Expression and gene amplification of actinin-4 in invasive ductal carcinoma of the pancreas.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

CONCLUSION:

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.

• Authors: Satoru Kikuchi, Kazufumi Honda, Hitoshi Tsuda, Nobuyoshi Hiraoka, Issei Imoto, Tomoo Kosuge, Tomoko Umaki, Kaoru Onozato, Miki Shitashige, Umio Yamaguchi, Masaya Ono, Akihiko Tsuchida, Tatsuya Aoki, Johji Inazawa, Setsuo Hirohashi, Tesshi Yamada
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 17 Pg. 5348-56 (Sep 01 2008) ISSN: 1078-0432 [Print] United States
• PMID: 18765526 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ACTN4 protein, human
• Actinin

Topics

• Actinin (antagonists & inhibitors, genetics)
• Aged
• Animals
• Carcinoma, Pancreatic Ductal (genetics)
• Cell Line, Tumor
• Female
• Gene Amplification
• Gene Expression
• Humans
• Male
• Mice
• Mice, SCID
• Neoplasm Invasiveness
• Neoplasm Transplantation
• Pancreatic Neoplasms (genetics)
• Transfection