Abstract
Gastric carcinoma (GC) is an aggressive cancer with a poor prognosis. We previously reported that MGr1-Ag was involved in multidrug resistance and anti-apoptosis in GC. However, the exact function of MGr1-Ag in GC proliferation is not clear. In this study, we found that MGr1-Ag was highly expressed in GC tissues and four GC cell lines compared with nontumor gastric tissues or gastric epithelial mucosa cells. The high expression of MGr1-Ag/37LRP was also consistent with the decreased median survival time of GC patients. We employed lenti-mediated RNA interference technique to knock down MGr1-Ag expression in SGC7901 and MKN45 cells, respectively, and observed its effects on GC cells growth in vitro and in vivo. Further study showed that knockdown of MGr1-Ag could inhibit GC cell proliferation by inhibiting the cell cycle S-phase entry and induced apoptosis. Soft agar colony formation assay indicated that the colony formation ability of SGC7901 and MKN45 cells decreased after lenti-MGr1-Ag small interfering RNA (siRNA) infection. Western blot revealed that cyclin D1 and Bcl-2 expression were downregulated whereas p27 and Bax were upregulated in lenti-MGr-siRNA-infected GC cells. Further study demonstrated that the proliferation effect of MGr1-Ag in GC is dependent on its laminin-binding region. Taken together, these data revealed a novel function of MGr1-Ag that can possibly be used as an independent prognostic factor and a potential therapeutic target for GC.
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Guo C, Ding J, Yao L, Sun L, Lin T, Song Y et al. Tumor suppressor gene Runx3 sensitizes gastric cancer cells to chemotherapeutic drugs by downregulating Bcl-2, MDR-1 and MRP-1. Int J Cancer 2005; 116: 155–160.
Jin H, Pan Y, He L, Zhai H, Li X, Zhao L et al. p75 neurotrophin receptor inhibits invasion and metastasis of gastric cancer. Mol Cancer Res 2007; 5: 423–433.
Pan Y, Zhao L, Liang J, Liu J, Shi Y, Liu N et al. Cellular prion protein promotes invasion and metastasis of gastric cancer. FASEB J 2006; 20: 1886–1888.
Li X, Pan Y, Fan R, Jin H, Han S, Liu J et al. Adenovirus-delivered CIAPIN1 small interfering RNA inhibits HCC growth in vitro and in vivo. Carcinogenesis 2008; 29: 1587–1593.
Fan K, Fan D, Cheng LF, Li C . Expression of multidrug resistance-related markers in gastric cancer. Anticancer Res 2000; 20: 4809–4814.
Shi Y, Han Y, Wang X, Zhao Y, Ning X, Xiao B et al. MGr1-Ag is associated with multidrug-resistant phenotype of gastric cancer cells. Gastric Cancer 2002; 5: 154–159.
Shi Y, Zhai H, Wang X, Wu H, Ning X, Han Y et al. Multidrug-resistance-associated protein MGr1-Ag is identical to the human 37-kDa laminin receptor precursor. Cell Mol Life Sci 2002; 59: 1577–1583.
Ford CL, Randal-Whitis L, Ellis SR . Yeast proteins related to the p40/laminin receptor precursor are required for 20S ribosomal RNA processing and the maturation of 40S ribosomal subunits. Cancer Res 1999; 59: 704–710.
Jackers P, Minoletti F, Belotti D, Clausse N, Sozzi G, Sobel ME et al. Isolation from a multigene family of the active human gene of the metastasis-associated multifunctional protein 37LRP/p40 at chromosome 3p21.3. Oncogene 1996; 13: 495–503.
Ewen ME, Oliver CJ, Sluss HK, Miller SJ, Peeper DS . p53-dependent repression of CDK4 translation in TGF-beta-induced G1 cell-cycle arrest. Genes Dev 1995; 9: 204–217.
Polymenis M, Schmidt EV . Coupling of cell division to cell growth by translational control of the G1 cyclin CLN3 in yeast. Genes Dev 1997; 11: 2522–2531.
Hengst L, Reed SI . Translational control of p27Kip1 accumulation during the cell cycle. Science 1996; 271: 1861–1864.
Annabi B, Currie JC, Bouzeghrane M, Dulude H, Daigneault L, Garde S et al. Contribution of the 37-kDa laminin receptor precursor in the anti-metastatic PSP94-derived peptide PCK3145 cell surface binding. Biochem Biophys Res Commun 2006; 346: 358–366.
