Hexokinase 2 is important for tumor growth and metastasis in pancreatic ductal adenocarcinoma Public Deposited

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  • March 20, 2019
Creator
  • Anderson, Marybeth
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer deaths in the United States. The majority of PDAC patients are diagnosed with metastatic disease, where treatment options are limited to cytotoxic chemotherapies that provide modest improvements in overall survival. Over 95% of PDAC tumors contain activating mutations in the oncogene KRAS, causing constitutive activation of key pathways promoting cancer cell proliferation, metabolism, and survival. Direct targeting of KRAS and its canonical effector pathways has proven ineffective for the treatment of advanced PDAC, suggesting that additional processes required for KRAS-driven tumorigenesis may be therapeutically beneficial. Metabolic reprogramming and increased glucose uptake were required for tumor growth in a genetically engineered mouse model of PDAC, suggesting that this pathway is important for PDAC tumorigenesis. We found the glycolytic enzyme hexokinase 2 (HK2) to be significantly upregulated in primary PDAC tumors and PDAC metastases. Increased expression of HK2 was associated with poor overall survival after curative surgery, suggesting that HK2 promotes aggressive tumor biology. HK2 was shown to be both necessary and sufficient for regulating glycolysis, primary tumor growth and metastasis of PDAC cell lines. Pharmacologic inhibition of lactate production abrogated HK2-driven invasion in PDAC cell lines, while addition of extracellular lactate promoted invasion, suggesting that HK2 promotes metastasis by regulating glycolysis. Given this, direct inhibition of HK2 or lactate production may be a promising approach for the treatment of advanced PDAC. Because HK2 was a driver of PDAC tumor growth and metastasis, candidate microRNAs (miRNAs) were examined for their ability to function as tumor suppressors by inhibiting HK2 expression. miR-148a and miR-216b were negatively correlated with HK2 and down regulated in PDAC tumors. Both miR-148a and miR-216b interacted with the 3’UTR of HK2 and inhibited HK2 expression in PDAC cell lines, suggesting that these miRNAs directly regulate HK2 in PDAC. Restoration of miR-148a and miR-216b expression mimicked the effects of HK2 knockdown on anchorage independent growth and invasion of PDAC cell lines, suggesting a potential role for these miRNAs as inhibitors of PDAC tumor growth and metastasis via their regulation of HK2.
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  • In Copyright
Advisor
  • Sethupathy, Praveen
  • Rathmell, W. Kimryn
  • Kim, William
  • Hammond, Scott
  • Yeh, Jen Jen
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2016
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