H-ras and Nm23-H1 gene expression and proteolytic activity in squamous cell carcinoma of the uterine cervix.
BACKGROUND
The invasive and metastatic potential of malignant cells results from complex interactions of numerous factors not yet fully understood. Genomic alterations such as ras overexpression and nm23-H1 inhibition have been found to be frequently associated with increased invasiveness in various cancers. On the other hand, secretion of different proteinases are necessary for malignant cells to traverse a network of matrix macromolecules, but the relationship between the genomic alterations and the proteolytic phenotype is still unclear. Our aim was to investigate whether the appearance of the proteolytic phenotype had any correlation with the expression of H-ras and nm23-H1 genes in carcinoma of the uterine cervix.


METHODS
Twenty-five samples from patients with carcinoma of the uterine cervix at different clinical stages were studied. Cathepsin B1, plasminogen activator, and collagenase activity were assessed in tissue cytosols using specific synthetic oligopeptides as substrates. The expression of H-ras and nm23-H1 was investigated by means of immunohistochemistry and in situ hybridization.


RESULTS
Our results showed that cathepsin B1 was the most consistently elevated proteinase, demonstrating a linear correlation with clinical staging. H-ras expression was found elevated in 40% of the cases. Nm23-H1 protein immunoreactivity was positive in 40% of the cases. No correlation was found among H-ras, cathepsin B1 activity, and survival rate. Among cases with high cysteine proteinase activity, a different clinical behavior depending on the expression of Nm23-H1 was observed. The cases with Nm23-H1 protein had a markedly better survival rate than those lacking this protein. In contrast, the absence of Nm23-H1 in association with high cathepsin B1 activity was a clear indicator of a poor prognosis.


CONCLUSIONS
These findings suggest a complex interaction between the proteolytic phenotype and the expression of H-ras and nm23-H1 genes in carcinoma of the cervix that influences the clinical behavior of the tumor.
Utrera-Barillas
D
D
Unidad de Investigación Médica en Enfermedades Oncológicas, Hospital de Oncología, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), México, D.F., Mexico.
Salcedo-Vargas
M
M
Gariglio-Vidal
P
P
Hernández-Hernández
D M
DM
Gutiérrez-Delgado
F
F
Benítez-Bribiesca
L
L
D014408:Biomarkers, Tumor / Q000032:analysis; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002401:Cathepsin B / Q000032:analysis; D017364:Collagenases / Q000032:analysis; D003600:Cytosol / Q000737:chemistry; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D007091:Image Processing, Computer-Assisted; D017403:In Situ Hybridization; D020559:Monomeric GTP-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D054778:NM23 Nucleoside Diphosphate Kinases; D009361:Neoplasm Invasiveness / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009367:Neoplasm Staging; D009701:Nucleoside-Diphosphate Kinase; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
D014408:Biomarkers, Tumor; D054778:NM23 Nucleoside Diphosphate Kinases; D009363:Neoplasm Proteins; D017395:Plasminogen Activator Inhibitor 1; D014157:Transcription Factors; C517938:NME1 protein, human; D009701:Nucleoside-Diphosphate Kinase; D002401:Cathepsin B; D017364:Collagenases; C501009:HRAS protein, human; D020559:Monomeric GTP-Binding Proteins; D016283:Proto-Oncogene Proteins p21(ras)