 may accelerate cancer cell energy metabolism to promote the growth of hepatocellular carcinoma by upregulating UCA1 and its downstream HXK2.