Hedgehog signaling in small-cell lung cancer: frequent in vivo but a rare event in vitro.
The hedgehog (HH) signaling pathway plays multiple roles during embryonic development and increasing evidence suggests that this embryonic pathway is involved in development and progression of several human cancers including those of the brain, skin, lung and gastrointestinal tract. To investigate HH signaling activity in small-cell lung cancer (SCLC), we have performed gene expression analysis on members of the HH pathway on a panel of 20 SCLC cell lines. Sonic hedgehog (SHH) expression was detected in only DMS79 and GLC16 and only DMS114 expressed detectable protein levels of GLI1, one of the key transcription factors of the pathway. Involvement of HH signaling in SCLC proliferation was investigated in a subset of cell lines using the HH signaling inhibitor cyclopamine or small interfering RNA (siRNA) against GLI1. Cells expressing GLI1 responded only weakly to both cyclopamine and RNA interference, suggesting that HH signaling plays only a minor role in the growth of SCLC cell lines. To investigate HH pathway activity in vivo, GLI1 immunohistochemistry was performed on SCLC tumors. Interestingly, GLI1 was expressed in most SCLC tumors studied, indicating that HH signaling is important for in vivo growth of SCLC but establishment of cell lines from SCLC tumors may lead to loss of expression of key HH pathway members. Thus, the data support the idea that the HH pathway may be a therapeutic target in SCLC. However, the data also suggest that the SCLC cells can circumvent the apparent in vivo requirement of HH signaling.
Vestergaard
Janni
J
Wilhelm Johannsen Centre for Functional Genome Research, Department of Medical Biochemistry and Genetics, University of Copenhagen, and Department of Radiation Biology, The Finsencenter, Copenhagen University Hospital, Denmark.
Pedersen
Mikkel W
MW
Pedersen
Nina
N
Ensinger
Christian
C
Tümer
Zeynep
Z
Tommerup
Niels
N
Poulsen
Hans Skovgaard
HS
Larsen
Lars Allan
LA
D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D053823:Hedgehog Proteins; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014704:Veratrum Alkaloids / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1
D053823:Hedgehog Proteins; D015513:Oncogene Proteins; D034741:RNA, Small Interfering; C509239:SHH protein, human; D015534:Trans-Activators; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; C000541:cyclopamine