<it>Perlecan</it>, a candidate gene for the CAPB locus, regulates prostate cancer cell growth via the Sonic Hedgehog pathway
<p>Abstract</p> <p>Background</p> <p>Genetic studies associated the CAPB locus with familial risk of brain and prostate cancers. We have identified <it>HSPG2 </it>(<it>Perlecan</it>) as a candidate gene for CAPB. Previously we have linked Perleca...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2006-03-01
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| Series: | Molecular Cancer |
| Online Access: | http://www.molecular-cancer.com/content/5/1/9 |
| _version_ | 1819053634191622144 |
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| author | Farach-Carson Cindy Shah Rajal B Dhir Rajiv DeGueme Amy M Kahler Andrea J Schlicht Michael J Hernandez Ana Datta Milton W Barrett Andrea Datta Sumana |
| author_facet | Farach-Carson Cindy Shah Rajal B Dhir Rajiv DeGueme Amy M Kahler Andrea J Schlicht Michael J Hernandez Ana Datta Milton W Barrett Andrea Datta Sumana |
| author_sort | Farach-Carson Cindy |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Genetic studies associated the CAPB locus with familial risk of brain and prostate cancers. We have identified <it>HSPG2 </it>(<it>Perlecan</it>) as a candidate gene for CAPB. Previously we have linked Perlecan to Hedgehog signaling in <it>Drosophila</it>. More recently, we have demonstrated the importance of Hedgehog signaling in humans for advanced prostate cancer.</p> <p>Results</p> <p>Here we demonstrate <it>Perlecan </it>expression in prostate cancer, and its function in prostate cancer cell growth through interaction and modulation of Sonic Hedgehog (SHH) signaling. <it>Perlecan </it>expression in prostate cancer tissues correlates with a high Gleason score and rapid cell proliferation. <it>Perlecan </it>is highly expressed in prostate cancer cell lines, including androgen insensitive cell lines and cell lines selected for metastatic properties. Inhibition of <it>Perlecan </it>expression in these cell lines decreases cell growth. Simultaneous blockade of Perlecan expression and androgen signaling in the androgen-sensitive cell line LNCaP was additive, indicating the independence of these two pathways. <it>Perlecan </it>expression correlates with SHH in tumor tissue microarrays and increased tumor cell proliferation based on Ki-67 immunohistochemistry. Inhibition of <it>Perlecan </it>expression by siRNA in prostate cancer cell lines decreases SHH signaling while expression of the downstream SHH effector <it>GLI1 </it>rescues the proliferation defect. Perlecan forms complexes with increasing amounts of SHH that correlate with increasing metastatic potential of the prostate cancer cell line. SHH signaling also increases in the more metastatic cell lines. Metastatic prostate cancer cell lines grown under serum-starved conditions (low androgen and growth factors) resulted in maintenance of <it>Perlecan </it>expression. Under low androgen, low growth factor conditions, <it>Perlecan </it>expression level correlates with the ability of the cells to maintain SHH signaling.</p> <p>Conclusion</p> <p>We have demonstrated that Perlecan, a candidate gene for the CAPB locus, is a new component of the SHH pathway in prostate tumors and works independently of androgen signaling. In metastatic tumor cells increased SHH signaling correlates with the maintenance of Perlecan expression and more Perlecan-SHH complexes. Perlecan is a proteoglycan that regulates extracellular and stromal accessibility to growth factors such as SHH, thus allowing for the maintenance of SHH signaling under growth factor limiting conditions. This proteoglycan represents an important central regulator of SHH activity and presents an ideal drug target for blocking SHH effects.</p> |
| first_indexed | 2024-12-21T12:38:51Z |
| format | Article |
| id | doaj.art-9330f273ecaa4e7d90f0c57c03080fb7 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-12-21T12:38:51Z |
