Exploration of Molecular Mechanisms of Diffuse Large B-cell Lymphoma Development Using a Microarray

  • Zhang, Zong-Xin (Department of Laboratory, Huzhou Central Hospital) ;
  • Shen, Cui-Fen (Department of Laboratory, Huzhou Central Hospital) ;
  • Zou, Wei-Hua (Department of Laboratory, Huzhou Central Hospital) ;
  • Shou, Li-Hong (Department of Laboratory, Huzhou Central Hospital) ;
  • Zhang, Hui-Ying (Department of Laboratory, Huzhou Central Hospital) ;
  • Jin, Wen-Jun (Department of Laboratory, Huzhou Central Hospital)
  • 발행 : 2013.03.30


Objective: We aimed to identify key genes, pathways and function modules in the development of diffuse large B-cell lymphoma (DLBCL) with microarray data and interaction network analysis. Methods: Microarray data sets for 7 DLBCL samples and 7 normal controls was downloaded from the Gene Expression Omnibus (GEO) database and differentially expressed genes (DEGs) were identified with Student's t-test. KEGG functional enrichment analysis was performed to uncover their biological functions. Three global networks were established for immune system, signaling molecules and interactions and cancer genes. The DEGs were compared with the networks to observe their distributions and determine important key genes, pathways and modules. Results: A total of 945 DEGs were obtained, 272 up-regulated and 673 down-regulated. KEGG analysis revealed that two groups of pathways were significantly enriched: immune function and signaling molecules and interactions. Following interaction network analysis further confirmed the association of DEGs in immune system, signaling molecules and interactions and cancer genes. Conclusions: Our study could systemically characterize gene expression changes in DLBCL with microarray technology. A range of key genes, pathways and function modules were revealed. Utility in diagnosis and treatment may be expected with further focused research.


