Primary cilia can both mediate and suppress Hedgehog pathway-dependent tumorigenesis.
Primary cilia are present on most mammalian cells and are implicated in transducing Hedgehog (Hh) signals during development; however, the prevalence of cilia on human tumors remains unclear, and the role of cilia in cancer has not been examined. Here we show that human basal cell carcinomas (BCCs) are frequently ciliated, and we test the role of cilia in BCC by conditionally deleting Kif3a (encoding kinesin family member 3A) or Ift88 (encoding intraflagellar transport protein 88), genes required for ciliogenesis, in two Hh pathway-dependent mouse tumor models. Ciliary ablation strongly inhibited BCC-like tumors induced by an activated form of Smoothened. In contrast, removal of cilia accelerated tumors induced by activated Gli2, a transcriptional effector of Hh signaling. These seemingly paradoxical effects are consistent with a dual role for cilia in mediating both the activation and the repression of the Hh signaling pathway. Our findings demonstrate that cilia function as unique signaling organelles that can either mediate or suppress tumorigenesis depending on the nature of the oncogenic initiating event.
Wong
Sunny Y
SY
Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco (UCSF), San Francisco, California, USA.
Seol
Allen D
AD
So
Po-Lin
PL
Ermilov
Alexandre N
AN
Bichakjian
Christopher K
CK
Epstein
Ervin H
EH
Dlugosz
Andrzej A
AA
Reiter
Jeremy F
JF
D000818:Animals; D002280:Basal Cell Carcinoma / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D002923:Cilia / Q000473:pathology / Q000502:physiology*; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D016547:Kinesins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051741:Kruppel-Like Transcription Factors / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D000072086:Smoothened Receptor; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000075746:Zinc Finger Protein Gli2
C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; C490202:Kif3a protein, mouse; D051741:Kruppel-Like Transcription Factors; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; C490898:Tg737Rpw protein, mouse; D025521:Tumor Suppressor Proteins; D000075746:Zinc Finger Protein Gli2; D016547:Kinesins
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