Molecular biology reports · 2026
Hypoxia-induced GP73 promotes the Warburg effect in hepatocellular carcinoma via HIF-1α.
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Abudureheman Mierkamilijiang, Zhu Diwen, Ren Weixin
Аннотация
BACKGROUND: Transarterial chemoembolization (TACE)-induced hypoxia is a key driver of hepatocellular carcinoma (HCC) progression. This study investigated whether Golgi protein 73 (GP73) drives the Warburg effect and epithelial-mesenchymal transition (EMT) via hypoxia-inducible factor-1α (HIF-1α) under hypoxia, thereby promoting HCC malignancy.
METHODS: HepG2 cells were exposed to hypoxia (1% O₂). Lentivirus-mediated GP73 overexpression (LV-GP73) and siRNA-mediated HIF-1α knockdown (si-HIF-1α) were established. Four groups were compared: H + LV-NC (negative control), H + LV-GP73, H + LV-GP73 + si-NC, and H + LV-GP73 + si-HIF-1α. Cell proliferation, apoptosis, migration, and invasion were assessed by colony formation, flow cytometry, and Transwell assays. Glycolysis and mitochondrial respiration were evaluated by biochemical kits and Seahorse XFe24 Analyzer. Protein levels were detected by Western blotting. Clinical validation was performed in peripheral blood mononuclear cells (PBMCs) from 169 HCC patients who underwent TACE.
RESULTS: GP73 overexpression significantly enhanced colony formation, migration, invasion, glucose consumption, lactate production, LDH activity, ATP levels, and extracellular acidification rate, while decreasing apoptosis (P < 0.05). It also showed a decreasing trend in oxygen consumption rate, indicating Warburg effect activation. It also upregulated HIF-1α, glycolytic enzymes (HK2, SLC2A1, LDHA, PGK1), and Vimentin, but downregulated E-cadherin (P < 0.05). Notably, HIF-1α knockdown reversed all these pro-tumorigenic phenotypes, metabolic reprogramming, and molecular changes. Clinical validation further confirmed that PBMCs from TACE-resistant patients exhibited significantly elevated GP73, HIF-1α, and HK2 expression at both mRNA and protein levels (all P < 0.001), consistent with the in vitro findings.
CONCLUSIONS: Under hypoxia, GP73 promotes the Warburg effect and EMT through HIF-1α stabilization, facilitating HCC progression. The GP73-HIF-1α axis is a critical mediator of TACE resistance and a potential therapeutic target. PBMC-based detection of this pathway may serve as a non-invasive strategy for monitoring TACE resistance risk.
METHODS: HepG2 cells were exposed to hypoxia (1% O₂). Lentivirus-mediated GP73 overexpression (LV-GP73) and siRNA-mediated HIF-1α knockdown (si-HIF-1α) were established. Four groups were compared: H + LV-NC (negative control), H + LV-GP73, H + LV-GP73 + si-NC, and H + LV-GP73 + si-HIF-1α. Cell proliferation, apoptosis, migration, and invasion were assessed by colony formation, flow cytometry, and Transwell assays. Glycolysis and mitochondrial respiration were evaluated by biochemical kits and Seahorse XFe24 Analyzer. Protein levels were detected by Western blotting. Clinical validation was performed in peripheral blood mononuclear cells (PBMCs) from 169 HCC patients who underwent TACE.
RESULTS: GP73 overexpression significantly enhanced colony formation, migration, invasion, glucose consumption, lactate production, LDH activity, ATP levels, and extracellular acidification rate, while decreasing apoptosis (P < 0.05). It also showed a decreasing trend in oxygen consumption rate, indicating Warburg effect activation. It also upregulated HIF-1α, glycolytic enzymes (HK2, SLC2A1, LDHA, PGK1), and Vimentin, but downregulated E-cadherin (P < 0.05). Notably, HIF-1α knockdown reversed all these pro-tumorigenic phenotypes, metabolic reprogramming, and molecular changes. Clinical validation further confirmed that PBMCs from TACE-resistant patients exhibited significantly elevated GP73, HIF-1α, and HK2 expression at both mRNA and protein levels (all P < 0.001), consistent with the in vitro findings.
CONCLUSIONS: Under hypoxia, GP73 promotes the Warburg effect and EMT through HIF-1α stabilization, facilitating HCC progression. The GP73-HIF-1α axis is a critical mediator of TACE resistance and a potential therapeutic target. PBMC-based detection of this pathway may serve as a non-invasive strategy for monitoring TACE resistance risk.