A Critical Role for GRP78/BiP in the Tumor Microenvironment for Neovascularization during Tumor Growth and Metastasis

Dong, Dezheng; Stapleton, Christopher J.; Luo, Biquan; Xiong, Shigang; Ye, Wei; Zhang, Yi; Jhaveri, Niyati; Zhu, Genyuan; Ye, Risheng; Li, Zhi; Bruhn, Kevin W.; Craft, Noah; Groshen, Susan; Hofman, Florence M.; Lee, Amy

doi:10.1158/0008-5472.can-10-3151

Cited by 135 publications

(132 citation statements)

References 37 publications

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“…It has been shown that human RA FLSs induce angiogenesis through a VEGF-mediated pathway in immunodeficient mice (del Rey et al, 2009). In parallel with this, we found that Grp78 down-regulation in FLSs resulted in a decrease in the extent of angiogenesis in Matrigel implants microvessel densities (Dong et al, 2011). Furthermore, knockdown of Grp78 using siRNA suppressed human microvascular endothelial cell proliferation and increased apoptosis (Dong et al, 2011).…”

Section: Reduction Of Synoviocyte Proliferation By the Down-regulatiosupporting

confidence: 62%

A novel pathogenic role of the ER chaperone GRP78/BiP in rheumatoid arthritis

Yoo¹,

You²,

Yoon³

et al. 2012

J Cell Biol

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An accumulation of misfolded proteins can trigger a cellular survival response in the endoplasmic reticulum (ER). In this study, we found that ER stress-associated gene signatures were highly expressed in rheumatoid arthritis (RA) synoviums and synovial cells. Proinflammatory cytokines, such as TNF and IL-1, increased the expression of GRP78/ BiP, a representative ER chaperone, in RA synoviocytes. RA synoviocytes expressed higher levels of GRP78 than osteoarthritis (OA) synoviocytes when stimulated by thapsigargin or proinflammatory cytokines. Down-regulation of Grp78 transcripts increased the apoptosis of RA synoviocytes while abolishing TNF-or TGF--induced synoviocyte proliferation and cyclin D1 up-regulation. Conversely, overexpression of the Grp78 gene prevented synoviocyte apoptosis. Moreover, Grp78 small interfering RNA inhibited VEGF 165 -induced angiogenesis in vitro and also significantly impeded synoviocyte proliferation and angiogenesis in Matrigel implants engrafted into immunodeficient mice. Additionally, repeated intraarticular injections of BiP-inducible factor X, a selective GRP78 inducer, increased synoviocyte proliferation and angiogenesis in the joints of mice with experimental OA. In contrast, mice with Grp78 haploinsufficiency exhibited the suppression of experimentally induced arthritis and developed a limited degree of synovial proliferation and angiogenesis. In summary, this study shows that the ER chaperone GRP78 is crucial for synoviocyte proliferation and angiogenesis, the pathological hallmark of RA. Ar ticle 873 angiogenesis in vitro and impeded synoviocyte proliferation and angiogenesis in Matrigel implants that were engrafted into immunodeficient mice. On the contrary, BiP-inducible factor X (BIX), a selective GRP78 inducer, prevented the apoptosis of FLSs and increased the progression of experimental osteoarthritis (OA) in mice, mimicking RA pathology. Moreover, heterozygous deficiency of the Grp78 gene resulted in a limited degree of inflammatory cell infiltration, angiogenesis, and synovial hyperplasia and prevented the progression of experimental arthritis in mice. Collectively, our results suggest that GRP78 is crucial for the survival and proliferation of RA synoviocytes and angiogenesis, which suggests that the ER chaperone GRP78 response contributes to the pathogenesis of RA.

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Section: Reduction Of Synoviocyte Proliferation By the Down-regulatiosupporting

confidence: 62%

A novel pathogenic role of the ER chaperone GRP78/BiP in rheumatoid arthritis

Yoo¹,

You²,

Yoon³

et al. 2012

J Cell Biol

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“…There is increasing evidence indicating that Hspa5 is involved in biogenesis and signal transduction and that it plays important roles in carcinogenesis (54,55). In this study, we investigated Hspa5 function during early embryonic development in Xenopus and showed for the first time that Hspa5 plays an essential role in pronephros formation that is mediated by RA-Lhx1 signaling.…”

Section: Discussionmentioning

confidence: 94%

Heat Shock 70-kDa Protein 5 (Hspa5) Is Essential for Pronephros Formation by Mediating Retinoic Acid Signaling

Shi

Wang

et al. 2015

Journal of Biological Chemistry

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Background:The function of Hspa5 in early embryonic development is not well understood. Results: Hspa5 is involved in mediating retinoic acid signaling and is required for pronephros. Conclusion: Hspa5 is essential for pronephros formation by mediating retinoic acid signaling. Significance: This is the first report on the cross-talk between physiological ER stress and transduction of retinoic acid signaling.

