Enhanced production and activation of progelatinase A mediated by membrane-type I matrix metalloproteinase in human papillary thyroid carcinomas

Hiroyuki Nakamura, Hirohisa Ueno, Taketoshi Shimada, Kaname Yamashita, Etsuhide Yamamoto, Masakuni Noguchi, Noboru Fujimoto, Hiroshi Sato, Motoharu Seiki, Yasunori Okada

Research output: Contribution to journalArticle

146 Citations (Scopus)

Abstract

Matrix metalloproteinases (MMPs) are believed to be involved in the invasion and metastasis of various human carcinomas. In the present study, the production levels of seven different MMPs (MMP-1, -2, -3, -7, -8, -9, and -13), the activation of the zymogen of MMP-2 (proMMP-2), the expression of membrane-type MMPs (MT1-, MT2-, and MT3-MMPs), and the tissue localization of the activated enzyme were examined in human invasive papillary thyroid carcinomas. Sandwich enzyme immunoassays revealed that among the MMPs examined, only the MMP-2 production level is significantly enhanced in the carcinoma tissues compared with the follicular adenoma and normal control thyroid tissues. Gelatin zymography indicated that the proMMP-2 activation ratio is considerably higher in carcinomas with lymph node metastasis than it is in those without metastasis, follicular adenomas, or normal controls (P < 0.01). Northern blot analysis of the expression of MT1-, MT2-, and MT3-MMPs, which are known to activate proMMP-2 in vitro, demonstrated the predominant expression of MT1-MMP mRNA in the carcinoma tissues (15 of 15 cases), whereas MT2-MMP expression was confined to 26% of the cases (4 of 15 cases), and no consistent expression of MT3-MMP was observed. MT1-MMP mRNA expression levels correlated with the proMMP-2 activation ratio (r = 0.692; P < 0.01), but such a correlation was not obtained with MT2-MMP. There was also a direct correlation between MT1-MMP expression and lymph node metastasis (P < 0.05). In situ hybridization indicated that both carcinoma and stromal cells express MT1-MMP transcripts (five of six cases). MT1-MMP was also immunolocalized to carcinoma and stromal cells in all of the carcinoma samples (26 of 26 cases), which were positive for MMP-2. In situ zymography indicated definite gelatinolytic activity in the carcinoma cell nests, which was abolished by incubation of the carcinoma samples with a synthetic MMP inhibitor before the reaction. These results suggest for the first time that among seven different MMPs, the production of proMMP-2 and its MT1-MMP-mediated activation in the carcinoma cell nests play an important role in the lymph node metastasis of human invasive papillary thyroid carcinomas.

Original languageEnglish
Pages (from-to)467-473
Number of pages7
JournalCancer Research
Volume59
Issue number2
Publication statusPublished - 1999 Jan 16

Fingerprint

Membrane-Associated Matrix Metalloproteinases
Matrix Metalloproteinase 14
Matrix Metalloproteinase 15
Carcinoma
Matrix Metalloproteinase 16
Matrix Metalloproteinase 2
Matrix Metalloproteinases
Neoplasm Metastasis
Lymph Nodes
Stromal Cells
Adenoma
Papillary Thyroid cancer
progelatinase
Messenger RNA
Matrix Metalloproteinase 1
Enzyme Precursors
Matrix Metalloproteinase Inhibitors
Gelatin
Immunoenzyme Techniques
Northern Blotting

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Nakamura, H., Ueno, H., Shimada, T., Yamashita, K., Yamamoto, E., Noguchi, M., ... Okada, Y. (1999). Enhanced production and activation of progelatinase A mediated by membrane-type I matrix metalloproteinase in human papillary thyroid carcinomas. Cancer Research, 59(2), 467-473.

Enhanced production and activation of progelatinase A mediated by membrane-type I matrix metalloproteinase in human papillary thyroid carcinomas. / Nakamura, Hiroyuki; Ueno, Hirohisa; Shimada, Taketoshi; Yamashita, Kaname; Yamamoto, Etsuhide; Noguchi, Masakuni; Fujimoto, Noboru; Sato, Hiroshi; Seiki, Motoharu; Okada, Yasunori.

In: Cancer Research, Vol. 59, No. 2, 16.01.1999, p. 467-473.

