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Primary cilia attenuate hedgehog signalling in neoplastic chondrocytes.

Publication ,  Journal Article
Ho, L; Ali, SA; Al-Jazrawe, M; Kandel, R; Wunder, JS; Alman, BA
Published in: Oncogene
November 21, 2013

Primary cilia can act as either a negative or positive regulator of the hedgehog (Hh) signaling pathway. Many cartilage tumors are characterized by abnormal activation of the Hh pathway. Here, we report that the presence of primary cilia occurs at a low frequency (12.4%) in neoplastic chondrocytes from malignant human chondrosarcomas, compared with chondrocytes from normal articular cartilage (67.7%). To determine the function of primary cilia in cartilaginous neoplasia, we studied benign cartilage tumors that are formed in mice by chondrocyte-specific overexpression of Gli2, a downstream transcriptional activator of the Hh pathway. Col2A1-Gli2 mice were crossed with Ift88+/- mice, which display a partial loss of ciliogenesis. Surprisingly, cartilage tumors developed in Ift88+/- mice that were phenotypically similar to those that arise in Col2A1-Gli2 mice. Further activation of the Hh pathway was observed in Col2A1-Gli2; Ift88+/- mice compared with either Col2A1-Gli2 or Ift88+/- mice, which was associated with an increased incidence of cartilage tumors. Chondrosarcomas were established in explant cultures, and treated with choral hydrate, which disrupts the functional primary cilia. Thus, treatment resulted in hyperactivity of the Hh signaling pathway, as well as cellular changes that could promote tumor growth. Primary cilia functions to inhibit Hh signaling in neoplastic chondrocytes. The activation of Hh signaling is sufficient to induce benign cartilage tumors without another oncogenic initiating event. Moreover, as primary cilia suppress Hh pathway activation in chondrosarcoma, cellular mechanisms inhibiting proper cilia function may be important in maintaining the neoplastic phenotype.

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Published In

Oncogene

DOI

EISSN

1476-5594

Publication Date

November 21, 2013

Volume

32

Issue

47

Start / End Page

5388 / 5396

Location

England

Related Subject Headings

  • Zinc Finger Protein Gli2
  • Tumor Suppressor Proteins
  • Tumor Cells, Cultured
  • Signal Transduction
  • Oncology & Carcinogenesis
  • Mice
  • Kruppel-Like Transcription Factors
  • Humans
  • Hedgehog Proteins
  • Collagen Type II
 

Citation

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Ho, L., Ali, S. A., Al-Jazrawe, M., Kandel, R., Wunder, J. S., & Alman, B. A. (2013). Primary cilia attenuate hedgehog signalling in neoplastic chondrocytes. Oncogene, 32(47), 5388–5396. https://doi.org/10.1038/onc.2012.588
Ho, L., S. A. Ali, M. Al-Jazrawe, R. Kandel, J. S. Wunder, and B. A. Alman. “Primary cilia attenuate hedgehog signalling in neoplastic chondrocytes.Oncogene 32, no. 47 (November 21, 2013): 5388–96. https://doi.org/10.1038/onc.2012.588.
Ho L, Ali SA, Al-Jazrawe M, Kandel R, Wunder JS, Alman BA. Primary cilia attenuate hedgehog signalling in neoplastic chondrocytes. Oncogene. 2013 Nov 21;32(47):5388–96.
Ho, L., et al. “Primary cilia attenuate hedgehog signalling in neoplastic chondrocytes.Oncogene, vol. 32, no. 47, Nov. 2013, pp. 5388–96. Pubmed, doi:10.1038/onc.2012.588.
Ho L, Ali SA, Al-Jazrawe M, Kandel R, Wunder JS, Alman BA. Primary cilia attenuate hedgehog signalling in neoplastic chondrocytes. Oncogene. 2013 Nov 21;32(47):5388–5396.

Published In

Oncogene

DOI

EISSN

1476-5594

Publication Date

November 21, 2013

Volume

32

Issue

47

Start / End Page

5388 / 5396

Location

England

Related Subject Headings

  • Zinc Finger Protein Gli2
  • Tumor Suppressor Proteins
  • Tumor Cells, Cultured
  • Signal Transduction
  • Oncology & Carcinogenesis
  • Mice
  • Kruppel-Like Transcription Factors
  • Humans
  • Hedgehog Proteins
  • Collagen Type II