Decreased expression of the RAS-GTPase activating protein RASAL1 is associated with colorectal tumor progression.
OBJECTIVE
Although colorectal cancer (CRC) progression has been associated with alterations in KRAS and RAS signaling, not all CRC cells have KRAS gene mutations. RAS activity is modulated by RAS-GTPase-activating proteins (RASGAPs), so we investigated the role of RASGAPs in CRC progression.


METHODS
The level of RASGAP expression in CRC cells was analyzed using quantitative real-time polymerase chain reaction. The expression of the RAS protein activator like-1 (RASAL1) was examined in clinical colorectal neoplasms using immunohistochemistry. The clinicopathologic (age, sex, and tumor site and grade) and molecular (KRAS gene mutation, as well as CTNNB1 and TP53 expression patterns) factors that could affect RASAL1 expression were examined.


RESULTS
Of 12 RASGAPs examined, expression levels of only RASAL1 decreased in CRC cells; RASAL1 expression decreased in most CRC cells with wild-type KRAS gene but rarely in those with mutant KRAS gene. A transfection assay showed that RASAL1 repressed RAS/mitogen-activated protein kinase signaling in response to growth factor stimulation and reduced proliferation of CRC cells that contained wild-type KRAS gene. RASAL1 expression was detected in 46.9% (30/64) of adenocarcinoma, 17.4% (8/46) of large adenoma, and no (0/42) small adenoma samples. RASAL1 expression levels were correlated with the presence of wild-type KRAS gene in CRC tumor samples (P= .0010), distal location (P= .0066), and abnormal expression of TP53 (P= .0208).


CONCLUSIONS
RASAL1 expression is reduced in CRC cells that contain wild-type KRAS gene. Reductions in RASAL1 expression were detected more frequently in advanced lesions than in small adenomas, suggesting that RASAL1 functions in the progression of benign colonic neoplasms.
Ohta
Miki
M
Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. ohtami-tky@umin.ac.jp
Seto
Motoko
M
Ijichi
Hideaki
H
Miyabayashi
Koji
K
Kudo
Yotaro
Y
Mohri
Dai
D
Asaoka
Yoshinari
Y
Tada
Motohisa
M
Tanaka
Yasuo
Y
Ikenoue
Tsuneo
T
Kanai
Fumihiko
F
Kawabe
Takao
T
Omata
Masao
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000737:chemistry / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D019175:DNA Methylation; D018450:Disease Progression; D005260:Female; D020868:Gene Silencing; D011905:Genes, ras; D006801:Humans; D008297:Male; D008875:Middle Aged; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000032:analysis / Q000502:physiology*; D020703:ras GTPase-Activating Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*
D025521:Tumor Suppressor Proteins; D020703:ras GTPase-Activating Proteins