| publishDate | 2006-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-9330f273ecaa4e7d90f0c57c03080fb72022-12-21T19:03:51ZengBMCMolecular Cancer1476-45982006-03-0151910.1186/1476-4598-5-9<it>Perlecan</it>, a candidate gene for the CAPB locus, regulates prostate cancer cell growth via the Sonic Hedgehog pathwayFarach-Carson CindyShah Rajal BDhir RajivDeGueme Amy MKahler Andrea JSchlicht Michael JHernandez AnaDatta Milton WBarrett AndreaDatta Sumana<p>Abstract</p> <p>Background</p> <p>Genetic studies associated the CAPB locus with familial risk of brain and prostate cancers. We have identified <it>HSPG2 </it>(<it>Perlecan</it>) as a candidate gene for CAPB. Previously we have linked Perlecan to Hedgehog signaling in <it>Drosophila</it>. More recently, we have demonstrated the importance of Hedgehog signaling in humans for advanced prostate cancer.</p> <p>Results</p> <p>Here we demonstrate <it>Perlecan </it>expression in prostate cancer, and its function in prostate cancer cell growth through interaction and modulation of Sonic Hedgehog (SHH) signaling. <it>Perlecan </it>expression in prostate cancer tissues correlates with a high Gleason score and rapid cell proliferation. <it>Perlecan </it>is highly expressed in prostate cancer cell lines, including androgen insensitive cell lines and cell lines selected for metastatic properties. Inhibition of <it>Perlecan </it>expression in these cell lines decreases cell growth. Simultaneous blockade of Perlecan expression and androgen signaling in the androgen-sensitive cell line LNCaP was additive, indicating the independence of these two pathways. <it>Perlecan </it>expression correlates with SHH in tumor tissue microarrays and increased tumor cell proliferation based on Ki-67 immunohistochemistry. Inhibition of <it>Perlecan </it>expression by siRNA in prostate cancer cell lines decreases SHH signaling while expression of the downstream SHH effector <it>GLI1 </it>rescues the proliferation defect. Perlecan forms complexes with increasing amounts of SHH that correlate with increasing metastatic potential of the prostate cancer cell line. SHH signaling also increases in the more metastatic cell lines. Metastatic prostate cancer cell lines grown under serum-starved conditions (low androgen and growth factors) resulted in maintenance of <it>Perlecan </it>expression. Under low androgen, low growth factor conditions, <it>Perlecan </it>expression level correlates with the ability of the cells to maintain SHH signaling.</p> <p>Conclusion</p> <p>We have demonstrated that Perlecan, a candidate gene for the CAPB locus, is a new component of the SHH pathway in prostate tumors and works independently of androgen signaling. In metastatic tumor cells increased SHH signaling correlates with the maintenance of Perlecan expression and more Perlecan-SHH complexes. Perlecan is a proteoglycan that regulates extracellular and stromal accessibility to growth factors such as SHH, thus allowing for the maintenance of SHH signaling under growth factor limiting conditions. This proteoglycan represents an important central regulator of SHH activity and presents an ideal drug target for blocking SHH effects.</p>http://www.molecular-cancer.com/content/5/1/9 |
| spellingShingle | Farach-Carson Cindy Shah Rajal B Dhir Rajiv DeGueme Amy M Kahler Andrea J Schlicht Michael J Hernandez Ana Datta Milton W Barrett Andrea Datta Sumana <it>Perlecan</it>, a candidate gene for the CAPB locus, regulates prostate cancer cell growth via the Sonic Hedgehog pathway Molecular Cancer |
| title | <it>Perlecan</it>, a candidate gene for the CAPB locus, regulates prostate cancer cell growth via the Sonic Hedgehog pathway |
| title_full | <it>Perlecan</it>, a candidate gene for the CAPB locus, regulates prostate cancer cell growth via the Sonic Hedgehog pathway |
| title_fullStr | <it>Perlecan</it>, a candidate gene for the CAPB locus, regulates prostate cancer cell growth via the Sonic Hedgehog pathway |
| title_full_unstemmed | <it>Perlecan</it>, a candidate gene for the CAPB locus, regulates prostate cancer cell growth via the Sonic Hedgehog pathway |
| title_short | <it>Perlecan</it>, a candidate gene for the CAPB locus, regulates prostate cancer cell growth via the Sonic Hedgehog pathway |
| title_sort | it perlecan it a candidate gene for the capb locus regulates prostate cancer cell growth via the sonic hedgehog pathway |
| url | http://www.molecular-cancer.com/content/5/1/9 |
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