  1. Klein RS, Rubin JB (2004). Immune and nervous system CXCL12 and CXCR4: parallel roles in patterning and plasticity. Trends Immunol, 25, 306-14.
  2. Koizumi K, Hojo S, Akashi T, et al (2007). Chemokine receptors in cancer metastasis and cancer cell-derived chemokines in host immune response. Cancer Sci, 98, 1652-8.
  3. Koutros S, Schumacher FR, Hayes RB, et al (2010). Pooled analysis of phosphatidylinositol 3-kinase pathway variants and risk of prostate cancer. Cancer Res, 70, 2389-96.
  4. Lenz G, Davis RE, Ngo VN, et al (2008). Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science, 319, 1676-9.
  5. Lokker NA, Sullivan CM, Hollenbach SJ, et al (2002). Plateletderived growth factor (PDGF) autocrine signaling regulates survival and mitogenic pathways in glioblastoma cells: evidence that the novel PDGF-C and PDGF-D ligands may play a role in the development of brain tumors. Cancer Res, 62, 3729-35.
  6. Lossos IS, Jones CD, Warnke R, et al (2001). Expression of a single gene, BCL-6, strongly predicts survival in patients with diffuse large B-cell lymphoma. Blood, 98, 945-51.
  7. Michl P, Buchholz M, Rolke M, et al (2001). Claudin-4: a new target for pancreatic cancer treatment using Clostridium perfringens enterotoxin. Gastroenterology, 121, 678-84.
  8. Mitra SK, Schlaepfer DD (2006). Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol, 18, 516-23.
  9. Montesinos-Rongen M, Schafer E, Siebert R, Deckert M Genes regulating the B cell receptor pathway are recurrently mutated in primary central nervous system lymphoma. Acta Neuropathol, 124, 905-6.
  10. Monti S, Savage KJ, Kutok JL, et al (2005). Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response. Blood, 105, 1851-61.
  11. Morin PJ (2005). Claudin proteins in human cancer: promising new targets for diagnosis and therapy. Cancer Res, 65, 9603-6.
  12. Muniz LR, Pacer ME, Lira SA, Furtado GC A critical role for dendritic cells in the formation of lymphatic vessels within tertiary lymphoid structures. J Immunol, 187, 828-34.
  13. Oikawa Y, Hansson J, Sasaki T, et al Melanoma cells produce multiple laminin isoforms and strongly migrate on alpha5 laminin(s) via several integrin receptors. Exp Cell Res, 317, 1119-33.
  14. Akbulut S (2012). Unusual cause of adult intussusception: diffuse large B-cell non-Hodgkin's lymphoma: a case report and review. Eur Rev Med Pharmacol Sci, 16, 1938.
  15. Bornfeldt KE, Raines EW, Graves LM, et al (1995). Plateletderived growth factor. Distinct signal transduction pathways associated with migration versus proliferation. Ann N Y Acad Sci, 766, 416-30.
  16. Cai W, Chen X (2006). Anti-angiogenic cancer therapy based on integrin alphavbeta3 antagonism. Anticancer Agents Med Chem, 6, 407-28.
  17. Chen J, Xu X, Wang H (2009). Expression of integrin-alpha(3) mRNA in meningiomas and its correlation with proliferation and invasion. J Huazhong Univ Sci Technolog Med Sci, 29, 94-6.
  18. Courtney KD, Corcoran RB, Engelman JA (2010). The PI3K pathway as drug target in human cancer. J Clin Oncol, 28, 1075-83.
  19. Davidson B, Elstrand MB, McMaster MT, et al (2005). HLA-G expression in effusions is a possible marker of tumor susceptibility to chemotherapy in ovarian carcinoma. Gynecol Oncol, 96, 42-7.
  20. Davis FG, McCarthy BJ, Berger MS (1999). Centralized databases available for describing primary brain tumor incidence, survival, and treatment: Central Brain Tumor Registry of the United States; Surveillance, Epidemiology, and End Results;and National Cancer Data Base. Neuro Oncol, 1, 205-11.
  21. Davis RE, Ngo VN, Lenz G, et al (2010). Chronic active B-cellreceptor signalling in diffuse large B-cell lymphoma. Nature, 463, 88-92.
  22. Dhawan P, Singh AB, Deane NG, et al (2005). Claudin-1 regulates cellular transformation and metastatic behavior in colon cancer. J Clin Invest, 115, 1765-76.
  23. Hannigan G, Troussard AA, Dedhar S (2005). Integrin-linked kinase: a cancer therapeutic target unique among its ILK. Nat Rev Cancer, 5, 51-63.
  24. Havenith MG, Arends JW, Simon R, et al (1988). Type IV collagen immunoreactivity in colorectal cancer. Prognostic value of basement membrane deposition. Cancer, 62, 2207-11.<2207::AID-CNCR2820621023>3.0.CO;2-L
  25. Huang da W, Sherman BT, Lempicki RA (2009). Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res, 37, 1-13.
  26. Iqbal J, Neppalli VT, Wright G, et al (2006). BCL2 expression is a prognostic marker for the activated B-cell-like type of diffuse large B-cell lymphoma. J Clin Oncol, 24, 961-8.
  27. Kakinuma T, Hwang ST (2006). Chemokines, chemokine receptors, and cancer metastasis. J Leukoc Biol, 79, 639-51.
  28. Katso R, Okkenhaug K, Ahmadi K, et al (2001). Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol, 17, 615-75.
  29. Kawano R, Ohshima K, Karube K, et al (2004). Prognostic significance of hepatocyte growth factor and c-MET expression in patients with diffuse large B-cell lymphoma. Br J Haematol, 127, 305-7.
  30. Agarwal R, D'Souza T, Morin PJ (2005). Claudin-3 and claudin-4 expression in ovarian epithelial cells enhances invasion and is associated with increased matrix metalloproteinase-2 activity. Cancer Res, 65, 7378-85.
  31. Oku N, Sasabe E, Ueta E, et al (2006). Tight junction protein claudin-1 enhances the invasive activity of oral squamous cell carcinoma cells by promoting cleavage of laminin-5 gamma2 chain via matrix metalloproteinase (MMP)-2 and membrane-type MMP-1. Cancer Res, 66, 5251-7.
  32. Rangel LB, Agarwal R, D'Souza T, et al (2003). Tight junction proteins claudin-3 and claudin-4 are frequently overexpressed in ovarian cancer but not in ovarian cystadenomas. Clin Cancer Res, 9, 2567-75.
  33. Rouas-Freiss N, Moreau P, Ferrone S, Carosella ED (2005). HLA-G proteins in cancer: do they provide tumor cells with an escape mechanism? Cancer Res, 65, 10139-44.
  34. Smith JR, Falkenhagen KM, Coupland SE, et al (2007). Malignant B cells from patients with primary central nervous system lymphoma express stromal cell-derived factor-1. Am J Clin Pathol, 127, 633-41.
  35. Sung CO, Kim SC, Karnan S, et al (2011). Genomic profiling combined with gene expression profiling in primary central nervous system lymphoma. Blood, 117, 1291-300.
  36. Takehara M, Nishimura T, Mima S, et al (2009). Effect of claudin expression on paracellular permeability, migration and invasion of colonic cancer cells. Biol Pharm Bull, 32, 825-31.
  37. Wee S, Lengauer C, Wiederschain D (2008). Class IA phosphoinositide 3-kinase isoforms and human tumorigenesis:implications for cancer drug discovery and development. Curr Opin Oncol, 20, 77-82.
  38. Xu Y, Liu L, Qiu X, et al CCL21/CCR7 promotes G2/M phase progression via the ERK pathway in human non-small cell lung cancer cells. PLoS One, 6, e21119.
  39. Yao WK, Wang YP, Peng F, et al (2012). [Expression of dendritic cell marker CD21 is a positive prognostic factor in diffuse large B-cell lymphoma]. Zhonghua Bing Li Xue Za Zhi, 41, 818-22.