Abstract
Pancreatic cancer is one of the most fatal cancers without druggable molecular targets. Hypoxia inducible factor-1 (HIF-1) is a heterodimeric transcriptional factor that promotes malignancy in various cancers including pancreatic cancer. Herein, we found that HIF-1 is accumulated in normoxic or moderate hypoxic areas of pancreatic cancer xenografts in vivo and is active even during normoxia in pancreatic cancer cells in vitro. This prompted us to analyze whether the HIF-1 activator Mint3 contributes to malignant features of pancreatic cancer. Mint3 depletion by shRNAs attenuated HIF-1 activity during normoxia and cell proliferation concomitantly with accumulated p21 and p27 protein in pancreatic cancer cells. Further analyses revealed that Mint3 increased transcription of the oncogenic ubiquitin ligase SKP2 in pancreatic cancer cells via HIF-1. This Mint3-HIF-1-SKP2 axis also promoted partial epithelial-mesenchymal transition, stemness features, and chemoresistance in pancreatic cancer cells. Even in vivo, Mint3 depletion attenuated tumor growth of orthotopically inoculated human pancreatic cancer AsPC-1 cells. Database and tissue microarray analyses showed that Mint3 expression is correlated with SKP2 expression in human pancreatic cancer specimens and high Mint3 expression is correlated with poor prognosis of pancreatic cancer patients. Thus, targeting Mint3 may be useful for attenuating the malignant features of pancreatic cancer.
Highlights
Pancreatic ductal adenocarcinoma is a highly aggressive and lethal tumor, characterized by invasiveness, rapid progression, and treatment resistance [1, 2]
To assess whether this HIF-1α protein localization in normoxic and mild hypoxic areas is observed in pancreatic cancer xenografts, we performed immunostaining of HIF-1α protein and pimonidazole, which forms adducts of thiol-containing proteins in cells with
Munc18-1-interacting protein 3 (Mint3) depletion decreased expression of the Hypoxia inducible factor-1 (HIF-1) target genes VEGFA and PDK1 (Supplementary Fig. S1). These results indicate that Mint3 is necessary for maintaining HIF-1 transcriptional activity during normoxia independently from HIF-1α protein levels in pancreatic cancer cells
Summary
Pancreatic ductal adenocarcinoma is a highly aggressive and lethal tumor, characterized by invasiveness, rapid progression, and treatment resistance [1, 2]. Mint depletion restricts tumor malignancy of pancreatic cancer cells by decreasing SKP2 expression via. The α subunit of HIF-1 is suppressed under normoxic conditions by two types of oxygen-dependent hydroxylases, HIF prolyl hydroxylase domain containing proteins (PHDs) and factor inhibiting HIF-1 (FIH-1) [4,5,6,7]. Whether and how Mint contributes to HIF-1 activation during normoxia and tumor malignancy in pancreatic cancer cells remain unclear. We found that Mint depletion decreased the expression of the S-phase kinase associated protein (SKP2) oncogene [18] via HIF-1 during normoxia, thereby attenuating malignant features such as cell proliferation, stemness, chemoresistance, and tumorigenicity in pancreatic cancer cells
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