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Doc-2/hDab2 expression is up-regulated in primary pancreatic cancer but reduced in metastasis
1Department of Visceral and Transplantation Surgery, University of Bern, Inselspital, Bern, Switzerland. helmut.friess@insel.ch
Summary:
DOC-2/hDab2 (DOC-2) has tumor suppressive functions in ovarian cancer and choriocarcinoma. In these tumors, it negatively influences mitogenic signal transduction of growth factors and blocks ras activity. Pancreatic cancer exhibits a high frequency of K-ras gene mutations; however, it is not known whether DOC-2 expression is altered in these tumors. Therefore, we investigated DOC-2 expression in 22 pancreatic adenocarcinomas and in 6 pancreatic cancer cell lines. Findings in human tumors were compared with normal controls and correlated with clinicopathological data. Additionally, the influence of K-ras on DOC-2 transcription was investigated. Northern blot and Western blot analyses both demonstrated an increase of DOC-2 mRNA and protein levels in primary pancreatic cancers in comparison with normal controls. In situ hybridization showed DOC-2 mRNA expression in the majority of cancer cells of primary tumors, as well as in chronic pancreatitis-like lesions surrounding the cancer mass. Immunohistochemistry mirrored the in situ hybridization findings. In contrast, levels of expression of DOC-2 in lymph node metastases were markedly decreased in comparison with levels in primary tumors. In addition, in 5 metastatic pancreatic cancer cell lines, DOC-2 mRNA and protein levels were low, whereas quantitative RT-PCR demonstrated relatively higher levels in a nonmetastatic pancreatic cancer cell line. In conclusion, DOC-2 is overexpressed in primary pancreatic adenocarcinoma but down-regulated in metastatic disease, suggesting a tumor suppressor function of DOC-2 in the late steps of pancreatic carcinogenesis.
Insights
DOC-2 protein is elevated in primary pancreatic cancer but decreases in metastatic disease. This suggests DOC-2 acts as a tumor suppressor in later stages of pancreatic cancer development.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- DOC-2/hDab2 (DOC-2) exhibits tumor suppressive functions in ovarian cancer and choriocarcinoma by inhibiting growth factor signaling and blocking Ras activity.
- Pancreatic cancer frequently harbors K-ras gene mutations, but the role of DOC-2 in this malignancy is unclear.
Purpose of the Study:
- To investigate DOC-2 expression patterns in pancreatic adenocarcinoma.
- To correlate DOC-2 expression with clinicopathological data and K-ras influence on its transcription.
Main Methods:
- Northern blot and Western blot analyses to assess DOC-2 mRNA and protein levels.
- In situ hybridization and immunohistochemistry for spatial expression analysis in tumors.
- Quantitative RT-PCR to compare expression in metastatic and non-metastatic cell lines.
Main Results:
- DOC-2 mRNA and protein levels were increased in primary pancreatic cancers compared to normal tissues.
- DOC-2 was expressed in primary tumors and surrounding chronic pancreatitis lesions, but significantly decreased in lymph node metastases.
- Metastatic pancreatic cancer cell lines showed low DOC-2 levels, while a non-metastatic cell line had higher levels.
Conclusions:
- DOC-2 is overexpressed in primary pancreatic adenocarcinoma.
- DOC-2 expression is down-regulated in metastatic pancreatic disease.
- These findings suggest a tumor suppressor role for DOC-2 in the progression of pancreatic cancer.