Jaseja M, Mergen L, Gillette K, Forbes K, Sehgal I, Copie V . Structure-function studies of the functional and binding epitope of the human 37 kDa laminin receptor precursor protein. J Pept Res 2005; 66: 9–18.
Sun L, Shi Y, Guo C, Yao L, Lin T, Du J et al. Regulation of multidrug resistance by MGr1-antigen in gastric cancer cells. Tumour Biol 2006; 27: 27–35.
Liu L, Zhang H, Sun L, Gao Y, Jin H, Liang S et al. ERK/MAPK activation involves hypoxia-induced MGr1-Ag/37LRP expression and contributes to apoptosis resistance in gastric cancer. Int J Cancer 2010; 127: 820–829.
Liu N, Bi F, Pan Y, Sun L, Xue Y, Shi Y et al. Reversal of the malignant phenotype of gastric cancer cells by inhibition of RhoA expression and activity. Clin Cancer Res 2004; 10 (18 Pt 1): 6239–6247.
Lois C, Hong EJ, Pease S, Brown EJ, Baltimore D . Germline transmission and tissue-specific expression of transgenes delivered by lentiviral vectors. Science 2002; 295: 868–872.
Milner AE, Levens JM, Gregory CD . Flow cytometric methods of analyzing apoptotic cells. Methods Mol Biol 1998; 80: 347–354.
Hundt C, Peyrin JM, Haik S, Gauczynski S, Leucht C, Rieger R et al. Identification of interaction domains of the prion protein with its 37-kDa/67-kDa laminin receptor. EMBO J 2001; 20: 5876–5886.
Liu L, Ning X, Sun L, Zhang H, Shi Y, Guo C et al. Hypoxia-inducible factor-1 alpha contributes to hypoxia-induced chemoresistance in gastric cancer. Cancer Sci 2008; 99: 121–128.
Liu L, Sun L, Zhang H, Li Z, Ning X, Shi Y et al. Hypoxia-mediated up-regulation of MGr1-Ag/37LRP in gastric cancers occurs via hypoxia-inducible-factor 1-dependent mechanism and contributes to drug resistance. Int J Cancer 2009; 124: 1707–1715.
Kazmin DA, Hoyt TR, Taubner L, Teintze M, Starkey JR . Phage display mapping for peptide 11 sensitive sequences binding to laminin-1. J Mol Biol 2000; 298: 431–445.
Rieger R, Edenhofer F, Lasmezas CI, Weiss S . The human 37-kDa laminin receptor precursor interacts with the prion protein in eukaryotic cells. Nat Med 1997; 3: 1383–1388.
Leucht C, Simoneau S, Rey C, Vana K, Rieger R, Lasmezas CI et al. The 37 kDa/67 kDa laminin receptor is required for PrP(Sc) propagation in scrapie-infected neuronal cells. EMBO Rep 2003; 4: 290–295.
Beausejour M, Noel D, Thibodeau S, Bouchard V, Harnois C, Beaulieu JF et al. Integrin/Fak/Src-mediated regulation of cell survival and anoikis in human intestinal epithelial crypt cells: selective engagement and roles of PI3-K isoform complexes. Apoptosis 2012; 17: 566–578.
Meng XN, Jin Y, Yu Y, Bai J, Liu GY, Zhu J et al. Characterisation of fibronectin-mediated FAK signalling pathways in lung cancer cell migration and invasion. Br J Cancer 2009; 101: 327–334.
Yamamoto D, Sonoda Y, Hasegawa M, Funakoshi-Tago M, Aizu-Yokota E, Kasahara T . FAK overexpression upregulates cyclin D3 and enhances cell proliferation via the PKC and PI3-kinase-Akt pathways. Cell Signal 2003; 15: 575–583.
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This study was supported by Grants (no. 81101765 and no. 81272349) from the National Nature Science Foundation of China.
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Liu, L., Sun, L., Wu, K. et al. MGr1-Ag/37LRP promotes growth and proliferation of gastric cancer in vitro and in vivo. Cancer Gene Ther 21, 355–363 (2014). https://doi.org/10.1038/cgt.2014.36
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DOI: https://doi.org/10.1038/cgt.2014.36
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