title: Evaluation of AKT phosphorylation and PTEN loss and their correlation with the resistance of rituximab in DLBCL.
abstract: BACKGROUND
  Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of lymphoma with quite high mortality. PTEN/PI3K/AKT signal pathway is constitutively activated and plays an oncogenic role in most tumors including non-Hodgkin's lymphoma (NHL). Since rituximab used in chemotherapy has been proved to improve the survival of DLBCL patients, rituximab resistance is a common clinical challenge in the treatment of DLBCL. The aims of the present study are to determine the different levels of several important biomarkers of PTEN/PI3K/AKT pathway in DLBCL patients who are resistant or sensitive to rituximab treatment, and investigate the potential clinical application of these biomarkers.
  
  
  METHODS
  48 patients with DLBCL who were treated by rituximab-based chemotherapy were divided into 2 groups according to their reactions to rituximab. The expression of p-AKT, PTEN, and Ki-67 protein in 48 DLBCL tissues were detected using immunohistochemistry and analyzed for the clinical pathological significance and the resistance to rituximab. Meanwhile, PTEN gene deletion was detected also by FISH, and mutation of PIK3CA was performed by sequencing analysis.
  
  
  RESULTS
  Activation of p-AKT in 12 of 48 (25.0%) and loss expression of PTEN in 15 of 48 (31.3%) DLBCL species were observed. P-AKT activation (P<0.05) and loss of PTEN expression (P<0.05) were significantly associative with high Ki-67 index. P-AKT and PTEN expression showed a significant negative correlation in all 48 DLBCL patients (r=-0.450, P<0.05), and the Spearman correlation coefficient in the resistant group (r=-0.769, P<0.05) was greater than in the sensitive group (r=-0.691, P<0.05).
  
  
  CONCLUSIONS
  Regulation of PTEN/PI3K/AKT signal pathway participates in the progression of DLBCL, and may be involved in the development of the resistance to rituximab for some DLBCL patients.
authors.affiliation: Department of Pathology, Henan Key Laboratory for Tumour Pathology, The First Affiliated Hospital of Zhengzhou University Zhengzhou 450002, Henan Province, P. R. China.
authors.forename: Yihui
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Endocrinology, Cancer Research Institute, The First Affiliated Hospital of Zhengzhou University Zhengzhou 450002, Henan Province, P. R. China.
authors.forename: Pengyu
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Cancer Research Institute, The First Affiliated Hospital of Zhengzhou University Zhengzhou 450002, Henan Province, P. R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Oncology, Cancer Research Institute, The First Affiliated Hospital of Zhengzhou University Zhengzhou 450002, Henan Province, P. R. China.
authors.forename: Huijie
authors.initials: H
authors.lastname: Fan
authors.affiliation: Department of Oncology, Cancer Research Institute, The First Affiliated Hospital of Zhengzhou University Zhengzhou 450002, Henan Province, P. R. China.
authors.forename: Mingzhi
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Cancer Research Institute, The First Affiliated Hospital of Zhengzhou University Zhengzhou 450002, Henan Province, P. R. China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D000069283:Rituximab / Q000627:therapeutic use; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000069283:Rituximab; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: AKT; PI3K; PTEN; lymphoma; rituximab resistance
references.citation: Curr Protein Pept Sci. 2010 Sep;11(6):425-35
references.pmid: 20491626
references.citation: Curr Hematol Malig Rep. 2006 Dec;1(4):205-13
references.pmid: 20425315
references.citation: Cell Cycle. 2013 Nov 1;12(21):3347-8
references.pmid: 24091535
references.citation: Leuk Lymphoma. 2009 Jun;50(6):873-85
references.pmid: 19373595
references.citation: Leukemia. 2007 Nov;21(11):2368-70
references.pmid: 17657213
references.citation: Nat Rev Cancer. 2002 Jul;2(7):489-501
references.pmid: 12094235
references.citation: Mod Pathol. 2003 Jun;16(6):607-12
references.pmid: 12808067
references.citation: Oncogene. 2007 Sep 13;26(42):6184-93
references.pmid: 17420722
references.citation: Proc Natl Acad Sci U S A. 2013 Jul 23;110(30):12420-5
references.pmid: 23840064
references.citation: Am J Pathol. 2014 Oct;184(10):2828-39
references.pmid: 25239565
references.citation: Clin Cancer Res. 2007 Jun 15;13(12):3577-84
references.pmid: 17575221
references.citation: Leuk Lymphoma. 2010 Jul;51(7):1305-14
references.pmid: 20443680
references.citation: Oncology. 2009;76(4):275-85
references.pmid: 19262067
references.citation: Mol Clin Oncol. 2013 Jan;1(1):47-52
references.pmid: 24649121
references.citation: N Engl J Med. 2008 Nov 27;359(22):2313-23
references.pmid: 19038878
references.citation: Int J Oncol. 2014 Dec;45(6):2187-92
references.pmid: 25270272
references.citation: Int J Oncol. 2012 Mar;40(3):639-44
references.pmid: 22200790
references.citation: Int J Cancer. 2008 Mar 1;122(5):1012-8
references.pmid: 17985348
references.citation: Oncogene. 2003 Oct 20;22(47):7359-68
references.pmid: 14576843
references.citation: PLoS One. 2014;9(4):e95219
references.pmid: 24777052
references.citation: Cancer Res. 2011 Feb 1;71(3):629-33
references.pmid: 21266353
references.citation: Acta Histochem. 2014 Jan;116(1):126-30
references.pmid: 24054064
references.citation: Drugs. 2007;67(3):333-50
references.pmid: 17335294
references.citation: Science. 2004 Apr 23;304(5670):554
references.pmid: 15016963
references.citation: Nature. 2000 Feb 3;403(6769):503-11
references.pmid: 10676951
references.citation: Ai Zheng. 2009 Feb;28(2):146-9
references.pmid: 19550126
references.citation: J Clin Oncol. 2006 Jan 10;24(2):306-14
references.pmid: 16330671
references.citation: Biomarkers. 2014 Nov;19(7):590-6
references.pmid: 25174622
references.citation: Carcinogenesis. 2007 Jul;28(7):1379-86
references.pmid: 17341655
references.citation: Breast Cancer Res Treat. 2011 Jul;128(2):447-56
references.pmid: 21594665
references.citation: Cancer Res. 2006 Apr 15;66(8):3963-6
references.pmid: 16618711
references.citation: Oncogene. 2007 May 28;26(25):3629-36
references.pmid: 17530016
references.citation: Oncol Res. 2011;19(12):563-71
references.pmid: 22812189
references.citation: Br J Haematol. 2010 May;149(4):560-8
references.pmid: 20201946
references.citation: Appl Immunohistochem Mol Morphol. 2011 Mar;19(2):173-83
references.pmid: 20930614
references.citation: Best Pract Res Clin Haematol. 2011 Jun;24(2):203-16
references.pmid: 21658619
references.citation: Curr Opin Oncol. 2001 Sep;13(5):325-34
references.pmid: 11555708
references.citation: N Engl J Med. 2008 Aug 7;359(6):613-26
references.pmid: 18687642
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):802-7
references.pmid: 15647370
references.citation: Trends Pharmacol Sci. 2011 Mar;32(3):131-40
references.pmid: 21236500
references.citation: Cancer Sci. 2009 Oct;100(10):1842-7
references.pmid: 19656156