Expression pattern of a gene for a secreted metalloproteinase during late stages of tumor progression

Abstract

We have reported that transin RNA, a 1.9-kb RNA coding for a novel, secreted proteinase, was overexpressed during the progression of benign mouse skin papillomas to malignant squamous cell carcinomas (SCCs) induced by a two-stage protocol (Proc Natl Acad Sci USA 83:9413, 1986). Recently a high degree of similarity has been demonstrated between rabbit stromelysin, a secreted metalloproteinase that degrades proteoglycans found in the basement membrane and the amino acid sequence predicted in rat transin cDNA. DNA sequencing of a mouse cDNA isolated from an SCC (initiated by 7,12-dimethylbenz[a]anthracene [DMBA] and promoted by 12-O-tetradecanoylphorbol-13-acetate [TPA]) showed greater than 85% nucleotide similarity and 90% amino acid similarity to the rat transin-1 cDNA nucleotide and predicted amino acid sequences. Using this mouse transin cDNA clone as a probe (labeled with 32P) we found enhanced levels of transin mRNA transcripts in SCCs induced by a protocol giving rise to metastatic tumors (repeated N-methyl-N-nitroso-N'-nitroguanidine [MNNG] treatments) compared with the level found in SCCs induced by a protocol that had a lower probability of giving rise to metastatic tumors (MNNG initiation followed by TPA promotion). A study of primary SCCs and metastatic lesions induced by repeated benzo[a]pyrene treatment showed that the levels of transin mRNA transcripts were reduced in the metastatic lesions in comparison to the primary tumors. Southern analysis of the DNA isolated from epidermis, papillomas, and SCCs indicated that neither transin gene amplification nor rearrangement accounted for increased levels of the transin mRNA transcripts. These data suggest a role for enhanced levels of transin production in the invasion and metastasis of chemically induced SCCs.

Antitumor Activity of Lantadenes in DMBA/TPA Induced Skin Tumors in Mice: Expression of Transcription Factors

“…Consistent with this, inappropriate signaling of NF-κB has been involved in tumor formation in lymphomas, breast, skin, and bladder cancers [20] and abnormally high NF-κB activity and low IκB levels which indicates that dysregulation of NF-κB may also contribute to skin carcinogenesis. Skin tumors show increased levels of AP-1 effector gene expression, correlating with the degree of malignancy [21,22]. Gene products promoting invasion and metastasis are also under AP-1 regulation [23].…”

The matrix metalloproteinase stromelysin-1 acts as a natural mammary tumor promoter

“…Like several other MMPs, Str1 was ®rst cloned and later recloned as a cancer-speci®c gene (Matrisian et al, 1985;Muller et al, 1988;Ostrowski et al, 1988). In addition to degrading numerous ECM components, Str1 can activate gelatinase B and the collagenases, and can activate several serpin-type serine proteinase inhibitors (Sternlicht and Werb, 1999, for review).…”

Negative regulation of the rat stromelysin gene promoter by retinoic acid is mediated by an AP1 binding site.

“…Transin RNA was shown to be more abundant in invasive mouse skin squamous cell carcinomas than in benign papillomas (Matrisian et al, 1986a), and to be dramatically elevated in carcinomas with a high propensity for metastasis (Ostrowski et al, 1988). We have recently shown that the protein encoded by the transin RNA is the rat equivalent of human stromelysins (Nicholson et al, 1989).…”