Sonic hedgehog signaling proteins and ATP-binding cassette G2 are aberrantly expressed in diffuse large B-cell lymphoma.
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.
Kim
Ji Eun
JE
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Singh
Rajesh R
RR
Cho-Vega
Jeong Hee
JH
Drakos
Elias
E
Davuluri
Yogesh
Y
Khokhar
Faisal A
FA
Fayad
Luis
L
Medeiros
L Jeffrey
LJ
Vega
Francisco
F
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000032:analysis*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D005260:Female; D053823:Hedgehog Proteins / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D051741:Kruppel-Like Transcription Factors / Q000032:analysis; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D008198:Lymph Nodes / Q000737:chemistry; D008224:Lymphoma, Follicular / Q000737:chemistry* / Q000401:mortality / Q000628:therapy; D016403:Lymphoma, Large B-Cell, Diffuse / Q000737:chemistry* / Q000401:mortality / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis*; D009419:Nerve Tissue Proteins / Q000032:analysis; D009687:Nuclear Proteins / Q000032:analysis; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000032:analysis*; D016896:Treatment Outcome; D015854:Up-Regulation; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C400551:GLI1 protein, human; C082593:GLI2 protein, human; C065683:GLI3 protein, human; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C509239:SHH protein, human; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3