RASEF is a novel diagnostic biomarker and a therapeutic target for lung cancer

• Published in: Molecular cancer research Vol. 11; no. 8; pp. 937 - 951
• Main Authors: Oshita, Hideto, Nishino, Ryohei, Takano, Atsushi, Fujitomo, Takashi, Aragaki, Masato, Kato, Tatsuya, Akiyama, Hirohiko, Tsuchiya, Eiju, Kohno, Nobuoki, Nakamura, Yusuke, Daigo, Yataro
• Format: Journal Article
• Language: English
• Published: United States 01-08-2013
• Subjects: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor - metabolism; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Cell Proliferation; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Male; MAP Kinase Signaling System; Middle Aged; Phosphorylation; Prognosis; ras Guanine Nucleotide Exchange Factors - genetics; ras Guanine Nucleotide Exchange Factors - metabolism
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.mcr-12-0685-t

Genome-wide gene expression profiling revealed that the Ras and EF-hand domain containing (RASEF) transcript was significantly transactivated in the majority of lung cancers. Using lung cancer cells, transient expression of RASEF promoted cell growth, whereas RASEF knockdown not only reduced its expression but resulted in growth suppression of the cancer cells. Immunohistochemical staining using tumor tissue microarrays consisting of 341 archived non-small cell lung cancers (NSCLC) revealed the association of strong RASEF positivity with poor prognosis (P = 0.0034 by multivariate analysis). Mechanistically, RASEF interacted with extracellular signal-regulated kinase (ERK) 1/2 and enhanced ERK1/2 signaling. Importantly, inhibiting the interaction between RASEF and ERK1/2 using a cell-permeable peptide that corresponded to the ERK1/2-interacting site of RASEF, suppressed growth of lung cancer cells. This study demonstrates that elevated RASEF promoted cell growth via enhanced ERK signaling and is associated with poor prognosis of NSCLC.
RASEF may play an important role in lung carcinogenesis and could serve as a vaiable prognostic biomarker and target for the development of new molecular therapies.