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Effects of STC1 overexpression on tumorigenicity and metabolism of hepatocellular carcinoma.

ABSTRACT: Stanniocalcin-1 (STC1) is a paracrine factor associated with inflammation and carcinogenesis. Using clinicopathological data, we previously reported that a greater expression of STC1 in hepatocellular carcinoma (HCC) was significantly correlated with smaller tumor size. The underlying mechanism on the correlation is not known. In this study, using a metastatic HCC cell-line (MHCC-97L, P) and lentiviral vector mediated-STC1 overexpression, the inoculation of STC1-overexpressing MHCC-97L (S1) cells in a nude mice xenograft model demonstrated reductions in tumor mass and volume. As compared with P cells, S1 cells exhibited epithelial phenotype with significantly lower plating efficiency and reduced migratory and proliferative potential. Using coulter counter for cell-sizing, S1 cells (17.6 ?m) were significantly smaller than P cells (19.6 ?m). Western blot analysis revealed that S1 cells exhibited reduced expression level of phosphorylated ribosomal protein S6 (p-rpS6). Moreover, an inhibition of the upstream kinase p70S6K was evident with the dephosphorylation of Thr389 in the linker domain of the kinase. The inhibition of p70S6K/p-rpS6 pathway was accompanied with reduced cellular ATP level and increase of p-AMPK in S1 cells. Significantly lower rates of glycolysis and extracellular O2 consumption in S1 cells exhibited a lower cellular energy status. Since a faster rate of ATP production is essential to support cancer growth and metastasis, the present study identified the effect of STC1-overexpression on reducing energy metabolism, leading to an activation of AMPK pathway but an inhibition of p70S6K/p-rpS6 signaling to reduce tumor growth.

SUBMITTER: Leung CC

PROVIDER: S-EPMC5805520 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Effects of STC1 overexpression on tumorigenicity and metabolism of hepatocellular carcinoma.

Leung Cherry Ct CC Wong Chris Kc CK

Oncotarget 20171221 6

Stanniocalcin-1 (STC1) is a paracrine factor associated with inflammation and carcinogenesis. Using clinicopathological data, we previously reported that a greater expression of STC1 in hepatocellular carcinoma (HCC) was significantly correlated with smaller tumor size. The underlying mechanism on the correlation is not known. In this study, using a metastatic HCC cell-line (MHCC-97L, P) and lentiviral vector mediated-STC1 overexpression, the inoculation of STC1-overexpressing MHCC-97L (S1) cell ...[more]

PMID: 29467934

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Project description:Background and Aims: Cancer cells prefer aerobic glycolysis to maintain growth advantages, but the role of long non-coding RNAs (lncRNAs) in glycometabolism still remains unclear. Here we identified one cytoplasmic lncRNA LINC01554 as a significantly downregulated lncRNA in hepatocellular carcinoma (HCC) and aimed to investigate its role in cellular glucose metabolism in the development and progression of HCC. Methods: Quantitative real-time PCR was used to determine the expression level of LINC01554. Downregulation of LINC01554 by miR-365a at transcriptional level was assessed by luciferase reporter assay. Subcellular fractionation assay and RNA fluorescence in situ hybridization were performed to detect the subcellular localization of LINC01554. RNA pull-down assay, mass spectrometry, and RNA immunoprecipitation assay were used to identify the underlying molecular mechanisms. The tumor-suppressive function of LINC01554 was determined by both in vitro assay and nude mice xenograft model. Results: LINC01554 was frequently downregulated in HCC, which was significantly associated with tumor invasion (P = 0.005), tumor size (P = 0.041), tumor staging (P = 0.023) and shorter survival (P = 0.035) of HCC patients. Luciferase reporter assay unraveled that LINC01554 was negatively regulated by miR-365a. Subcellular fractionation assay and RNA FISH revealed the cytoplasmic predominance of LINC01554 in MIHA cells and HCC clinical samples. Ectopic expression of LINC01554 inhibited HCC cell growth, colony formation in soft agar, foci formation, and tumor formation in nude mice. LINC01554 promoted the ubiquitin-mediated degradation of PKM2 and inhibited Akt/mTOR signaling pathway to abolish aerobic glycolysis in HCC cells. Further study found that LINC01554-knockout could effectively reverse the tumor-suppressive effect of LINC01554. Conclusions: Our results identify LINC01554 as a novel tumor suppressor in HCC and unravel its underlying molecular mechanism in reprogramming cellular glucose metabolism. LINC01554 could possibly serve as a novel prognostic biomarker and provide the rationale for HCC therapy.

Dataset Information

Effects of STC1 overexpression on tumorigenicity and metabolism of hepatocellular carcinoma.

Publications

Effects of STC1 overexpression on tumorigenicity and metabolism of hepatocellular carcinoma.

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