Loss of FBP1 facilitates aggressive features of hepatocellular carcinoma cells through the Warburg effect

Abstract

Reprogrammed metabolism has been identified as an emerging hallmark in cancer cells. It has been demonstrated that fructose-1, 6-bisphosphatase 1 (FBP1) as a rate-limiting enzyme in gluconeogenesis plays critical roles in tumor initiation and progression in several cancer types. However, function of FBP1 in hepatocellular carcinoma (HCC) is still not clear. In this study, we observed that the expression of FBP1 was obviously downregulated in the cell lines and tissues of HCC. Downregulation of FBP1 in HCC tissues was correlated with a lower overall survival rate and had a relatively higher tendency of tumor recurrence (n = 224). Silencing FBP1 could significantly promote colony formation, proliferation and metastasis of HCC cells, while ectopic overexpression of FBP1 resulted in impaired abilities of colony formation, proliferation and metastasis in vitro and in vivo. Mechanistically, silencing FBP1 facilitated glycolysis in HCC cell lines, which may be responsible for aggressiveness of HCC cells. We further found that targeting the Warburg effect using the specific inhibitor FX11 could suppress the aggressiveness of HCC cells which was mediated by loss of FBP1. These findings indicate that FBP1 appears to be a tumor suppressor in HCC. Strategies to restore the levels and activities of FBP1 might be developed to treat patients with HCC.

Inhibiting histone deacetylases suppresses glucose metabolism and hepatocellular carcinoma growth by restoring FBP1 expression

“…In our study, we first examined FBP1 expression level in 90 HCC and adjacent benign tissues. Consistent with the finding of previous studies2021, we demonstrated that FBP1 protein level in HCC tissues was significantly lower than that in adjacent benign tissues in both the cohort of HCC patients and in the TCGA dataset. Most importantly, we demonstrate that low expression of FBP1 associated with the tumor size and the TNM stage of HCC.…”

“…Our data and those from TCGA show that FBP1 is highly expressed in tumor-adjacent benign tissues. It has been reported previously that FBP1 expression is downregulated in HCC patient samples and cell lines2021. In our study, we first examined FBP1 expression level in 90 HCC and adjacent benign tissues.…”

Modularity of the metabolic gene network as a prognostic biomarker for hepatocellular carcinoma

“…For example, a group of samples characterized by high glycolytic activity showed significantly higher modularity than a group of samples characterized by high OXPHOS activity, and worse prognosis. The result is consistent with the experimental observation that hepatocarcinogenesis initiates with a switch of metabolism from OXPHOS to glycolysis, and glycolysis is maintained to facilitate the aggressive features of advanced HCCs [32,33].…”

A first case of hepatocellular carcinoma in the baboon (Papio spp.) placenta

“…FABP1 expression is down-regulated in cell lines and tissues in HCC, and decreased expression of FABP1 correlates with lower survival rates and a higher tumor recurrence through a mechanism of increased aerobic glycolysis. 67 In line with these observations, FABP was negative in the presented case, which is also in agreement with the recent reports about the association of HCC with lack of FABP-1 staining. 44 Another marker of HCC is Arginase -1 68 with high expression in well-differentiated tumors.…”

“…In general, FABP1 plays critical roles in tumor initiation and progression in several types of cancer. FABP1 expression is down‐regulated in cell lines and tissues in HCC, and decreased expression of FABP1 correlates with lower survival rates and a higher tumor recurrence through a mechanism of increased aerobic glycolysis . In line with these observations, FABP was negative in the presented case, which is also in agreement with the recent reports about the association of HCC with lack of FABP‐1 staining .…”