pVHL co-ordinately regulates CXCR4/CXCL12 and MMP2/MMP9 expression in human clear-cell renal cell carcinoma.

K Struckmann; Kd Mertz; S Steu; M Storz; P Staller; W Krek; P Schraml; H Moch

doi:10.1002/path.2310

pVHL co-ordinately regulates CXCR4/CXCL12 and MMP2/MMP9 expression in human clear-cell renal cell carcinoma.

K Struckmann, Kd Mertz, S Steu, M Storz, P Staller, W Krek, P Schraml, H Moch

52 Citations (Scopus)

Abstract

Loss of pVHL function, characteristic for clear-cell renal cell carcinoma (ccRCC), causes increased expression of CXCR4 chemokine receptor, which triggers expression of metastasis-associated MMP2/MMP9 in different human cancers. The impact of pVHL on MMP2/MMP9 expression and their relationship to CXCR4 and its ligand CXCL12 in ccRCC is unclear. By using reverse transcription PCR, immunofluorescence and immunohistochemistry, strong mRNA and protein expression of CXCR4, CXCL12, MMP2, MMP9 and MMP inhibitors TIMP1 and TIMP2 was found in VHL-null 786-O ccRCC cells. Loss of CXCR4/CXCL12 expression after restoration of VHL function in these cells was accompanied by a significant reduction of MMP2 and MMP9 expression, whereas neither TIMP1 nor TIMP2 expression was affected. Using real-time PCR analysis, higher MMP2 (p = 0.0134) and MMP9 (p = 0.067) mRNA expression levels were detected in primary ccRCC with strong CXCR4 compared to cases with weak CXCR4 expression. There was no association between CXCR4 and TIMP1 or TIMP2 mRNA expression. MMP2 protein expression data obtained by immunohistochemistry on a tissue microarray uncovered positive cytoplasmic staining in 290/380 (76%) primary ccRCCs. Co-expression of CXCR4 and MMP2 was found in 282 of these tumours (74%). Our in vitro and in vivo data strongly indicate that pVHL coordinately regulates expression of metastasis-associated genes CXCR4/CXCL12 and MMP2/MMP9 but the exact molecular mechanism of this regulation remains to be determined. Co-expression of CXCR4 and CXCL12, as demonstrated in VHL-null 786-O cells, might enable ccRCC progression and metastatic dissemination by autocrine receptor stimulation, even in the absence of exogenous CXCL12.

Original language	English
Journal	Journal of Pathology
Volume	214
Issue number	4
Pages (from-to)	464-71
Number of pages	7
ISSN	0022-3417
DOIs	https://doi.org/10.1002/path.2310
Publication status	Published - 2008

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@article{28a2460051a511dd8d9f000ea68e967b,

title = "pVHL co-ordinately regulates CXCR4/CXCL12 and MMP2/MMP9 expression in human clear-cell renal cell carcinoma.",

abstract = "Loss of pVHL function, characteristic for clear-cell renal cell carcinoma (ccRCC), causes increased expression of CXCR4 chemokine receptor, which triggers expression of metastasis-associated MMP2/MMP9 in different human cancers. The impact of pVHL on MMP2/MMP9 expression and their relationship to CXCR4 and its ligand CXCL12 in ccRCC is unclear. By using reverse transcription PCR, immunofluorescence and immunohistochemistry, strong mRNA and protein expression of CXCR4, CXCL12, MMP2, MMP9 and MMP inhibitors TIMP1 and TIMP2 was found in VHL-null 786-O ccRCC cells. Loss of CXCR4/CXCL12 expression after restoration of VHL function in these cells was accompanied by a significant reduction of MMP2 and MMP9 expression, whereas neither TIMP1 nor TIMP2 expression was affected. Using real-time PCR analysis, higher MMP2 (p = 0.0134) and MMP9 (p = 0.067) mRNA expression levels were detected in primary ccRCC with strong CXCR4 compared to cases with weak CXCR4 expression. There was no association between CXCR4 and TIMP1 or TIMP2 mRNA expression. MMP2 protein expression data obtained by immunohistochemistry on a tissue microarray uncovered positive cytoplasmic staining in 290/380 (76%) primary ccRCCs. Co-expression of CXCR4 and MMP2 was found in 282 of these tumours (74%). Our in vitro and in vivo data strongly indicate that pVHL coordinately regulates expression of metastasis-associated genes CXCR4/CXCL12 and MMP2/MMP9 but the exact molecular mechanism of this regulation remains to be determined. Co-expression of CXCR4 and CXCL12, as demonstrated in VHL-null 786-O cells, might enable ccRCC progression and metastatic dissemination by autocrine receptor stimulation, even in the absence of exogenous CXCL12.",

author = "K Struckmann and Kd Mertz and S Steu and M Storz and P Staller and W Krek and P Schraml and H Moch",

note = "Keywords: Carcinoma, Renal Cell; Chemokine CXCL12; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neoplasm Proteins; Protein Array Analysis; RNA, Messenger; RNA, Neoplasm; Receptors, CXCR4; Reverse Transcriptase Polymerase Chain Reaction; Tumor Cells, Cultured; Von Hippel-Lindau Tumor Suppressor Protein",

year = "2008",

doi = "10.1002/path.2310",

language = "English",

volume = "214",

pages = "464--71",

journal = "Journal of Pathology",

issn = "0022-3417",

publisher = "JohnWiley & Sons Ltd",

number = "4",

}

TY - JOUR

T1 - pVHL co-ordinately regulates CXCR4/CXCL12 and MMP2/MMP9 expression in human clear-cell renal cell carcinoma.

