Squamous cell carcinoma of the cervix metastatic to the skin.

Carcinoma of the cervix is a common neoplasm, which annually affects 50,000 women in the United States. When cervical carcinoma metastasizes, it most often involves the lung, bone, and liver; only rarely does it metastasize to the skin. We describe a patient with previously diagnosed carcinoma of the cervix who presented with a lesion on the lateral aspect of her left leg.

Relationship between ornithine decarboxylase and cytoskeletal organization in cultured human keratinocytes: cellular responses to phorbol esters, cytochalasins, and alpha-difluoromethylornithine.

Changes in cell shape occur during the cell cycle and influence cell proliferation and differentiation. In order to study how altered cell proliferation and cell shape are interrelated, we have studied ornithine decarboxylase (ODC) regulation in cultured normal human epidermal keratinocytes (NHEK). Cytoskeletal disruptors have been reported to modulate regulation of ODC; the products of ODC, the polyamines, influence actin polymerization rates in vitro, and polyamine auxotrophs have profoundly disrupted cytoskeletons. Therefore, altered ODC levels could be involved in signaling changes in cell shape and an intact cytoskeleton could transduce signals to regulate ODC levels. We had previously observed that the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), which profoundly alters cell shape, markedly suppresses ODC biosynthesis in NHEK solely at posttranscriptional/protein synthesis levels. TPA treatment caused NHEK to rapidly assume a rounded morphology that was accompanied by a change in actin organization, as determined by rhodamine-phalloidin labeling. Immunolocalization of ODC showed a perinuclear/nuclear distribution in untreated NHEK and a more diffuse pattern after TPA treatment that was apparent within 15-30 min. Changes in ODC enzyme activity are not significant until 60 min after TPA treatment. NHEK treated with cytochalasin B or D to inhibit actin polymerization exhibited a diffuse ODC localization that could be reversed by removal of the cytochalasin; inhibition of ODC by alpha-difluoromethylornithine caused a diffuse ODC localization. All treatments resulted in cytoskeletal remodeling. These data are the first evidence for a distinct subcellular localization for ODC and suggest that changes in ODC localization may be an initial step in regulation of ODC activity. Furthermore, changes in ODC activity cause an altered cytoskeleton, suggesting one means by which growth regulatory signals can be transduced to the cytoskeleton from various signaling pathways.

Post-transcriptional suppression of human ornithine decarboxylase gene expression by phorbol esters in human keratinocytes.

The induction of ornithine decarboxylase levels by the phorbol ester 12-0-tetradecanoyl-phorbol-13-acetate (TPA) in mouse skin has been shown to be integral to tumor promotion by TPA, and changes in ornithine decarboxylase activity indicate the proliferative state of many different cell types. However, in cultured human epidermal cells, TPA has been reported to be antiproliferative. Therefore, to elucidate pathways that TPA activates in cultured human skin cells, we have examined the levels at which TPA regulates ornithine decarboxylase gene expression in two immortalized human epidermal keratinocyte cell lines, and in normal neonatal keratinocytes. We have found that in cultured human keratinocytes, TPA cases a marked decrease in ornithine decarboxylase enzyme activity (50-90%), with no detectable effect on ornithine decarboxylase mRNA levels. TPA decreased steady-state levels of ornithine decarboxylase immunoreactive protein (approximately 50-67%), accounting for the 50-90% suppression of ornithine decarboxylase activity levels, as well as decreasing new synthesis of ornithine decarboxylase protein (48-50%). However, measurement of ornithine decarboxylase protein half-life showed no significant effect of TPA. Also, prolonged treatment of keratinocytes with phorbol esters abolished the suppression of ornithine decarboxylase activity by TPA. Our data, therefore, suggest that phorbol esters suppress ornithine decarboxylase gene expression predominantly by decreasing ornithine decarboxylase mRNA translatability.