Abstract
The actin-binding protein Girdin is involved in a variety of cellular processes, including pancreatic cancer. The objective of this study is to explore the role and the mechanism of Girdin in pancreatic cancer by quantitative acetylome and phosphorylome analysis. We firstly found that Girdin was overexpressed in pancreatic cancer tissue and increased expression of Girdin was associated with tumor size and stage of patients with pancreatic cancer. We established the shRNA knockdown of Girdin in PANC-1 and Aspc-1 cells, and we found that shGirdin inhibited proliferation, migration and invasion, and promoted apoptosis. Subsequently, we identified and quantified 5,338 phosphorylated sites in 2,263 proteins that changed in response to Girdin knockdown, and identified a similar set of Girdin-responsive acetylome data as well. Additional data revealed that down-regulation of Girdin affected Cortactin phosphorylation and acetylation, suggesting Cortactin as an important regulatory target of Girdin. Moreover, we found that overexpression of Cortactin could rescue the effect of shGirdin on proliferation, apoptosism, migration and invasion of pancreatic cancer cells. In general, our results provided new insights into the mechanisms of Girdin function including cell proliferation, migration and invasion, and offer biomarker candidates for clinical evaluation of Girdin.
Highlights
Pancreatic cancer (PC) is a digestive tract malignant tumor with an extremely poor prognosis [1], and the median survival in terminal patients is less than 6 months [2]
We subsequently identified the correlation of Girdin expression and clinicopathological characteristics of pancreatic cancer patients
real-time PCR (RT-PCR) and western blot analysis were employed to detect the expressions of Girdin and Cortactin, and the results showed that Cortactin overexpression showed no effect on Girdin expression (Figure 7A)
Summary
Pancreatic cancer (PC) is a digestive tract malignant tumor with an extremely poor prognosis [1], and the median survival in terminal patients is less than 6 months [2]. Gemcitabine was the first choice of chemotherapy drugs for treating advanced pancreatic cancer [3]. Clinically, it is not ideal and does not inhibit pancreatic cancer metastasis [4]. The ubiquitously expressed actin-binding protein Girdin/ APE (Akt-phosphorylation enhancer) plays a crucial role in cytoskeleton remodeling, cell migration, and tumor metastasis. Girdin is essential for vessel remodeling during angiogenesis [9] It is phosphorylated and activated by the serine/threonine kinase Akt, which is a downstream target of PI3K regulation of cell polarization and migration [10]. In a variety of malignant tumor tissues, Girdin was highly expressed and was correlated with postoperative recurrence and tumor metastasis [11]. The relationship between Girdin and pancreatic cancer remains unclear
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