Top

Published in:

01-12-2006 | Original paper

Association of elevated GRP78 expression with increased lymph node metastasis and poor prognosis in patients with gastric cancer

Authors: Jun Zhang, Yixing Jiang, Zhiliang Jia, Qiang Li, Weida Gong, Liwei Wang, Daoyan Wei, James Yao, Shengyun Fang, Keping Xie

Published in: Clinical & Experimental Metastasis | Issue 7-8/2006

Abstract

Glucose-regulated protein 78 (GRP78) has been implicated in the protection of tumor cells from cytotoxic damage and apoptosis and thus assists cells in survival under oxygen-deprivation and nutrient-stress conditions. However, its expression and potential role in gastric cancer development and progression have not been reported. In the present study, we determined the level of GRP78 expression in the primary tumor in 86 cases of resected gastric cancer by using immunohistochemistry and analyzed the relationships between GRP78 and clinicopathological characteristics. We found that GRP78 was overexpressed in the tumor specimens when compared with the expression in adjacent tumor-free gastric mucosa. Furthermore, the level of GRP78 expression in both primary tumors and metastatic lymph nodes was inversely correlated with patient survival. Overexpression of GRP78 was directly correlated with Sp1 expression and increased lymph node metastasis. Knocking down GRP78 expression inhibited tumor cell invasion in vitro and growth and metastasis in a xenograft nude mouse model. Therefore, our data imply that dysregulated expression of GRP78 may contribute to the development and progression of gastric cancer.

Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108PubMedCrossRef

Berardi R, Scartozzi M, Romagnoli E, Antognoli S, Cascinu S (2004) Gastric cancer treatment: a systematic review. Oncol Rep 11:911–916PubMed

Hofler H, Becker KF (2003) Molecular mechanisms of carcinogenesis in gastric cancer. Recent Results Cancer Res 162:65–72PubMed

Zheng L, Wang L, Ajani J, Xie K (2004) Molecular basis of gastric cancer development and progression. Gastric Cancer 7:61–77PubMedCrossRef

Gething MJ (1999) Role and regulation of the ER chaperone BiP. Semin Cell Dev Biol 10:465–472PubMedCrossRef

Liu H, Miller E, van de Water B, Stevens JL (1998) Endoplasmic reticulum stress proteins block oxidant-induced Ca2+ increases and cell death. J Biol Chem 273:12858–12862PubMedCrossRef

Little E, Ramakrishnan M, Roy B, Gazit G, Lee AS (1994) The glucose-regulated proteins (GRP78 and GRP94): functions, gene regulation, and applications. Crit Rev Eukaryot Ggene Expr 4:1–18

Jamora C, Dennert G, Lee AS (1996) Inhibition of tumor progression by suppression of stress protein GRP78/BiP induction in fibrosarcoma B/C10ME. Proc Natl Acad Sci USA 93:7690–7694PubMedCrossRef

Reddy RK, Lu J, Lee AS (1999) The endoplasmic reticulum chaperone glycoprotein GRP94 with Ca(2+)-binding and antiapoptotic properties is a novel proteolytic target of calpain during etoposide-induced apoptosis. J Biol Chem 274:28476–28483PubMedCrossRef

10.

Bernstein H, Payne CM, Bernstein C, Schneider J, Beard SE, Crowley CL (1999) Activation of the promoters of genes associated with DNA damage, oxidative stress, ER stress and protein malfolding by the bile salt, deoxycholate. Toxicol Lett 108:37–46PubMedCrossRef

11.

McCormick TS, McColl KS, Distelhorst CW (1997) Mouse lymphoma cells destined to undergo apoptosis in response to thapsigargin treatment fail to generate a calcium-mediated grp78/grp94 stress response. J Biol Chem 272:6087–6092PubMedCrossRef

12.

