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Mint3 depletion restricts tumor malignancy of pancreatic cancer cells by decreasing SKP2 expression via HIF-1

Authors
  • Kanamori, Akane1
  • Matsubara, Daisuke2
  • Saitoh, Yurika1, 3
  • Fukui, Yuya1
  • Gotoh, Noriko4
  • Kaneko, Shuichi4
  • Seiki, Motoharu1
  • Murakami, Yoshinori1
  • Inoue, Jun-ichiro1
  • Sakamoto, Takeharu4
  • 1 The University of Tokyo,
  • 2 Jichi Medical University,
  • 3 Teikyo University of Science,
  • 4 Kanazawa University,
Type
Published Article
Journal
Oncogene
Publisher
Nature Publishing Group UK
Publication Date
Aug 21, 2020
Volume
39
Issue
39
Pages
6218–6230
Identifiers
DOI: 10.1038/s41388-020-01423-8
PMID: 32826949
PMCID: PMC7515798
Source
PubMed Central
Keywords
License
Unknown

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.

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