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Induction of Differentiation-dependent Apoptosis in Human Esophageal Squamous Cell Carcinoma by Adenovirus-mediated p21^sdi1 Gene Transfer¹

Section of Molecular Oncology, First Department of Surgery [Y. K., To. F., Ta. F., J. S. N. T.], Department of Cell Chemistry, Institute of Cellular and Molecular Biology [T. Y.], Okayama University Medical School, Okayama 700-8558, Japan; First Department of Surgery, Shiga University of Medical Science, Shiga 520-2192, Japan [T. I.]; Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 [S. K., J. A. R.]; and Department of Pharmacy, The University of New Mexico, Albuquerque, New Mexico 87131-2006 [L. G. H.]

When keratinocytes withdraw from the cell cycle, they migrate from the basal to the superficial layers of the epidermis and undergo morphological and biochemical changes during the process of terminal differentiation. These differentiation features of keratinocytes are known to be altered or reduced in esophageal cancer cells. Therefore, we examined the effects of transferring the cyclin-dependent kinase inhibitor p21^sdi1 gene into human esophageal cancer cell lines as well as normal keratinocytes using an adenovirus vector system. Ectopic expression of p21^sdi1 protein resulted in cell cycle arrest at the G₁ phase and produced morphological changes, such as enlarged nuclei and a flattened cellular shape, changes specific to the differentiated phenotype. The human involucrin protein is a specific product of keratinocyte differentiation, which is selectively expressed in the suprabasal epidermal layers. Western blot analysis and immunohistochemical staining demonstrated that involucrin expression was 3- to 5-fold enhanced by the forced expression of p21^sdi1 in esophageal cancer cells, whereas only a mild up-regulation up to 1.2-fold occurred in normal keratinocytes. We also found that exogenous introduction of the p21^sdi1 gene transcriptionally activated the upstream promoter function of the involucrin gene. These stimulatory effects on involucrin expression were not observed when another cyclin-dependent kinase inhibitor gene, p16^INK4a, was transduced. Moreover, p21^sdi1 expression in esophageal cancer cells transduced with p21^sdi1 led to a rapid apoptotic cell death after a transient dormant phase, although keratinocytes transduced with p21^sdi1 survived longer by terminally withdrawing from the cell cycle. These results may have an important implication for understanding the biology of differentiation-dependent apoptosis in human esophageal squamous cell carcinoma.

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