Glucose-regulated protein 94 mediates cancer progression via AKT and eNOS in hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is a crucial health issue worldwide. High glucose-regulated protein 94 (GRP94) expression has been observed in different types of cancer, suggesting a link between tumor progression and GRP94 expression. However, the mechanisms underlying the role of GRP94 in HCC progression remain unclear. We used specific small hairpin RNA (shRNA) to manipulate GRP94 expression in HCC cells. Tissue arrays, MTT assays, xCELLigence assays, and in vivo xenograft model were performed to identify clinicopathological correlations and to analyze cell growth. We found that high GRP94 expression reflected a poor response and a lower survival rate. In vitro and in vivo studies showed that silencing GRP94 suppressed cancer progression. Mechanistically, GRP94 knockdown reduced AKT, phospho-AKT, and eNOS levels but did not influence the AMPK pathway. Our results demonstrated that GRP94 is a key molecule in HCC progression that modulates the AKT pathway and eNOS levels. Our findings suggest that GRP94 may be a new prognostic and therapeutic target for HCC.
Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.
Chien-Yu
CY
Huang
Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia.|Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|National Dermatology Center, Ulaanbaatar, Mongolia.
Uyanga
U
Batzorig
Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Wan-Li
WL
Cheng
Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.|Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Surgery, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Division of General Surgery, Taipei Medical University and Hospital, 250 Wu-Xin Street, Taipei City, 110, Taiwan.
Ming-Te
MT
Huang
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
Wei- Yu
W
Chen
Department of Surgery, College of Medicine, Taipei Medical University, Taipei, Taiwan. poliwei@tmu.edu.tw.|Division of General Surgery, Taipei Medical University and Hospital, 250 Wu-Xin Street, Taipei City, 110, Taiwan. poliwei@tmu.edu.tw.|Cancer Research Center, Taipei Medical University and Hospital, 250 Wu-Xin Street, Taipei City, 110, Taiwan. poliwei@tmu.edu.tw.|Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan. poliwei@tmu.edu.tw.
Po-Li
PL
Wei
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. r5424012@tmu.edu.tw.|Department of Surgery, College of Medicine, Taipei Medical University, Taipei, Taiwan. r5424012@tmu.edu.tw.|Division of General Surgery, Taipei Medical University and Hospital, 250 Wu-Xin Street, Taipei City, 110, Taiwan. r5424012@tmu.edu.tw.|Cancer Research Center, Taipei Medical University and Hospital, 250 Wu-Xin Street, Taipei City, 110, Taiwan. r5424012@tmu.edu.tw.
Yu-Jia
YJ
Chang
D055372:AMP-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D051379:Mice; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D008562:Membrane Glycoproteins; C053387:endoplasmin; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases
AKT; GRP94; HCC; Proliferation; eNOS