HSulf-1 modulates FGF2- and hypoxia-mediated migration and invasion of breast cancer cells

Ashwani Khurana, Peng Liu, Pasquale Mellone, Laura Lorenzon, Bruno Vincenzi, Kaustubh Datta, Bo Yang, Robert J. Linhardt, Wilma Lingle, Jeremy Chien, Alfonso Baldi, Viji Shridhar

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Abstract

HSulf-1 modulates the sulfation states of heparan sulfate proteoglycans critical for heparin binding growth factor signaling. In the present study, we show that HSulf-1 is transcriptionally deregulated under hypoxia in breast cancer cell lines. Knockdown of HIF-1α rescued HSulf-1 downregulation imposed by hypoxia, both at the RNA and protein levels. Chromatin immunoprecipitation with HIF-1α and HIF-2α antibodies confirmed recruitment of HIF-α proteins to the two functional hypoxia-responsive elements on the native HSulf-1 promoter. HSulf-1 depletion in breast cancer cells resulted in an increased and sustained bFGF2 (basic fibroblast growth factor) signaling and promoted cell migration and invasion under hypoxic conditions. In addition, FGFR2 (fibroblast growth factor receptor 2) depletion in HSulf-1-silenced breast cancer cells attenuated hypoxia-mediated cell invasion. Immunohistochemical analysis of 53 invasive ductal carcinomas and their autologous metastatic lesions revealed an inverse correlation for the expression of HSulf-1 to CAIX in both the primary tumors (P ≥ 0.0198) and metastatic lesions (P ≥ 0.0067), respectively, by χ2 test. Finally, HSulf-1 expression levels in breast tumors by RNA in situ hybridization showed that high HSulf-1 expression is associated with increased disease-free and overall survival (P ≥ 0.03 and P ≥ 0.0001, respectively). Collectively, these results reveal an important link between loss of HSulf-1 under hypoxic microenvironment and increased growth factor signaling, cell migration, and invasion.

Original languageEnglish (US)
Pages (from-to)2152-2161
Number of pages10
JournalCancer Research
Volume71
Issue number6
DOIs
StatePublished - Mar 15 2011

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Fibroblast Growth Factor 2
Breast Neoplasms
Cell Movement
Intercellular Signaling Peptides and Proteins
Receptor, Fibroblast Growth Factor, Type 2
RNA
Cell Hypoxia
Heparan Sulfate Proteoglycans
Ductal Carcinoma
Chromatin Immunoprecipitation
Disease-Free Survival
In Situ Hybridization
Heparin
Proteins
Down-Regulation
Cell Line
Hypoxia
Antibodies
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Khurana, A., Liu, P., Mellone, P., Lorenzon, L., Vincenzi, B., Datta, K., ... Shridhar, V. (2011). HSulf-1 modulates FGF2- and hypoxia-mediated migration and invasion of breast cancer cells. Cancer Research, 71(6), 2152-2161. https://doi.org/10.1158/0008-5472.CAN-10-3059

HSulf-1 modulates FGF2- and hypoxia-mediated migration and invasion of breast cancer cells. / Khurana, Ashwani; Liu, Peng; Mellone, Pasquale; Lorenzon, Laura; Vincenzi, Bruno; Datta, Kaustubh; Yang, Bo; Linhardt, Robert J.; Lingle, Wilma; Chien, Jeremy; Baldi, Alfonso; Shridhar, Viji.

In: Cancer Research, Vol. 71, No. 6, 15.03.2011, p. 2152-2161.

Research output: Contribution to journalArticle

Khurana, A, Liu, P, Mellone, P, Lorenzon, L, Vincenzi, B, Datta, K, Yang, B, Linhardt, RJ, Lingle, W, Chien, J, Baldi, A & Shridhar, V 2011, 'HSulf-1 modulates FGF2- and hypoxia-mediated migration and invasion of breast cancer cells', Cancer Research, vol. 71, no. 6, pp. 2152-2161. https://doi.org/10.1158/0008-5472.CAN-10-3059
Khurana, Ashwani ; Liu, Peng ; Mellone, Pasquale ; Lorenzon, Laura ; Vincenzi, Bruno ; Datta, Kaustubh ; Yang, Bo ; Linhardt, Robert J. ; Lingle, Wilma ; Chien, Jeremy ; Baldi, Alfonso ; Shridhar, Viji. / HSulf-1 modulates FGF2- and hypoxia-mediated migration and invasion of breast cancer cells. In: Cancer Research. 2011 ; Vol. 71, No. 6. pp. 2152-2161.
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