Expression and gene amplification of actinin-4 in invasive ductal carcinoma of the pancreas.
OBJECTIVE
An invasive growth pattern is one of the hallmarks of pancreatic ductal carcinoma. Actinin-4 is an actin-binding protein associated with enhanced cell motility, invasive growth, and lymph node metastasis. Actinin-4 might play an important role in the development and progression of pancreatic cancer.


METHODS
The expression of actinin-4 was examined immunohistochemically in 173 cases of invasive pancreatic ductal carcinoma. The copy number of the actinin-4 (ACTN4) gene was calculated by fluorescence in situ hybridization. The expression of actinin-4 was stably knocked down by short hairpin RNA, and tumorigenicity was evaluated by orthotopic implantation into mice with severe combined immunodeficiency.


RESULTS
The expression level of actinin-4 was increased in 109 (63.0%) of 173 cases of pancreatic cancer. Kaplan-Meier survival curves revealed that patients with increased expression of actinin-4 had a significantly poorer outcome (P=0.00001, log-rank test). Multivariate analysis by the Cox proportional hazard model showed that high expression of actinin-4 was the most significant independent negative predictor of survival (hazard ratio, 2.33; P=0.000009). Amplification (defined as more than four copies per interphase nucleus) of the ACTN4 gene was detected in 11 (37.9%) of 29 cases showing increased expression of actinin-4. Knockdown of actinin-4 expression inhibited the destructive growth of cancer cells in the pancreatic parenchyma.


CONCLUSIONS
Recurrent amplification of chromosome 19q13.1-2 has been reported in pancreatic cancer, but the exact target gene has not been identified. Actinin-4 contributes to the invasive growth of pancreatic ductal carcinoma, and ACTN4 is one of the candidate oncogenes in this chromosome locus.
Kikuchi
Satoru
S
Chemotherapy Division, Cancer Proteomics Project, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
Honda
Kazufumi
K
Tsuda
Hitoshi
H
Hiraoka
Nobuyoshi
N
Imoto
Issei
I
Kosuge
Tomoo
T
Umaki
Tomoko
T
Onozato
Kaoru
K
Shitashige
Miki
M
Yamaguchi
Umio
U
Ono
Masaya
M
Tsuchida
Akihiko
A
Aoki
Tatsuya
T
Inazawa
Johji
J
Hirohashi
Setsuo
S
Yamada
Tesshi
T