Research output: Contribution to journalArticle

Nakamura, H, Ueno, H, Shimada, T, Yamashita, K, Yamamoto, E, Noguchi, M, Fujimoto, N, Sato, H, Seiki, M & Okada, Y 1999, 'Enhanced production and activation of progelatinase A mediated by membrane-type I matrix metalloproteinase in human papillary thyroid carcinomas', Cancer Research, vol. 59, no. 2, pp. 467-473.
Nakamura, Hiroyuki ; Ueno, Hirohisa ; Shimada, Taketoshi ; Yamashita, Kaname ; Yamamoto, Etsuhide ; Noguchi, Masakuni ; Fujimoto, Noboru ; Sato, Hiroshi ; Seiki, Motoharu ; Okada, Yasunori. / Enhanced production and activation of progelatinase A mediated by membrane-type I matrix metalloproteinase in human papillary thyroid carcinomas. In: Cancer Research. 1999 ; Vol. 59, No. 2. pp. 467-473.
@article{bd801babfeac4bec8622a63189cfb1b2,
title = "Enhanced production and activation of progelatinase A mediated by membrane-type I matrix metalloproteinase in human papillary thyroid carcinomas",
abstract = "Matrix metalloproteinases (MMPs) are believed to be involved in the invasion and metastasis of various human carcinomas. In the present study, the production levels of seven different MMPs (MMP-1, -2, -3, -7, -8, -9, and -13), the activation of the zymogen of MMP-2 (proMMP-2), the expression of membrane-type MMPs (MT1-, MT2-, and MT3-MMPs), and the tissue localization of the activated enzyme were examined in human invasive papillary thyroid carcinomas. Sandwich enzyme immunoassays revealed that among the MMPs examined, only the MMP-2 production level is significantly enhanced in the carcinoma tissues compared with the follicular adenoma and normal control thyroid tissues. Gelatin zymography indicated that the proMMP-2 activation ratio is considerably higher in carcinomas with lymph node metastasis than it is in those without metastasis, follicular adenomas, or normal controls (P < 0.01). Northern blot analysis of the expression of MT1-, MT2-, and MT3-MMPs, which are known to activate proMMP-2 in vitro, demonstrated the predominant expression of MT1-MMP mRNA in the carcinoma tissues (15 of 15 cases), whereas MT2-MMP expression was confined to 26{\%} of the cases (4 of 15 cases), and no consistent expression of MT3-MMP was observed. MT1-MMP mRNA expression levels correlated with the proMMP-2 activation ratio (r = 0.692; P < 0.01), but such a correlation was not obtained with MT2-MMP. There was also a direct correlation between MT1-MMP expression and lymph node metastasis (P < 0.05). In situ hybridization indicated that both carcinoma and stromal cells express MT1-MMP transcripts (five of six cases). MT1-MMP was also immunolocalized to carcinoma and stromal cells in all of the carcinoma samples (26 of 26 cases), which were positive for MMP-2. In situ zymography indicated definite gelatinolytic activity in the carcinoma cell nests, which was abolished by incubation of the carcinoma samples with a synthetic MMP inhibitor before the reaction. These results suggest for the first time that among seven different MMPs, the production of proMMP-2 and its MT1-MMP-mediated activation in the carcinoma cell nests play an important role in the lymph node metastasis of human invasive papillary thyroid carcinomas.",
author = "Hiroyuki Nakamura and Hirohisa Ueno and Taketoshi Shimada and Kaname Yamashita and Etsuhide Yamamoto and Masakuni Noguchi and Noboru Fujimoto and Hiroshi Sato and Motoharu Seiki and Yasunori Okada",
year = "1999",
month = "1",
day = "16",
language = "English",
volume = "59",
pages = "467--473",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "2",

}

TY - JOUR

T1 - Enhanced production and activation of progelatinase A mediated by membrane-type I matrix metalloproteinase in human papillary thyroid carcinomas

