ArticleOncogene2014
GRP78 as a regulator of liver steatosis and cancer progression mediated by loss of the tumor suppressor PTEN.
Article in Oncogene, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 76 citations in OpenAlex.
- Deficiency of PTEN Confers Hypersensitivity to Fatty Acid-Mediated ER Stress in Transformed Hepatocytes.International journal of molecular sciences · 2026Article
- Physiological roles of phosphoinositides and inositol phosphates: Implications for metabolic dysfunction-associated steatotic liver disease.Clinical science (London, England : 1979) · 2025Review
- Impaired RelA signaling and lipid metabolism dysregulation in hepatocytes: driving forces in the progression of metabolic dysfunction-associated steatotic liver disease.Cell death discovery · 2025Article
- Article
- Impact of Obesity-Related Endoplasmic Reticulum Stress on Cancer and Associated Molecular Targets.Biomedicines · 2024Review
- Multidimensional pan-cancer analysis of HSPA5 and its validation in the prognostic value of bladder cancer.Heliyon · 2024Article
- Targeting PAK4 reverses cisplatin resistance in NSCLC by modulating ER stress.Cell death discovery · 2024Article
- 6-Gingerol, a Bioactive Compound ofJournal of experimental pharmacology · 2024Article
- HSP70 Family in Cancer: Signaling Mechanisms and Therapeutic Advances.Biomolecules · 2023Review
- GRP78 Activity Moderation as a Therapeutic Treatment against Obesity.International journal of environmental research and public health · 2022Review
- Vincosamide Has a Function for Inhibiting Malignant Behaviors of Hepatocellular Carcinoma Cells.World journal of oncology · 2022Article
- Animal Models of Hepatocellular Carcinoma: Current Applications in Clinical Research.Journal of hepatocellular carcinoma · 2022Review
- PERK mediates resistance to BRAF inhibition in melanoma with impaired PTEN.NPJ precision oncology · 2021Article
- Coordination of the unfolded protein response during hepatic steatosis identifies CHOP as a specific regulator of hepatocyte ballooning.Cell stress & chaperones · 2020Article
- Differential regulation of the unfolded protein response in outbred deer mice and susceptibility to metabolic disease.Disease models & mechanisms · 2019Article
- Signaling through non-membrane nuclear phosphoinositide binding proteins in human health and disease.Journal of lipid research · 2019Review
- Liver function and dysfunction - a unique window into the physiological reach of ER stress and the unfolded protein response.The FEBS journal · 2019Review
- Xuebijing Injection Maintains GRP78 Expression to PreventFrontiers in pharmacology · 2019Article
- Mouse models for investigating the underlying mechanisms of nonalcoholic steatohepatitis-derived hepatocellular carcinoma.World journal of gastroenterology · 2018Review
- Experimental study of inhibitory effects of diallyl trisulfide on the growth of human osteosarcoma Saos-2 cells by downregulating expression of glucose-regulated protein 78.OncoTargets and therapy · 2018Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Glucose-regulated protein 78 (GRP78), a molecular chaperone widely elevated in human cancers, is critical for endoplasmic reticulum (ER) protein folding, stress signaling and PI3K/AKT activation. Genetic knockout models of GRP78 revealed that GRP78 maintains homeostasis of metabolic organs, including liver, pancreas and adipose tissues. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) are the most common liver cancers. There is a lack of effective therapeutics for HCC and CC, highlighting the need to further understand liver tumorigenic mechanisms. PTEN (phosphatase and tenson homolog deleted on chromosome 10), a tumor suppressor that antagonizes the PI3K/AKT pathway, is inactivated in a wide range of tumors, including 40-50% of human liver cancers. To elucidate the role of GRP78 in liver cancer, we created a mouse model with biallelic liver-specific deletion of Pten and Grp78 mediated by Albumin-Cre-recombinase (cP(f/f)78(f/f)). Interestingly, in contrast to PTEN, deletion of GRP78 was progressive but incomplete. At 3 months, cP(f/f)78(f/f) livers showed hepatomegaly, activation of lipogenic genes, exacerbated steatosis and liver injury, implying that GRP78 protects the liver against PTEN-null-mediated pathogenesis. Furthermore, in response to liver injury, we observed increased proliferation and expansion of bile duct and liver progenitor cells in cP(f/f)78(f/f) livers. Strikingly, bile duct cells in cP(f/f)78(f/f) livers maintained wild-type (WT) GRP78 level, whereas adjacent areas showed GRP78 reduction. Analysis of signaling pathways revealed selective JNK activation, β-catenin downregulation, along with PDGFRα upregulation, which was unique to cP(f/f)78(f/f) livers at 6 months. Development of both HCC and CC was accelerated and was evident in cP(f/f)78(f/f) livers at 8-9 months, coinciding with intense GRP78 expression in the cancer lesions, and GRP78 expression in adjacent normal areas reverted back to the WT level. In contrast, c78(f/f) livers showed no malignancy even at 14 months. These studies reveal that GRP78 is a novel regulator for PTEN-loss-mediated liver injury and cancer progression.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.