β1C integrin is a spliced variant of the human β1 integrin family that inhibits cell proliferation, at variance with β1A that stimulates it. During the transition from normal to neoplastic endometrium, both variants are down-regulated at the mRNA level, but only β1C at the protein level, suggesting a key role of the regulation of β1C integrin expression in the pathogenesis of endometrial cancer. In this study we show for the first time that, besides β1A and β1C, the β1B spliced variant is expressed in human endometrium, and is up-regulated in hyperplastic and neoplastic endometria in comparison with normal proliferative endometria. To investigate the mechanisms of regulation of β1 integrin expression during endometrial cancer progression we compared the transcriptional activity of the β1 integrin gene in normal and diseased endometria by nuclear run-on analysis and we found it significantly reduced in endometrial adenocarcinoma. On the contrary, hyperplastic endometria showed a 2-fold increase in the β1 transcription rate that directly correlated with the increase in β1B, β1C and β1A steady-state mRNA levels. Finally, we compared the activity of the distal and proximal promoters of the β1 gene integrin gene in normal and diseased endometria and we found the activity of the proximal promoter decreased in neoplastic endometria and increased in hyperplastic tissues, whereas the activity of the distal promoter did not change in different endometrial physio/pathological conditions. These findings suggest a complex pattern for regulation of the expression of β1 integrin variants during endometrial malignant transformation.

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