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10.1245/s10434-006-9274-7
Annals of Surgical Oncology 14:1405-1415 (2007)
© 2007 Society of Surgical Oncology
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Original Article

STAT1 Activation-Induced Apoptosis of Esophageal Squamous Cell Carcinoma Cells In Vivo

Junichi Kaganoi, MD, PhD1,2, Go Watanabe, MD, PhD1, Michio Okabe, MD1, Shiro Nagatani, MD1, Atsushi Kawabe, MD, PhD1, Yutaka Shimada, MD, PhD1, Masayuki Imamura, MD, PhD3 and Yoshiharu Sakai, MD, PhD1

1 Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
2 Kitano Hospital, Tazuke Kofukai Medical Research Institute, 2-4-20 Ohgimachi, Kita-ku, Osaka 530-8480, Japan
3 Osaka Saiseikai Noe Hospital, Imafukuhigashi, Zyoto-ku, Osaka 536-0002, Japan

Correspondence: Address correspondence and reprint requests to: Go Watanabe, MD, PhD; E-mail: gowata{at}kuhp.kyoto-u.ac.jp

Background: The induction of apoptosis might be a promising treatment for cancers refractory to conventional therapies, such as esophageal cancer. In this study, we examined whether epidermal growth factor–induced growth inhibition results from apoptosis of esophageal squamous cell carcinoma (SCC) cells as a result of STAT1 activation and evaluated whether interferon gamma (IFN-{gamma}) can induce apoptosis of cancer cells in vivo.

Methods: To assess the function of STAT1, we established stable transfectants expressing dominant-negative STAT1. Apoptosis was assessed by several experimental techniques, including flow cytometry. Differentiation was evaluated by Western blot test with involucrin used as a marker. In vivo, cancer cells were injected into male BALB/c nu/nu mice. Two weeks later, the mice started to receive injections of IFN-{gamma} or saline into a tail vein four times per week. Concentrations of IFN-{gamma} in the tumors were analyzed by enzyme-linked immunosorbent assay. Apoptosis was evaluated by TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) staining.

Results: Epidermal growth factor inhibited the growth of esophageal SCC cells by causing apoptosis through several pathways involving STAT1 activation. IFN-{gamma} induced the apoptosis of cancer cells, but it also promoted the differentiation (not apoptosis) of primary cultured cells derived from normal esophageal epithelium. IFN-{gamma} also inhibited the growth of xenograft tumors of esophageal SCC cells in vivo.

Conclusions: Our results suggest that IFN-{gamma} is one candidate for cytokine-based therapy of cancer. IFN-{gamma}–induced STAT1 activation might be involved in the apoptosis of esophageal SCC cells and in the terminal differentiation of normal squamous cells. Further studies of STAT1 signaling pathways may provide the basis for new targeted therapeutic strategies for esophageal SCC.

Key Words: Interferon • STAT1 • Epidermal growth factor • Esophageal cancer






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