Key result
Low expression of Pfn1 in pancreatic adenocarcinoma was significantly correlated with shortened patient survival (median 14.2 months versus 20.9 months for high expression).
Why the study?
Does Profilin-1 expression reduce tumorigenicity and tumor growth in pancreatic cancer?
Observational (n=72)
No
Does Profilin-1 expression reduce tumorigenicity and tumor growth in pancreatic cancer?
Absolute Event Rate: 14.2% vs 20.9%
p-value: p=0.008
Profilin-1 acts as a tumor suppressor in pancreatic cancer by destabilizing HIF1α via SIRT3, suggesting a novel mechanism independent of its cytoskeleton-related activity.
Pfn1 modulation may offer PDAC therapeutic insight; leaves open clinical translation pending prospective validation.
BACKGROUND: Tumor cells exhibit abnormal actin remodeling profiles, which involve the altered expressions of several important actin-binding proteins. Profilin1 (Pfn1), originally identified as an actin-associated protein, has been linked to several human malignancies. Our recent studies suggested that Pfn1 facilitates apoptosis in pancreatic cancer cells. Here, we investigated the exact role of Profilin1 (Pfn1) in pancreatic adenocarcinoma (PDAC) and the underlying mechanisms. METHODS: Pfn1 protein expression in PDAC specimens was analyzed by immunohistochemistry using a tissue microarray (TMA) containing PDAC tumor tissue and corresponding normal tissue samples from 72 patients. The effect of Pfn1 expression on cancer proliferation was assessed in cells by up- and down-regulation of Pfn1 in vitro and in vivo. Immunoprecipitation and mass spectrometry were used to identify the Pfn1-associated proteins and potential pathways. RESULTS: Pfn1 was downregulated in clinical pancreatic adenocarcinoma specimens compared with the surrounding benign tissues. Univariate survival analysis of the PDAC cohorts showed that low expression of Pfn1 was significantly correlated with shortened patient survival (mean 14.2 months versus 20.9 months, P < 0.05). Restoration of Pfn1 in pancreatic cancer cells with low endogenous Pfn1 expression resulted in a nontumorigenic phenotype, suggesting that Pfn1 may be a negative regulator of pancreatic cancer progression. Overexpression of Pfn1 in vivo decreased the tumor volume in orthotopic xenograft nude mice models. Pfn1 upregulated the expression of SIRT3, leading to HIF1α destabilization. This data revealed that aberrant Pfn1 expression contributes to pancreatic cancer progression. CONCLUSIONS: Our data suggest that Pfn1 is a tumor suppressor in pancreatic cancer that acts via a novel mechanism of regulating the SIRT3-HIF1α axis, independently of its cytoskeleton-related activity.
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Yao et al. (2014) conducted an observational in Pancreatic adenocarcinoma (n=72). Low Pfn1 expression vs. High Pfn1 expression was evaluated on Median cancer-specific survival (months) (p=0.008). Low expression of Pfn1 in pancreatic adenocarcinoma was significantly correlated with shortened patient survival (median 14.2 months versus 20.9 months for high expression).
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