Twist promotes angiogenesis in pancreatic cancer by targeting miR-497/VEGFA axis.

An Liu,Xuehong Cai,Jia Xu,Chenggang Huang,Dinghua Yang

doi:10.18632/oncotarget.8269

Abstract

Angiogenesis is a critical step in the growth and dissemination of malignant diseases, including pancreatic cancer. Twist has been shown to stimulate angiogenesis in the tumor site. However, whether Twist contributes to angiogenesis in pancreatic cancer remains unknown. In this paper, we found that the expression of Twist was significantly increased in human pancreatic cancer cell lines and pancreatic cancer specimens. It is also closely engaged to adverse clinical feature, diminished survival and angiogenesis in pancreatic cancer patients. The up-regulation of Twist was found to be promoting cell growth, invasion and tubule formation of human umbilical vein endothelial cells (HUVECs) in vitro. By contrast, the silencing of Twist inhibited orthotopic xenograft tumor growth, metastasis and angiogenesis. Subsequent investigations disclosed that Twist was regulated by miR-497 directly, leading to the increased level of Vascular Endothelial Growth Factor-A (VEGFA). Moreover, gain-of-function and loss-of-function studies demonstrated that miR-497 could suppress the pro-proliferative, angiogenic and metastatic ability of pancreatic cancer cells. The ectopic expression of VEGFA obviously abrogated the anti-angiogenic effect induced by Twist knockdown, whereas the silencing of VEGFA markedly rescued the pro-angiogenic effect of Twist. By analyzing the expression levels of miR-497, Twist was found inversely correlated with miR-497 in pancreatic cancer tissues, and a positive correlation was found between Twist and VEGFA levels in pancreatic cancer specimens. In conclusion, our results suggested that the Twist/miR-497/VEGFA axis is significantly correlated with metastasis and angiogenesis in pancreatic cancer.

Highlights

Pancreatic cancer is the 7th most frequent cause of cancer death worldwide, with approximately 43,920 people in the United States have suffered from pancreatic cancer, and causing 37,390 people died from pancreatic cancer in 2012 [1, 2]
For further investigate the interrelationship between Twist, miR-497 and Vascular Endothelial Growth Factor-A (VEGFA) in pancreatic cancer, we examined the effect of Twist/miR-497/VEGFA axis in metastasis and angiogenesis in pancreatic cancer cells both in vitro and in vivo
We first examined the relative expression of Twist in several pancreatic cancer cell lines, namely Bxpc-3, MIA PaCa-2, Capan-1, Panc-1 and HPAC, along with human pancreatic duct epithelial cells (HPDEC), which is a human non-malignant pancreatic duct epithelial cell line, by Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western bolt

Summary

Introduction

Pancreatic cancer is the 7th most frequent cause of cancer death worldwide, with approximately 43,920 people in the United States have suffered from pancreatic cancer, and causing 37,390 people died from pancreatic cancer in 2012 [1, 2]. As a highly aggressive malignant disease, survival at advanced stages of pancreatic cancer is poor. The 5-year survival rate of patients with pancreatic cancer is the lowest amongst all solid cancers, with a median survival of 6 months [3]. During the last two decades, despite the availability of myriad of treatment modalities, the 5-year overall survival for pancreatic cancer only slightly improved [4]. The identification of potential biomarkers for the prediction of recurrence, disease-free survival and overall survival remains a priority. Along with the advance in the study of the cellular immunology and molecular etiology of pancreatic cancer, novel therapeutic strategies, such as immunological therapy and genetic treatment, have emerged [5, 6]

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Conclusion