Abstract
The purpose of this study was to detect the expressions of GRP78 and Bax in human non-small cell lung cancer (NSCLC) tissues, to analyze their correlations with carcinogenesis and the development of NSCLC, and to investigate the relationship of GRP78 expression to metastasis and apoptosis in the NSCLC cell line HCC827. The positive expression rates of GRP78 and Bax in NSCLC lung tissues were 59.7% and 34.7% by RT-PCR, respectively. The mRNA and protein expression levels of GRP78 in NSCLC tissues were significantly higher than that in the relatively normal surrounding lung tissues (p < 0.05); the lesser the degree of tumor differentiation was, the higher the mRNA and protein expression levels of GRP78 were (p < 0.05). The mRNA and protein expression levels of GRP78 from patients in advanced pathological stages (III–IV) were significantly higher than the corresponding levels in patients in early pathological stages (I–II) (p < 0.05); the mRNA and protein expression levels of GRP78 in patients with positive lymph node metastasis were significantly higher than those in patients with negative lymph node metastasis (p < 0.05). The mRNA and protein expression levels of Bax in the above cases showed the opposite trend of the mRNA and protein expression levels of GRP78. However, the mRNA and protein expression levels of both GRP78 and Bax were independent of the patient’s sex, the patient’s age, the tumor size and the histological type (adenocarcinoma or squamous cell carcinoma) of NSCLC (p > 0.05). The mRNA expression level of GRP78 and the mRNA expression level of Bax in human NSCLC tissues were negatively correlated (r = −0.353, p = 0.002). After transfection of GRP78 siRNA in HCC827 cells, the GRP78 protein expression level was significantly decreased (p < 0.01), while the Bax protein expression level was significantly increased (p < 0.01); the number of cells that passed through the Transwell chamber was significantly less in the non-transfected control group compared to the transfected control group (p < 0.01). The number of apoptotic cells was significantly greater in the non-transfected control group compared to the transfected control group (p < 0.01). The expression levels of GRP78 and Bax were related to the carcinogenesis, development and metastasis of NSCLC. GRP78 expression with siRNA interference in the human NSCLC cell line HCC827 can reduce metastasis and promote apoptosis in HCC827 cells.
Similar content being viewed by others
References
Giangreco A, Groot KR, Janes SM (2007) Lung cancer and lung stem cells: Strange bedfellows? Am J Respir Crit Care Med 175:547–553
Shao WL, Wang DY, He JX (2010) The role of gene expression profiling in early-stage non-small cell lung cancer. J Thorac Dis 2:89–99
Yang HH, Zhang Q, He JX, Lu WJ (2010) Regulation of calcium signaling in lung cancer. J Thorac Dis 2:52–56
Xiao DK, He JX (2010) Epithelial mesenchymal transition and lung cancer. J Thorac Dis 2:154–159
Korpanty G, Smyth E, Carney DN (2011) Update on anti-angiogenic therapy in non-small cell lung cancer: Are we making progress? J Thorac Dis 3:19–29
Shash E, Peccatori FA, Azim HA Jr (2011) Optimizing the use of epidermal growth factor receptor inhibitors in advanced non-small-lung cancer (NSCLC). J Thorac Dis 3:57–64
McKeage MJ, Jameson MB (2010) AS1404-201 Study Group Investigators. Comparative outcomes of squamous and non-squamous non-small cell lung cancer (NSCLC) patients in phase II studies of ASA404 (DMXAA)—retrospective analysis of pooled data. J Thorac Dis 2:199–204
Zhang LH, Zhang X (2010) Roles of GRP78 in physiology and cancer. J Cell Biochem 110:1299–1305
Shiu RP, Pastan IH (1979) Properties and purification of a glucose-regulated protein from chick embryo fibroblasts. Biochim Biophys Acta 576:141–150
Ni M, Lee AS (2007) ER chaperones in mammalian development and human diseases. FEBS Lett 581:3641–3651
Quinones QJ, de Ridder GG, Pizzo SV (2008) GRP78: a chaperone with diverse roles beyond the endoplasmic reticulum. Histol Histopathol 23:1409–1416
Haas IG (1994) BiP (GRP78), an essential hsp70 resident protein in the endoplasmic reticulum. Experientia 50:1012–1020
Banhegyi G, Baumeister P, Benedetti A, Dong D, Fu Y, Lee AS, Li J, Mao C, Margittai E, Ni M (2007) Endoplasmic reticulum stress. Ann N Y Acad Sci 1113:58–71
Kimata Y, Kohno K (2011) Endoplasmic reticulum stress-sensing mechanisms in yeast and mammalian cells. Curr Opin Cell Biol 23:135–142
de Ridder G, Ray R, Misra UK, Pizzo SV (2011) Modulation of the unfolded protein response by GRP78 in prostate cancer. Methods Enzymol 489:245–257
