Sonic hedgehog signaling proteins and ATP-binding cassette G2 are aberrantly expressed in diffuse large B-cell lymphoma

Mod Pathol. 2009 Oct;22(10):1312-20. doi: 10.1038/modpathol.2009.98. Epub 2009 Jul 10.

Abstract

Dysregulation of the sonic hedgehog (SHH) signaling pathway has been shown in several cancer types, but has not been explored in diffuse large B-cell lymphoma. We assessed 67 cases of diffuse large B-cell lymphoma for expression of SHH (ligand), GLI1, GLI2 and GLI3 (transcriptional effectors of SHH signaling), and the ATP-binding cassette (ABC)G2 (a downstream target of SHH signaling), using immunohistochemistry. For comparison, we assessed the expression levels of these proteins in 28 cases of follicular lymphoma, 5 chronic lymphocytic leukemia/small lymphocytic lymphoma, and 5 reactive lymph nodes. In diffuse large B-cell lymphoma, SHH was expressed in 61 of 67 (91%) cases, GLI1 in 62 of 67 (93%), GLI2 in 41 of 56 (73%), and GLI3 in 22 of 56 (39%). Expression of ABCG2 was detected in 52 of 55 (95%) cases and was high in 15 (27%) cases. SHH expression positively correlated with expression levels of ABCG2 (P=0.05). Patients with diffuse large B-cell lymphoma with high ABCG2 expression showed significantly shorter overall survival (P=0.031) and failure-free survival (P=0.029) compared with patients with tumors with low or no expression of ABCG2. Diffuse large B-cell lymphomas expressed SHH, and GLI1, GLI2, and GLI3 more frequently and more intensely than cases of follicular lymphoma or chronic lymphocytic leukemia/small lymphocytic lymphoma. In conclusion, our data show that SHH signaling proteins and ABCG2 are aberrantly expressed in diffuse large B-cell lymphoma and that ABCG2 expression has prognostic implications. These findings also provide evidence that dysregulation of the SHH pathway may be involved in the pathogenesis of diffuse large B-cell lymphoma.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / analysis*
  • Adult
  • Aged
  • Aged, 80 and over
  • Cell Line, Tumor
  • Female
  • Hedgehog Proteins / analysis*
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Kruppel-Like Transcription Factors / analysis
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
  • Leukemia, Lymphocytic, Chronic, B-Cell / mortality
  • Leukemia, Lymphocytic, Chronic, B-Cell / therapy
  • Lymph Nodes / chemistry
  • Lymphoma, Follicular / chemistry*
  • Lymphoma, Follicular / mortality
  • Lymphoma, Follicular / therapy
  • Lymphoma, Large B-Cell, Diffuse / chemistry*
  • Lymphoma, Large B-Cell, Diffuse / mortality
  • Lymphoma, Large B-Cell, Diffuse / therapy
  • Male
  • Middle Aged
  • Neoplasm Proteins / analysis*
  • Nerve Tissue Proteins / analysis
  • Nuclear Proteins / analysis
  • Signal Transduction*
  • Time Factors
  • Transcription Factors / analysis*
  • Treatment Outcome
  • Up-Regulation
  • Zinc Finger Protein GLI1
  • Zinc Finger Protein Gli2
  • Zinc Finger Protein Gli3

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • GLI1 protein, human
  • GLI2 protein, human
  • GLI3 protein, human
  • Hedgehog Proteins
  • Kruppel-Like Transcription Factors
  • Neoplasm Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • SHH protein, human
  • Transcription Factors
  • Zinc Finger Protein GLI1
  • Zinc Finger Protein Gli2
  • Zinc Finger Protein Gli3