Reddy RK, Mao C, Baumeister P, Austin RC, Kaufman RJ, Lee AS (2003) Endoplasmic reticulum chaperone protein GRP78 protects cells from apoptosis induced by topoisomerase inhibitors: role of ATP binding site in suppression of caspase-7 activation. J Biol Chem 278:20915–20924PubMedCrossRef

13.

Koomagi R, Mattern J, Volm M (1999) Glucose-related protein (GRP78) and its relationship to the drug-resistance proteins P170, GST-pi, LRP56 and angiogenesis in non-small cell lung carcinomas. Anticancer Res 19:4333–4336PubMed

14.

Fernandez PM, Tabbara SO, Jacobs LK, et al (2000) Overexpression of the glucose-regulated stress gene GRP78 in malignant but not benign human breast lesions. Breast Cancer Res Treat 59:15–26PubMedCrossRef

15.

Uramoto H, Sugio K, Oyama T, et al (2005) Expression of endoplasmic reticulum molecular chaperone Grp78 in human lung cancer and its clinical significance. Lung Cancer 49:55–62PubMedCrossRef

16.

Koong AC, Chen EY, Lee AS, Brown JM, Giaccia AJ (1994) Increased cytotoxicity of chronic hypoxic cells by molecular inhibition of GRP78 induction. Int J Radiat Oncol Biol Phys 28:661–666PubMed

17.

Wang L, Wei D, Huang S, et al (2003) Transcription factor Sp1 expression is a significant predictor of survival in human gastric cancer. Clin Cancer Res 9:6371–6380PubMed

18.

Abdelrahim M, Samudio I, Smith R III, Burghardt R, Safe S (2002) Small inhibitory RNA duplexes for Sp1 mRNA block basal and estrogen-induced gene expression and cell cycle progression in MCF-7 breast cancer cells. J Biol Chem 277:28815–28822PubMedCrossRef

19.

Bond GL, Hu W, Levine A (2005) A single nucleotide polymorphism in the MDM2 gene: from a molecular and cellular explanation to clinical effect. Cancer Res 65:5481–5484PubMedCrossRef

20.

Zu K, Bihani T, Lin A, et al (2006) Enhanced selenium effect on growth arrest by BiP/GRP78 knockdown in p53-null human prostate cancer cells. Oncogene 25:546–554PubMed

21.

Dong D, Ko B, Baumeister P, et al (2005) Vascular targeting and antiangiogenesis agents induce drug resistance effector GRP78 within the tumor microenvironment. Cancer Res 65:5785–5791PubMedCrossRef

22.

Huang S, Mills L, Mian B, et al (2002) Fully humanized neutralizing antibodies to interleukin-8 (ABX-IL8) inhibit angiogenesis, tumor growth, and metastasis of human melanoma. Am J Pathol 161:125–134PubMed

23.

Wei D, Gong W, Kanai M, et al (2005) Drastic down-regulation of Kruppel-like factor 4 expression is critical in human gastric cancer development and progression. Cancer Res 65:2746–2754PubMedCrossRef

24.

Luo S, Baumeister P, Yang S, Abcouwer SF, Lee AS (2003) Induction of Grp78/BiP by translational block: activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE site independent of the endoplasmic reticulum stress elements. J Biol Chem 278:37375–37385PubMedCrossRef

25.

Cho DY, Yang GH, Ryu CJ, Hong HJ (2003) Molecular chaperone GRP78/BiP interacts with the large surface protein of hepatitis B virus in vitro and in vivo. J Virol 77:2784–2788PubMedCrossRef

26.

Moennikes O, Loeppen S, Buchmann A, et al (2004) A constitutively active dioxin/aryl hydrocarbon receptor promotes hepatocarcinogenesis in mice. Cancer Res 64:4707–4710PubMedCrossRef

27.

Hori O, Matsumoto M, Kuwabara K, et al (1996) Exposure of astrocytes to hypoxia/reoxygenation enhances expression of glucose-regulated protein 78 facilitating astrocyte release of the neuroprotective cytokine interleukin 6. J Neurochem 66:973–979PubMedCrossRef

28.

