Abstract
BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most malignant diseases because of its non-symptomatic tumorigenesis. We previous found heat shock factor 1 (HSF1) was critical for PDAC progression and the aim of this study was to clarified the mechanisms on early activation of HSF1 and its role in the pancreatic cancer tumorigenesis.MethodsThe expression and location of HSF1 on human or mice pancreatic tissues were examined by immunohistochemically staining. We mainly used pancreatic acinar cell 3-dimensional (3D) culture and a spontaneous pancreatic precancerous lesion mouse model called LSL-KrasG12D/+; Pdx1-Cre (KC) (and pancreatitis models derived from KC mice) to explore the pro-tumorigenesis mechanisms of the HSF1 in vitro and in vivo. Bioinformatics and molecular experiments were used to explore the underlying mechanisms between HSF1 and epidermal growth factor receptor (EGFR).ResultsIn this study, we found that pharmacological inhibition of HSF1 slowed pancreatic cancer initiation and suppressed the pancreatitis-induced formation of pancreatic precancerous lesion. Next, bioinformatics analysis revealed the closely linked between HSF1 and EGFR pathway and we also confirmed their parallel activation in pancreatic precancerous lesions. Besides, the pharmacological inhibition of EGFR suppressed the initiation of pancreatic cancer and the activation of HSF1 in vivo. Indeed, we demonstrated that the EGFR activation that mediated pancreatic cancer tumorigenesis was partly HSF1-dependent in vitro.ConclusionHence, we concluded that the EGFR-HSF1 axis promoted the initiation of pancreatic cancer.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant diseases because of its nonsymptomatic tumorigenesis
Studies have shown that heat shock factor 1 (HSF1) was continuously activated and its downstream HSP70/90 were obviously elevated in many cancers [7, 8], and we found that the abnormal activation of HSF1 and its targets even in pancreatic intraepithelial neoplasias (PanINs), the most common precancerous lesion of pancreatic cancer, which indicates that HSF1 activation is an early event in pancreatic cancer and HSF1 may participates in the initiation of pancreatic cancer
In this study, compared to normal pancreatic acinar, we found that the starting significant accumulation of HSF1 in the cytoplasmic of human pancreatic acinar-ductal metaplasia (ADM) structure (Fig. 1a); these activated HSF1 were quickly translocated into nucleus of precancerous lesions even as the in early PanINs formation and lasted until invasive PDAC stage, along with an abundant desmoplastic reaction (Fig. 1b), which means HSF1 and its activation may participate in the initiation of human pancreatic cancer
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant diseases because of its nonsymptomatic tumorigenesis. We previous found heat shock factor 1 (HSF1) was critical for PDAC progression and the aim of this study was to clarified the mechanisms on early activation of HSF1 and its role in the pancreatic cancer tumorigenesis. As ADM is a necessary process for the malignant transformation of pancreatic acinar cells (into pancreatic precancerous lesions PanINs), it is reasonable to believe that EGFR and its downstream pathways play a critical role in the initiation of pancreatic cancer [12]. Tang Z and colleagues proved that MEK, a classic downstream target of EGFR mediated MAPK pathway, is pivotal in maintaining the proteostasis of melanoma cells by phosphorylating and activating HSF1, which means that Ras-MEK-HSF1 and the upstream molecule EGFR may play an important role in the initiation and progression of melanoma [6]. The role of the EGFRHSF1 axis in the tumorigenesis of pancreatic cancer needs to be investigated
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