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

Lemjabbar-Alaoui H, van Zante A, Singer MS, Xue Q, Wang YQ, Tsay D, He B, Jablons DM, Rosen SD - Oncogene (2009)

Bottom Line: 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.Our findings support an essential role for Sulf-2 in lung cancer, the leading cancer killer.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy, University of California, San Francisco, CA 94143, USA.

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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Effects of Sulf-2 knockdown on the tumorigenicity of lung cancer cell lines: The indicated lines with mock knockdown (PLV-Ctrl, black lines) or Sulf-2 knockdown (PLV-1413, dashed lines) were injected subcutaneously into nude mice and tumor volume was monitored over time. The values shown are means (+SEM) of 4–5 mice. * indicates p< 0.05.
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Figure 5: Effects of Sulf-2 knockdown on the tumorigenicity of lung cancer cell lines: The indicated lines with mock knockdown (PLV-Ctrl, black lines) or Sulf-2 knockdown (PLV-1413, dashed lines) were injected subcutaneously into nude mice and tumor volume was monitored over time. The values shown are means (+SEM) of 4–5 mice. * indicates p< 0.05.

Mentions: To examine the contribution of Sulf-2 to the tumorigenicity of the NSCLC cell lines, we injected control-transduced or Sulf-2 knockdown cells subcutaneously into nude mice and monitored tumor growth. Tumors derived from H460, H292, Calu-6, P-ST and B-ST cells with knockdown grew at markedly slower rates than those from the control cells (60–85% reduction) (Fig. 5). Furthermore, the harvested tumors were greatly reduced in weight (Supplementary Fig. 7), consistent with an observed decrease in cell proliferation and an increase in apoptosis within the tumors (Supplementary Figs. 8a and 8b). Transduction of H1975 cells with SULF2 shRNA had no effect on tumorigenicity (Fig. 5).


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

Lemjabbar-Alaoui H, van Zante A, Singer MS, Xue Q, Wang YQ, Tsay D, He B, Jablons DM, Rosen SD - Oncogene (2009)

Effects of Sulf-2 knockdown on the tumorigenicity of lung cancer cell lines: The indicated lines with mock knockdown (PLV-Ctrl, black lines) or Sulf-2 knockdown (PLV-1413, dashed lines) were injected subcutaneously into nude mice and tumor volume was monitored over time. The values shown are means (+SEM) of 4–5 mice. * indicates p< 0.05.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2818095&req=5

Figure 5: Effects of Sulf-2 knockdown on the tumorigenicity of lung cancer cell lines: The indicated lines with mock knockdown (PLV-Ctrl, black lines) or Sulf-2 knockdown (PLV-1413, dashed lines) were injected subcutaneously into nude mice and tumor volume was monitored over time. The values shown are means (+SEM) of 4–5 mice. * indicates p< 0.05.
Mentions: To examine the contribution of Sulf-2 to the tumorigenicity of the NSCLC cell lines, we injected control-transduced or Sulf-2 knockdown cells subcutaneously into nude mice and monitored tumor growth. Tumors derived from H460, H292, Calu-6, P-ST and B-ST cells with knockdown grew at markedly slower rates than those from the control cells (60–85% reduction) (Fig. 5). Furthermore, the harvested tumors were greatly reduced in weight (Supplementary Fig. 7), consistent with an observed decrease in cell proliferation and an increase in apoptosis within the tumors (Supplementary Figs. 8a and 8b). Transduction of H1975 cells with SULF2 shRNA had no effect on tumorigenicity (Fig. 5).

Bottom Line: 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.Our findings support an essential role for Sulf-2 in lung cancer, the leading cancer killer.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy, University of California, San Francisco, CA 94143, USA.

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.

Show MeSH
Related in: MedlinePlus