Jacquier-Sarlin MR, Dreher D, Polla BS (1996) Selective induction of the glucose-regulated protein grp78 in human monocytes by bacterial extracts (OM-85): a role for calcium as second messenger. Biochem Biophys Res Commun 226:166–171PubMedCrossRef

29.

Abdelrahim M, Liu S, Safe S (2005) Induction of endoplasmic reticulum-induced stress genes in Panc-1 pancreatic cancer cells is dependent on Sp proteins. J Biol Chem 280:16508–16513PubMedCrossRef

30.

Lim SO, Park SG, Yoo JH, et al (2005) Expression of heat shock proteins (HSP27, HSP60, HSP70, HSP90, GRP78, GRP94) in hepatitis B virus-related hepatocellular carcinomas and dysplastic nodules. World J Gastroenterol 11:2072–2079PubMed

31.

Hsu WM, Hsieh FJ, Jeng YM, et al (2005) GRP78 expression correlates with histologic differentiation and favorable prognosis in neuroblastic tumors. Int J Cancer 113:920–927PubMedCrossRef

32.

Sugawara S, Takeda K, Lee A, Dennert G (1993) Suppression of stress protein GRP78 induction in tumor B/C10ME eliminates resistance to cell mediated cytotoxicity. Cancer Res 53:6001–6005PubMed

33.

Dorner AJ, Wasley LC, Kaufman RJ (1992) Overexpression of GRP78 mitigates stress induction of glucose regulated proteins and blocks secretion of selective proteins in Chinese hamster ovary cells. EMBO J 11:1563–1571PubMed

34.

Chatterjee S, Cheng MF, Berger SJ, Berger NA (1994) Induction of M(r) 78,000 glucose-regulated stress protein in poly(adenosine diphosphate-ribose) polymerase- and nicotinamide adenine dinucleotide-deficient V79 cell lines and its relation to resistance to the topoisomerase II inhibitor etoposide. Cancer Res 54:4405–4411PubMed

35.

Gomer CJ, Ferrario A, Rucker N, Wong S, Lee AS (1991) Glucose regulated protein induction and cellular resistance to oxidative stress mediated by porphyrin photosensitization. Cancer Res 51:6574–6579PubMed

36.

Courey AJ, Tjian R (1992) Mechanisms of transcription factor Sp1. In: von Hippel H, Yager TD, Gill SC (eds) Transcription regulation. Cold Spring Harbor, NY, Cold Spring Harbor Laboratory Press, pp 743–769

Title: Association of elevated GRP78 expression with increased lymph node metastasis and poor prognosis in patients with gastric cancer
Authors: Jun Zhang
Yixing Jiang
Zhiliang Jia
Qiang Li
Weida Gong
Liwei Wang
Daoyan Wei
James Yao
Shengyun Fang
Keping Xie
Publication date: 01-12-2006
Publisher: Kluwer Academic Publishers
Published in: Clinical & Experimental Metastasis / Issue 7-8/2006
Print ISSN: 0262-0898
Electronic ISSN: 1573-7276
DOI: https://doi.org/10.1007/s10585-006-9051-9

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 7-8/2006

RhoGDIβ lacking the N-terminal regulatory domain suppresses metastasis by promoting anoikis in v-src-transformed cells

Patterns of EphA2 protein expression in primary and metastatic pancreatic carcinoma and correlation with genetic status

Host matrix metalloproteinase-9 contributes to tumor vascularization without affecting tumor growth in a model of prostate cancer bone metastasis

HOXD3-overexpression increases integrin αvβ3 expression and deprives E-cadherin while it enhances cell motility in A549 cells

A novel orthotopic murine model provides insights into cellular and molecular characteristics contributing to human osteosarcoma

Recombinant human prothrombin kringle-2 inhibits B16F10 melanoma metastasis through inhibition of neovascularization and reduction of matrix metalloproteinase expression

Keynote webinar | Spotlight on antibody–drug conjugates in cancer