Published online before print July 16, 2009

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(American Journal of Pathology. 2009;175:867-881.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080489

Down-Regulation of DUSP6 Expression in Lung Cancer

Its Mechanism and Potential Role in Carcinogenesis

Koji Okudela^*, Takuya Yazawa^*, Tetsukan Woo, Masashi Sakaeda^*, Jun Ishii^*, Hideaki Mitsui^*, Hiroaki Shimoyamada^*, Hanako Sato^*, Michihiko Tajiri, Nobuo Ogawa, Munetaka Masuda, Takashi Takahashi^¶, Haruhiko Sugimura^|| and Hitoshi Kitamura^*

From the Departments of Pathology^* and Surgery, Yokohama City University Graduate School of Medicine, Yokohama; the Division of General Thoracic Surgery, Kanagawa Cardiovascular and Respiratory Disease Center Hospital, Yokohama; the Department of Anatomy, St. Marianna University School of Medicine, Kawasaki; the Division of Molecular Carcinogenesis,^¶ Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya; and the Department of Pathology,|| Hamamatsu Medical University, School of Medicine, Hamamatsu, Japan

Our preliminary studies revealed that oncogenic KRAS (KRAS/V12) dramatically suppressed the growth of immortalized airway epithelial cells (NHBE-T, with viral antigen-inactivated p53 and RB proteins). This process appeared to be a novel event, different from the so-called premature senescence that is induced by either p53 or RB, suggesting the existence of a novel tumor suppressor that functions downstream of oncogenic KRAS. After a comprehensive search for genes whose expression levels were modulated by KRAS/V12, we focused on DUSP6, a pivotal negative feedback regulator of the RAS-ERK pathway. A dominant-negative DUSP6 mutant, however, failed to rescue KRAS/V12-induced growth suppression, but conferred a stronger anchorage-independent growth activity to the surviving subpopulation of cells generated from KRAS/V12-transduced NHBE-T. DUSP6 expression levels were found to be weaker in most lung cancer cell lines than in NHBE-T, and DUSP6 restoration suppressed cellular growth. In primary lung cancers, DUSP6 expression levels decreased as both growth activity and histological grade of the tumor increased. Loss of heterozygosity of the DUSP6 locus was found in 17.7% of cases and was associated with reduced expression levels. These results suggest that DUSP6 is a growth suppressor whose inactivation could promote the progression of lung cancer. We have here identified an important factor involved in carcinogenesis through a comprehensive search for downstream targets of oncogenic KRAS.