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“…It serves as a central regulator of endoplasmic reticulum (ER) homeostasis due to its multiple functional roles in protein folding and ER calcium binding, and its control of transmembrane ER stress sensor activation (10,11). GRP78 upregulation has been suggested to correlate to metastases (12,13). GAL3, one of the β-galactoside-binding proteins, has been associated with cell proliferation, recognition, adhesion, differentiation, immunomodulation, apoptosis and angiogenesis.…”

Section: A B Resultsmentioning

confidence: 99%

GRP78 and GAL3, differentially regulated by lymph node homogenates, as potential biomarkers for lymph node metastasis in mouse hepatocellular carcinoma cells

et al. 2012

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Abstract. In order to systematically evaluate the influence of lymph nodes (LNs) in lymph node metastases (LNM) of hepatocellular carcinoma (HCC), we set up a new in vitro model in which Hca-F and Hca-P cells were cultured in medium containing lymph node homogenates (LNHs). Differential protein expression was measured by two-dimensional gel electrophoresis (2-DE) combined with matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry (MALDI TOF/TOF MS). Results from protein identification revealed two metastatic correlative proteins, 78-kDa glucose-regulated protein (GRP78) and galectin-3 (GAL3). Western blotting confirmed that GRP78, a protein positively correlated with metastasis, increased 2.4-fold in Hca-F cells but decreased to almost a half in Hca-P cells (P<0.05). However, GAL3, a protein negatively correlated with metastasis, was decreased by a half in Hca-F cells but slightly increased non-significantly in Hca-P cells. Thus, our results reveal that some components of LNHs may facilitate a permissive environment for cancer cells with high metastasis potential to eventually metastasize. GRP78 and GAL3 may serve as potential biomarkers for the diagnosis of LNM in HCC. IntroductionHepatocellular carcinoma (HCC) is one of the most common types of malignant tumors and the third leading cause of cancer mortality worldwide (1). Currently, surgery is the preferred treatment method for liver cancer, but the five-year survival rate remains extremely low. Autopsy studies confirm that nearly one-third of all HCC patients have lymph node metastasis (LNM), which is the leading cause for distant metastasis and mortality; however, the molecular mechanisms of LNM from liver cancer remain unclear (2).Hca-F and Hca-P cells are gynogenetic HCC cell lines generated from mice. They are well-characterized with different metastasis potentials exclusive to lymph nodes when inoculated subcutaneously in 615 mice. Hca-F cells have a high metastatic potential (LNM rate >75%), while Hca-P cells have low metastatic potential (LNM rate <25%) (3,4). Therefore, Hca-F and Hca-P cell lines were more appropriate for investigating the mechanisms of LNM in comparison to clinical samples, since high metastatic subclone cells exist in primary cancers as a minority (5).The critical role of the cancerous microenvironment (cellular and non-cellular) is increasingly recognized as an important factor markedly influencing cancer development and metastasis (6,7). The tumor microenvironment plays a decisive role in regulating the process of hepatocarcinogenesis, epithelial-mesenchymal transition (EMT), tumor invasion and metastasis (8). Additionally, global gene expression profiling of HCC has revealed that the tumor microenvironment is also an important factor in the biological and prognostic classification of HCC. The tumor microenvironment can be classified into cellular and non-cellular components. The major cellular components include fibroblasts, hepatic stellate cells, immune cells and endothelial cells. These c...

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A Critical Role for GRP78/BiP in the Tumor Microenvironment for Neovascularization during Tumor Growth and Metastasis

Cited by 135 publications

References 37 publications

A novel pathogenic role of the ER chaperone GRP78/BiP in rheumatoid arthritis

A novel pathogenic role of the ER chaperone GRP78/BiP in rheumatoid arthritis

Heat Shock 70-kDa Protein 5 (Hspa5) Is Essential for Pronephros Formation by Mediating Retinoic Acid Signaling

GRP78 and GAL3, differentially regulated by lymph node homogenates, as potential biomarkers for lymph node metastasis in mouse hepatocellular carcinoma cells

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