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Sulf-2, a heparan sulfate endosulfatase, promotes human lung carcinogenesis

Oncogene volume 29, pages 635–646 (2010)Cite this article

Abstract

Heparan sulfate (HS) proteoglycans (HSPGs) bind to multiple growth factors/morphogens and regulate their signaling. 6-O-sulfation (6S) of glucosamine within HS chains is critical for many of these ligand interactions. Sulf-1 and Sulf-2, which are extracellular neutral-pH sulfatases, provide a novel post-synthetic mechanism for regulation of HSPG function by removing 6S from intact HS chains. The Sulfs can thereby modulate several signaling pathways, including the promotion of Wnt signaling. We found induction of SULF2 transcripts and Sulf-2 protein in human lung adenocarcinoma and squamous cell carcinoma, the two major classes of non-small-cell lung carcinomas (NSCLCs). We confirmed widespread Sulf-2 protein expression in tumor cells of 10/10 surgical specimens of human lung squamous carcinomas. We studied five Sulf-2+ NSCLC cell lines, including two, which were derived by cigarette-smoke transformation of bronchial epithelial cells. shRNA-mediated Sulf-2 knockdown in these lines caused an increase in 6S on their cell surface and in parallel reversed their transformed phenotype in vitro, eliminated autocrine Wnt signaling and strongly blunted xenograft tumor formation in nude mice. Conversely, forced Sulf-2 expression in non-malignant bronchial epithelial cells produced a partially transformed phenotype. Our findings support an essential role for Sulf-2 in lung cancer, the leading cancer killer.

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Acknowledgements

RB4CD12 was a kind gift from Drs Guido Jenniskens and Toin van Kuppevelt of Nijmegen Medical Center. We thank Dr Roman Nawroth for preliminary work with lung cancer cell lines. We thank Drs Zena Werb, Joanna Phillips and Inna Maltseva for comments on the paper. This work was performed with support from the Tobacco-Related Disease Research Program of the University of California Grant 17RT-0216, NIH P01 AI053194 and NIH R21 CA122025; Susan Komen Breast Cancer Foundation PDF0402844 to SDR; NIH RO1 HL075602 to Dr Zena Werb; The Larry Hall and Zygielbaum Memorial Trust, and The Kazan, McClain, Edises, Abrams, Fernandez, Lyons & Farrise Foundation to DMJ and NIH R01CA125030 to BH.

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Authors and Affiliations

  1. Department of Anatomy, University of California, San Francisco, CA, USA

    H Lemjabbar-Alaoui, M S Singer, Q Xue, Y -Q Wang, D Tsay & S D Rosen

  2. Department of Pathology, University of California, San Francisco, CA, USA

    A van Zante

  3. Department of Surgery, Thoracic Oncology Laboratory, Comprehensive Cancer Center, University of California, San Francisco, CA, USA

    B He & D M Jablons

  4. Comprehensive Cancer Center, University of California, San Francisco, CA, USA

    S D Rosen

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  1. H Lemjabbar-Alaoui
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  2. A van Zante
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Correspondence to S D Rosen.

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Lemjabbar-Alaoui, H., van Zante, A., Singer, M. et al. Sulf-2, a heparan sulfate endosulfatase, promotes human lung carcinogenesis. Oncogene 29, 635–646 (2010). https://doi.org/10.1038/onc.2009.365

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