Plasminogen inhibitor activator,
type 2 (PAI-2)

Monocyte arginine-serpin
Monocyte-derived plasminogen activator inhibitor
PLANH2

Gene: PLANH2 maps to 18q21.2-q22 (Samia J.A. et al., 1990). It spans 16.5 kilobases and has eight exons. Several response elements have been identified in the promoter region which are necessary for constitutive and phorbol ester and retinoic acid induced expression of the gene; these include two AP-1 sites, and response elements for cAMP, glucocorticoids and retinoic acid. There appear to be two common PAI-2 alleles that differ by six nucleotides in exons 1, 4, and 8. The structure of the PAI-2 gene is quite different from that of PAI-1 although these two inhibitors have common target protease specificity. In contrast, the structure of the PAI-2 gene is very similar to that of the chicken ovalbumin gene. When protein sequences are aligned to obtain maximal identity, six of the seven intron positions in the PAI-2 gene are identical to those in the chicken ovalbumin gene (Ye R.D. et al., 1989).
mRNA: size: ~2.0 kb (Webb A.C. et al., 1987).
Protein: 450 amino acids. A large body of information has accumulated on the biology, biochemistry, and clinical aspects of PAI2, suggesting that it is involved in many physiologic and pathologic processes. However, its precise role in placenta, in pregnancy plasma, in skin, and in inflammatory conditions, as well as the diagnostic and therapeutic possibilities of PAI2, remained to be established (Kruithof E.K.O. et al., 1995).

Cell lines:

Tumors:
- The concentrations of cathepsin D, uPA, PAI-1, and PAI-2 were analysed in the cytosols of 43 benign and 87 malignant mammary tumors. The mean levels of these markers were significantly higher in malignant tumors than in benign tumors. The increases were about 4-, 5-, 74-, and 29-fold, respectively. PAI-2 was increased in menopausal women's tumors. When cathepsin D, uPA, PAI-1, and PAI-2 levels in malignant tumors were compared, positive correlations were found for all combinations (Foucré D. et al., 1991).

- An immunoenzymatic method was used to assay uPA, PAI-1 and PAI-2 in cytosols prepared from 314 primary breast tumours. The patients were followed up for a minimum of 6 years and all relevant clinical and laboratory findings were recorded. Univariate analysis confirmed the poor outcome of patients whose tumours contained large amounts of uPA and PAI-1. In addition, low levels of PAI-2 correlated with shorter disease-free survival in the overall population, post-menopausal women, and women without lymph node involvement (Bouchet C. et al., 1994).

- In 1012 routinely prepared tumor cytosols of patients with primary breast cancer (median follow-up, 71 months), no significant association between the level of PAI-2 and prognosis, while in tumors with high uPA values, PAI-2 (test for trend) was associated with a prolonged relapse-free survival, metastasis-free survival, and overall survival (Foekens J.A. et al., 1995).

. - In a study of 50 breast cancers, a low level of PAI-2 expression was significantly associated with lymph node involvement. The uPA, uPAR, and PAI-1 expressions tended to be at high levels in such metastatic cancers. Also, positive expression of uPA, uPAR, and PAI-1 was significantly correlated with negative expression of PAI-2 (Ishikawa N. et al., 1996).

- In a retrospective study of surgically resected breast cancers from 73 patients, PAI-2 expression in cancer cells was associated with a good prognosis (Umeda T. et al., 1997).

- In a study of 152 primary breast carcinomas and 18 benign breast tumours, PAI-2 levels appeared significantly higher in primary breast carcinomas. In these latter, PAI-2 levels correlated weakly but significantly with those of uPA and PAI-1, but not with tissue type plasminogen activator (tPA) or uPA receptor (uPAR) levels. Using Northern blotting, mRNA for PAI-2 was found in 28.6% of 49 primary breast cancers. In contrast to findings at the protein level, PAI-2 mRNA levels failed to correlate with those for uPA or PAI-1. On the basis of additional data, it was concluded that, unlike PAI-1, high levels of PAI-2 may be a favourable prognostic marker in breast cancer (Duggan C. et al., 1997).

- It has been suggested that uPA family members, including PAI-2, and sex steroid receptors may be measured in the same cytosol fraction from breast tumor homogenates (Descotes F. et al., 1998).

Antalis T.M. et al. (1988) Cloning and expression of a cDNA coding for a human monocyte-derived plasminogen activator inhibitor. Proc. Nat. Acad. Sci. USA 85, 985-989.
Bouchet C. et al. (1994) Prognostic value of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitors PAI-1 and PAI-2 in breast carcinomas. Br. J. Cancer 69, 398-405.
Descotes F. et al. (1998) Tissue extraction procedures for investigation of urokinase plasminogen activator (uPA) and its inhibitors PAI-1 and PAI-2 in human breast carcinomas. Breast Cancer Res. Treat. 49, 135-143.
Duggan C. et al. (1997) Plasminogen activator inhibitor type 2 in breast cancer. Br. J. Cancer 76, 622-627.
Foekens J.A. et al. (1995) Plasminogen activator inhibitor-2: prognostic relevance in 1012 patients with primary breast cancer. Cancer Res. 55, 1423-1427.
Foucré D. et al. (1991) Relationship between cathepsin D, urokinase, and plasminogen activator inhibitors in malignant vs benign breast tumours. Br. J. Cancer 64, 926-932.
Ishikawa N. et al. (1996) Inverse correlation between mRNA expression of plasminogen activator inhibitor-2 and lymph node metastasis in human breast cancer. Jpn. J. Cancer Res. 87, 480-487.
Kruithof E.K.O. et al. (1995) Biological and clinical aspects of plasminogen activator inhibitor type 2. Blood 86, 4007-4024 (Review).
Samia J.A. et al. (1990) Chromosomal organization and localization of the human urokinase inhibitor gene: perfect structural conservation with ovalbumin. Genomics 6, 159-167.
Umeda T. et al. (1997) Cellular localization of urokinase-type plasminogen activator, its inhibitors, and their mRNAs in breast cancer tissues. J. Pathol. 183, 388-397.
Webb A.C. et al. (1987) Human monocyte arg-serpin cDNA: sequence, chromosomal assignment, and homology to plasminogen activator-inhibitor. J. Exp. Med. 166, 77-94.
Webb A.C. et al. (1989) Localization of the urokinase-type plasminogen activator inhibitor (PLANH2) gene to the long arm of chromosome 18 at 18q21.2-q22. (Abstract) Cytogenet. Cell Genet. 51, 1103.
Ye R.D. et al. (1989) Structure of the gene for human plasminogen activator inhibitor-2. The nearest mammalian homologue of chicken ovalbumin. J. Biol. Chem. 264, 5495-5502.

Plasminogen activator inhibitor, type 1 (PAI-1), tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA)