Abstract
Caveolin-1 exhibits a stage-dependent, functional fluctuation during pancreatic cancer development, but the underlying mechanisms remain unclear. Here, we report that cavin-1, a structural protein of caveolae, modulates the oncogenic function of caveolin-1 and cooperates with caveolin-1 to enhance pancreatic cancer aggressiveness. Cavin-1 expression is associated with caveolin-1 in pancreatic cancer tissue samples and cell lines, and predicts the metastatic potential of pancreatic cancer. Interactome analyses further revealed the physical interaction of cavin-1 and caveolin-1 and their colocalization in pancreatic cancer cells. Cavin-1 stabilizes caveolin-1 expression or activity by inhibiting its internalization and subsequent lysosomal degradation. More in-depth functional experiments showed that caveolin-1-enhanced aggressiveness of pancreatic cancer cells is dependent on the presence of cavin-1. In contrast, cavin-1 depletion inhibited the invasion and metastasis of pancreatic cancer cells, which could not be restored by caveolin-1-rescue construct. Tissue microarray analyses in two independent clinic cohorts also supported the augment of cavin-1 on the prognostic potency of caveolin-1, and showed that combination of cavin-1 with caveolin-1 predicted worse survival in pancreatic cancer patients. Of note, the phenotypes because of cavin-1 could not be achieved by other cavins such as cavin-2, and the tumor-promoting role of cavin-1 in pancreatic cancer was found to be largely dependent on caveolin-1 expression, which highlights the critical role of cavin-1/caveoin-1 in pancreatic cancer progression, and suggests that the interruption of cavin-1/caveolin-1 interaction is a promising therapeutic strategy for pancreatic cancer.
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Abbreviations
- EMT:
-
epithelial–mesenchymal transition
- IP:
-
immunoprecipitation
- RT–PCR:
-
reverse transcription polymerase chain reaction
- qRT–PCR:
-
quantitative real-time polymerase chain reaction
- GST:
-
glutathione S-transferase
- PI3K:
-
phosphoinositide 3-kinase
- TMA:
-
tissue microarray
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Acknowledgements
We thank Zhi-Qiang Meng for providing the pancreatic cancer cells SW1990HM and Huan-Yu Xia for assistance in collecting the patient data. This research project was supported by grants from the National Natural Science Foundation of China (81172005 and 81172276), the National Natural Science Foundation of Shanghai (11ZR1407000) and PhD Programs Foundation of Ministry of Education of China (20110071120096).
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Liu, L., Xu, HX., Wang, WQ. et al. Cavin-1 is essential for the tumor-promoting effect of caveolin-1 and enhances its prognostic potency in pancreatic cancer. Oncogene 33, 2728–2736 (2014). https://doi.org/10.1038/onc.2013.223
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DOI: https://doi.org/10.1038/onc.2013.223
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