Lee AS (2007) GRP78 induction in cancer: therapeutic and prognostic implications. Cancer Res 67:3496–3499
Li J, Lee AS (2006) Stress induction of GRP78/BiP and its role in cancer. Curr Mol Med 6:45–54
Fu Y, Lee AS (2006) Glucose regulated proteins in cancer progression, drug resistance and immunotherapy. Cancer Biol Ther 5:741–744
Sarkar FH, Rahman KM, Li Y (2003) Bax translocation to mitochondria is an important event in inducing apoptotic cell death by indole-3-carbinol (I3C) treatment of breast cancer cells. J Nutr 133:2434S–2439S
Ranganathan AC, Zhang L, Adam AP, Aguirre-Ghiso JA (2006) Functional coupling of p38-induced up-regulation of BiP and activation of RNA-dependent protein kinase-like endoplasmic reticulum kinase to drug resistance of dormant carcinoma cells. Cancer Res 66:1702–1711
Salgia R, Hensing T, Campbell N, Salama AK, Maitland M, Hoffman P, Villaflor V, Vokes EE (2011) Personalized treatment of lung cancer. Semin Oncol 38:274–283
Gu X, Ma C, Yuan D, Song Y (2011) Circulating soluble intercellular adhesion molecule-1 in lung cancer: a systematic review. Transl Lung Cancer Res 2011 Aug 15. doi:10.3978/j.issn.2218-6751.08.01
Bremnes RM, Donnem T, Al-Saad S, Al-Shibli K, Andersen S, Sirera R, Camps C, Marinez I, Busund LT (2011) The role of tumor stroma in cancer progression and prognosis: emphasis on carcinoma-associated fibroblasts and non-small cell lung cancer. J Thorac Oncol 6:209–217
Wagner M, Moore DD (2011) Endoplasmic reticulum stress and glucose homeostasis. Curr Opin Clin Nutr Metab Care 14:367–373
Doyle KM, Kennedy D, Gorman AM, Gupta S, Healy SJ, Samali A (2011) Unfolded proteins and endoplasmic reticulum stress in neurodegenerative disorders. J Cell Mol Med 15:2025–2039
Watson GW, Andley UP (2011) Activation of the unfolded protein response by a cataract-associated alpha A-crystallin mutation. Biochem Biophys Res Commun 401:192–196
Backer MV, Backer JM, Chinnaiyan P (2011) Targeting the unfolded protein response in cancer therapy. Methods Enzymol 491:37–56
Schardt JA, Mueller BU, Pabst T (2011) Activation of the unfolded protein response in human acute myeloid leukemia. Methods Enzymol 489:227–243
Daneshmand S, Quek ML, Lin E, Lee C, Cote RJ, Hawes D, Cai J, Groshen S, Lieskovsky G, Skinner DG (2007) Glucose-regulated protein GRP78 is up-regulated in prostate cancer and correlates with recurrence and survival. Hum Pathol 38:1547–1552
Zheng HC, Takahashi H, Li XH, Hara T, Masuda S, Guan YF, Takano Y (2008) Overexpression of GRP78 and GRP94 are markers for aggressive behavior and poor prognosis in gastric carcinomas. Hum Pathol 39:1042–1049
Fernandez PM, Tabbara SO, Jacobs LK, Manning FC, Tsangaris TN, Schwartz AM, Kennedy KA, Patierno SR (2000) Overexpression of the glucose-regulated stress gene GRP78 in malignant but not benign human breast lesions. Breast Cancer Res Treat 59:15–26
Liu FS, Jan YJ, Lai CR, Twu NF, Lu CH, Hung MJ, Hsieh YT, Chiou LC (2008) Expression analysis of apoptosis-related markers TP53, BCL-2, BAX and c-MYC in female genital tract sarcomas. J Chin Med Assoc 71:628–634
Zheng HC, Nakamura T, Zheng Y, Nakanishi Y, Tabuchi Y, Uchiyama A, Takahashi H, Takano Y (2009) SV40 T antigen disrupted the cell metabolism and the balance between proliferation and apoptosis in lens tumors of transgenic mice. J Cancer Res Clin Oncol 135:1521–1532
Chiu CC, Lin CY, Lee LY, Chen YJ, Lu YC, Wang HM, Liao CT, Chang JT, Cheng AJ (2011) Molecular chaperones as a common set of proteins that regulate the invasion phenotype of head and neck cancer. Clin Cancer Res 17:4629–4641
Cohen M, Petignat P (2011) Purified autoantibodies against glucose-regulated protein 78 (GRP78) promote apoptosis and decrease invasiveness of ovarian cancer cells. Cancer Lett 309:104–109
Zhong Q, Zhou B, Ann DK, Minoo P, Liu Y, Banfalvi A, Krishnaveni MS, Dubourd M, Demaio L, Willis BC (2011) Role of ER stress in EMT of alveolar epithelial cells: effects of misfolded surfactant protein. Am J Respir Cell Mol Biol 45:498–509
Zhou H, Zhang Y, Fu Y, Chan L, Lee AS (2011) A novel mechanism of anti-apoptotic function of 78 kDa glucose-regulated protein (GRP78), an endocrine resistance factor in breast cancer, through release of B-cell lymphoma 2 (BCL-2) from BCL-2-interacting killer (BIK). J Biol Chem 286:25687–25696
Conflict of interest
The authors declare no conflicts of interest.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Sun, Q., Hua, J., Wang, Q. et al. Expressions of GRP78 and Bax associate with differentiation, metastasis, and apoptosis in non-small cell lung cancer. Mol Biol Rep 39, 6753–6761 (2012). https://doi.org/10.1007/s11033-012-1500-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-012-1500-8