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Loss of MAL Expression in Precancerous Lesions of the Esophagus

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Abstract

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.

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Acknowledgments

We thank Ms. M. Oda and Ms. T. Shimooka for their technical support and Dr. K. Obara for his advice for the regarding pathological information. We also appreciate the cooperation of Drs. Kosaka and Motoyama. Financial support: This work was supported by the following grant sponsors: CREST; Japan Science and Technology Agency (JST); Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (Grant nos. 17109013, 17591411, 17591413, and 17015032).

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Authors and Affiliations

  1. Department of Surgical Oncology, Medical Institute of Bioregulation, Kyushu University, 4546 Tsurumihara, Beppu, 874-0838, Japan

    Koshi Mimori MD, PhD, Kohjiro Nishida MD, Yoshito Nakamura MD, Keisuke Ieta MD, Atsushi Sasaki MD, PhD & Masaki Mori MD, PhD, FACS

  2. Department of Pathology, Medical Institute of Bioregulation, Kyushu University, 4546 Tsurumihara, Beppu, 874-0838, Japan

    Yasuji Yoshikawa MD, PhD

  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

    Hideshi Ishii MD, PhD

  4. Centro de Biologia Molecular “Severo Ochoa”, Faculatad de Ciencias, Universidad Autónoma de Madrid, Cantoblanco, Madrid, 28049, Spain

    Miguel A. Alonso MD

Authors
  1. Koshi Mimori MD, PhD
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  2. Kohjiro Nishida MD
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  3. Yoshito Nakamura MD
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  4. Keisuke Ieta MD
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  5. Yasuji Yoshikawa MD, PhD
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  6. Atsushi Sasaki MD, PhD
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  7. Hideshi Ishii MD, PhD
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  8. Miguel A. Alonso MD
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  9. Masaki Mori MD, PhD, FACS
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Corresponding author

Correspondence to Masaki Mori MD, PhD, FACS.

Additional information

This investigation was presented on March 25, 2006 at the 59th Annual Meeting of the Society of Surgical Oncology at the San Diego Marriott Hotel, San Diego, California.

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Mimori, K., Nishida, K., Nakamura, Y. et al. Loss of MAL Expression in Precancerous Lesions of the Esophagus. Ann Surg Oncol 14, 1670–1677 (2007). https://doi.org/10.1245/s10434-006-9064-2

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  • DOI: https://doi.org/10.1245/s10434-006-9064-2

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