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10.1245/s10434-006-9064-2
Annals of Surgical Oncology 14:1670-1677 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Loss of MAL Expression in Precancerous Lesions of the Esophagus

Koshi Mimori, MD, PhD1, Kohjiro Nishida, MD1, Yoshito Nakamura, MD1, Keisuke Ieta, MD2, Yasuji Yoshikawa, MD, PhD2, Atsushi Sasaki, MD, PhD1, Hideshi Ishii, MD, PhD3, Miguel A. Alonso, MD4 and Masaki Mori, MD, PhD, FACS1

1 Department of Surgical Oncology, Medical Institute of Bioregulation, Kyushu University, 4546 Tsurumihara, Beppu, 874-0838, Japan
2 Department of Pathology, Medical Institute of Bioregulation, Kyushu University, 4546 Tsurumihara, Beppu, 874-0838, Japan
3 Division of Stem Cell Regulation/Molecular Hematopoiesis, Jichi Medical School, Center for Molecular Medicine, Yakushiji 3311-1, Minami Kawauchi-Cho, Kawachi-Gun, 329-0498, Japan
4 Centro de Biologia Molecular "Severo Ochoa," Faculatad de Ciencias, Universidad Autónoma de Madrid, Cantoblanco, Madrid, 28049, Spain

Correspondence: Address correspondence and reprint requests to: Masaki Mori, MD, PhD, FACS; E-mail: mmori{at}beppu.kyushu-u.ac.jp

Background: We have identified a novel function of MAL (T-cell differentiation-related gene) as a candidate suppressor gene in esophageal cancer. As the role of MAL expression in esophageal carcinogenesis is as yet undetermined, MAL expression in a rat multi-step carcinogenic model and in precancerous lesions of the human esophagus was investigated. Microarray analysis between MAL-transfectant and control cells was also carried out to clarify how MAL confers its anti-tumor effects.

Materials and Methods: (1) In the rat model, MAL expression levels in laser microdissected normal esophageal epithelium, dysplastic tissues and carcinoma tissues were examined by reverse transcription (RT)-PCR. (2) Immunostaining with MAL antibody was performed in 10 dysplastic lesions adjacent to cancer in six cases of esophageal cancer. (3) We established a MAL transfectant using a Tet-off vector in esophageal cancer cells and performed microarray analysis under MAL-positive and MAL-negative conditions.

Results: (1) In the rat model, MAL mRNA expression was observed only in the normal samples. (2) MAL expression was observed distinctively in differentiated or keratinized normal tissues and was not observed in either dysplastic lesions or carcinoma tissue. (3) Up-regulated genes in MAL-positive cells included keratin 18 (transfectant/control = 2.94) and keratin 10 (t/c = 2.82).

Conclusion: MAL expression was lost in dysplastic lesions of the rat carcinoma model as well as the human esophagus. The up-regulated keratins revealed by microarray analysis and the strong staining of the differentiated normal tissues in immunohistochemical study support the role of MAL as a regulator of differentiation in esophageal epithelium.

Key Words: MAL • Esophageal cancer • Dysplasia • Differentiation • Keratin






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