Paracrine HGF/c-MET enhances the stem cell-like potential and glycolysis of pancreatic cancer cells via activation of YAP/HIF-1α

Exp Cell Res. 2018 Oct 1;371(1):63-71. doi: 10.1016/j.yexcr.2018.07.041. Epub 2018 Jul 26.

Abstract

Pancreatic stellate cells (PSCs), a pivotal component of the tumor microenvironment, contribute to tumor growth and metastasis. PSC-derived factors are essential for triggering the generation and maintenance of cancer stem cells (CSCs). However, the mechanisms by which paracrine signals regulate CSC-like properties such as glycolytic metabolism have not been fully elucidated. Here, we report that two pancreatic cancer cell lines, Panc-1 and MiaPaCa-2, reacted differently when treated with hepatocyte growth factor (HGF) secreted from PSCs. MiaPaCa-2 cells showed little response with regard to CSC-like properties after HGF treatment. We have shown that in Panc-1 cells by activating its cognate receptor c-MET, paracrine HGF resulted in YAP nuclear translocation and HIF-1α stabilization, thereby promoting the expression of CSC pluripotency markers NANOG, OCT-4 and SOX-2 and tumor sphere formation ability. Furthermore, HGF/c-MET/YAP/HIF-1α signaling enhanced the expression of Hexokinase 2 (HK2) and promoted glycolytic metabolism, which may facilitate CSC-like properties. Collectively, our study demonstrated that HGF/c-MET modulates tumor metabostemness by regulating YAP/HIF-1α and may hold promise as a potential therapeutic target against pancreatic cancer.

Keywords: Cancer stem cells; Glycolysis; HGF/c-MET; HIF-1α; Pancreatic stellate cells; YAP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Cell Line, Tumor
  • Culture Media, Conditioned / metabolism
  • Culture Media, Conditioned / pharmacology
  • Gene Expression Regulation, Neoplastic*
  • Glycolysis / genetics
  • Hepatocyte Growth Factor / genetics*
  • Hepatocyte Growth Factor / metabolism
  • Hepatocyte Growth Factor / pharmacology
  • Hexokinase / genetics
  • Hexokinase / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Nanog Homeobox Protein / genetics
  • Nanog Homeobox Protein / metabolism
  • Octamer Transcription Factor-3 / genetics
  • Octamer Transcription Factor-3 / metabolism
  • Pancreas / metabolism
  • Pancreas / pathology
  • Pancreas / surgery
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / surgery
  • Pancreatic Stellate Cells / metabolism
  • Pancreatic Stellate Cells / pathology
  • Paracrine Communication / genetics
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism
  • Primary Cell Culture
  • Protein Transport
  • Proto-Oncogene Proteins c-met / genetics*
  • Proto-Oncogene Proteins c-met / metabolism
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism
  • Signal Transduction
  • Spheroids, Cellular / drug effects
  • Spheroids, Cellular / metabolism
  • Spheroids, Cellular / pathology
  • Transcription Factors
  • Tumor Microenvironment
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Culture Media, Conditioned
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • NANOG protein, human
  • Nanog Homeobox Protein
  • Octamer Transcription Factor-3
  • POU5F1 protein, human
  • Phosphoproteins
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • Hepatocyte Growth Factor
  • HK2 protein, human
  • Hexokinase
  • Proto-Oncogene Proteins c-met