AU - Nakamura, Hiroyuki

AU - Ueno, Hirohisa

AU - Shimada, Taketoshi

AU - Yamashita, Kaname

AU - Yamamoto, Etsuhide

AU - Noguchi, Masakuni

AU - Fujimoto, Noboru

AU - Sato, Hiroshi

AU - Seiki, Motoharu

AU - Okada, Yasunori

PY - 1999/1/16

Y1 - 1999/1/16

N2 - Matrix metalloproteinases (MMPs) are believed to be involved in the invasion and metastasis of various human carcinomas. In the present study, the production levels of seven different MMPs (MMP-1, -2, -3, -7, -8, -9, and -13), the activation of the zymogen of MMP-2 (proMMP-2), the expression of membrane-type MMPs (MT1-, MT2-, and MT3-MMPs), and the tissue localization of the activated enzyme were examined in human invasive papillary thyroid carcinomas. Sandwich enzyme immunoassays revealed that among the MMPs examined, only the MMP-2 production level is significantly enhanced in the carcinoma tissues compared with the follicular adenoma and normal control thyroid tissues. Gelatin zymography indicated that the proMMP-2 activation ratio is considerably higher in carcinomas with lymph node metastasis than it is in those without metastasis, follicular adenomas, or normal controls (P < 0.01). Northern blot analysis of the expression of MT1-, MT2-, and MT3-MMPs, which are known to activate proMMP-2 in vitro, demonstrated the predominant expression of MT1-MMP mRNA in the carcinoma tissues (15 of 15 cases), whereas MT2-MMP expression was confined to 26% of the cases (4 of 15 cases), and no consistent expression of MT3-MMP was observed. MT1-MMP mRNA expression levels correlated with the proMMP-2 activation ratio (r = 0.692; P < 0.01), but such a correlation was not obtained with MT2-MMP. There was also a direct correlation between MT1-MMP expression and lymph node metastasis (P < 0.05). In situ hybridization indicated that both carcinoma and stromal cells express MT1-MMP transcripts (five of six cases). MT1-MMP was also immunolocalized to carcinoma and stromal cells in all of the carcinoma samples (26 of 26 cases), which were positive for MMP-2. In situ zymography indicated definite gelatinolytic activity in the carcinoma cell nests, which was abolished by incubation of the carcinoma samples with a synthetic MMP inhibitor before the reaction. These results suggest for the first time that among seven different MMPs, the production of proMMP-2 and its MT1-MMP-mediated activation in the carcinoma cell nests play an important role in the lymph node metastasis of human invasive papillary thyroid carcinomas.

AB - Matrix metalloproteinases (MMPs) are believed to be involved in the invasion and metastasis of various human carcinomas. In the present study, the production levels of seven different MMPs (MMP-1, -2, -3, -7, -8, -9, and -13), the activation of the zymogen of MMP-2 (proMMP-2), the expression of membrane-type MMPs (MT1-, MT2-, and MT3-MMPs), and the tissue localization of the activated enzyme were examined in human invasive papillary thyroid carcinomas. Sandwich enzyme immunoassays revealed that among the MMPs examined, only the MMP-2 production level is significantly enhanced in the carcinoma tissues compared with the follicular adenoma and normal control thyroid tissues. Gelatin zymography indicated that the proMMP-2 activation ratio is considerably higher in carcinomas with lymph node metastasis than it is in those without metastasis, follicular adenomas, or normal controls (P < 0.01). Northern blot analysis of the expression of MT1-, MT2-, and MT3-MMPs, which are known to activate proMMP-2 in vitro, demonstrated the predominant expression of MT1-MMP mRNA in the carcinoma tissues (15 of 15 cases), whereas MT2-MMP expression was confined to 26% of the cases (4 of 15 cases), and no consistent expression of MT3-MMP was observed. MT1-MMP mRNA expression levels correlated with the proMMP-2 activation ratio (r = 0.692; P < 0.01), but such a correlation was not obtained with MT2-MMP. There was also a direct correlation between MT1-MMP expression and lymph node metastasis (P < 0.05). In situ hybridization indicated that both carcinoma and stromal cells express MT1-MMP transcripts (five of six cases). MT1-MMP was also immunolocalized to carcinoma and stromal cells in all of the carcinoma samples (26 of 26 cases), which were positive for MMP-2. In situ zymography indicated definite gelatinolytic activity in the carcinoma cell nests, which was abolished by incubation of the carcinoma samples with a synthetic MMP inhibitor before the reaction. These results suggest for the first time that among seven different MMPs, the production of proMMP-2 and its MT1-MMP-mediated activation in the carcinoma cell nests play an important role in the lymph node metastasis of human invasive papillary thyroid carcinomas.

UR - http://www.scopus.com/inward/record.url?scp=0033556368&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033556368&partnerID=8YFLogxK

M3 - Article

C2 - 9927064

AN - SCOPUS:0033556368

VL - 59

SP - 467

EP - 473

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 2

ER -