AU - Struckmann, K

AU - Mertz, Kd

AU - Steu, S

AU - Storz, M

AU - Staller, P

AU - Krek, W

AU - Schraml, P

AU - Moch, H

N1 - Keywords: Carcinoma, Renal Cell; Chemokine CXCL12; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neoplasm Proteins; Protein Array Analysis; RNA, Messenger; RNA, Neoplasm; Receptors, CXCR4; Reverse Transcriptase Polymerase Chain Reaction; Tumor Cells, Cultured; Von Hippel-Lindau Tumor Suppressor Protein

PY - 2008

Y1 - 2008

N2 - Loss of pVHL function, characteristic for clear-cell renal cell carcinoma (ccRCC), causes increased expression of CXCR4 chemokine receptor, which triggers expression of metastasis-associated MMP2/MMP9 in different human cancers. The impact of pVHL on MMP2/MMP9 expression and their relationship to CXCR4 and its ligand CXCL12 in ccRCC is unclear. By using reverse transcription PCR, immunofluorescence and immunohistochemistry, strong mRNA and protein expression of CXCR4, CXCL12, MMP2, MMP9 and MMP inhibitors TIMP1 and TIMP2 was found in VHL-null 786-O ccRCC cells. Loss of CXCR4/CXCL12 expression after restoration of VHL function in these cells was accompanied by a significant reduction of MMP2 and MMP9 expression, whereas neither TIMP1 nor TIMP2 expression was affected. Using real-time PCR analysis, higher MMP2 (p = 0.0134) and MMP9 (p = 0.067) mRNA expression levels were detected in primary ccRCC with strong CXCR4 compared to cases with weak CXCR4 expression. There was no association between CXCR4 and TIMP1 or TIMP2 mRNA expression. MMP2 protein expression data obtained by immunohistochemistry on a tissue microarray uncovered positive cytoplasmic staining in 290/380 (76%) primary ccRCCs. Co-expression of CXCR4 and MMP2 was found in 282 of these tumours (74%). Our in vitro and in vivo data strongly indicate that pVHL coordinately regulates expression of metastasis-associated genes CXCR4/CXCL12 and MMP2/MMP9 but the exact molecular mechanism of this regulation remains to be determined. Co-expression of CXCR4 and CXCL12, as demonstrated in VHL-null 786-O cells, might enable ccRCC progression and metastatic dissemination by autocrine receptor stimulation, even in the absence of exogenous CXCL12.

AB - Loss of pVHL function, characteristic for clear-cell renal cell carcinoma (ccRCC), causes increased expression of CXCR4 chemokine receptor, which triggers expression of metastasis-associated MMP2/MMP9 in different human cancers. The impact of pVHL on MMP2/MMP9 expression and their relationship to CXCR4 and its ligand CXCL12 in ccRCC is unclear. By using reverse transcription PCR, immunofluorescence and immunohistochemistry, strong mRNA and protein expression of CXCR4, CXCL12, MMP2, MMP9 and MMP inhibitors TIMP1 and TIMP2 was found in VHL-null 786-O ccRCC cells. Loss of CXCR4/CXCL12 expression after restoration of VHL function in these cells was accompanied by a significant reduction of MMP2 and MMP9 expression, whereas neither TIMP1 nor TIMP2 expression was affected. Using real-time PCR analysis, higher MMP2 (p = 0.0134) and MMP9 (p = 0.067) mRNA expression levels were detected in primary ccRCC with strong CXCR4 compared to cases with weak CXCR4 expression. There was no association between CXCR4 and TIMP1 or TIMP2 mRNA expression. MMP2 protein expression data obtained by immunohistochemistry on a tissue microarray uncovered positive cytoplasmic staining in 290/380 (76%) primary ccRCCs. Co-expression of CXCR4 and MMP2 was found in 282 of these tumours (74%). Our in vitro and in vivo data strongly indicate that pVHL coordinately regulates expression of metastasis-associated genes CXCR4/CXCL12 and MMP2/MMP9 but the exact molecular mechanism of this regulation remains to be determined. Co-expression of CXCR4 and CXCL12, as demonstrated in VHL-null 786-O cells, might enable ccRCC progression and metastatic dissemination by autocrine receptor stimulation, even in the absence of exogenous CXCL12.

U2 - 10.1002/path.2310

DO - 10.1002/path.2310

M3 - Journal article

C2 - 18189328

SN - 0022-3417

VL - 214

SP - 464

EP - 471

JO - Journal of Pathology

JF - Journal of Pathology

IS - 4

ER -

pVHL co-ordinately regulates CXCR4/CXCL12 and MMP2/MMP9 expression in human clear-cell renal cell carcinoma.

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