Anterior gradient protein 2 expression in high grade head and neck squamous cell carcinoma correlated with cancer stem cell and epithelial mesenchymal transition

Oncotarget. 2015 Apr 20;6(11):8807-21. doi: 10.18632/oncotarget.3556.

Abstract

Anterior gradient protein 2 (AGR2) is a novel biomarker with potential oncogenic role. We sought to investigate the diagnostic and prognostic role of AGR2 on head and neck squamous cell carcinoma (HNSCC) with an emphasis on its correlation of cancer stemloid cells (CSC) and epithelial mesenchymal transition (EMT). We found that AGR2 protein levels were higher in HNSCC than in normal oral mucosa. High levels of AGR2 were associated with the T category, pathological grade and lymph node metastasis of HNSCC. Expression of AGR2 increased in recurring HNSCC after radiotherapy and in post cisplatin-based chemotherapeutic tissues. In HNSCC cell lines, knock-down of AGR2 induced apoptosis, reduced sphere formation, and down-regulated Survivin, Cyclin D1, Bcl2, Bcl2l1, Slug, Snail, Nanog and Oct4. In addition, over-expressed AGR2 in transgenic mice with spontaneous HNSCC was associated with lost function of Tgfbr1 and/ or lost function of Pten. In vitro knockdown TGFBR1 in HNSCC cell lines increased AGR2 expression. These results suggest that AGR2 is involved in EMT and self-renewal of CSC and may present a potential therapeutic target (oncotarget) for HNSCC.

Keywords: AGR2; HNSCC; cancer stemloid cell; epithelial mesenchymal transition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Apoptosis
  • Apoptosis Regulatory Proteins / biosynthesis
  • Apoptosis Regulatory Proteins / genetics
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology*
  • Carcinoma, Squamous Cell / therapy
  • Cell Line, Tumor
  • Cell Self Renewal / genetics
  • Cisplatin / administration & dosage
  • Cisplatin / pharmacology
  • Epithelial-Mesenchymal Transition / genetics*
  • Fluorouracil / administration & dosage
  • Fluorouracil / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / radiation effects
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / metabolism
  • Head and Neck Neoplasms / pathology*
  • Head and Neck Neoplasms / therapy
  • Humans
  • Kaplan-Meier Estimate
  • Lymphatic Metastasis
  • Mice, Knockout
  • Mouth Mucosa / chemistry
  • Mucoproteins
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Neoplastic Stem Cells / metabolism*
  • Oncogene Proteins
  • PTEN Phosphohydrolase / deficiency
  • PTEN Phosphohydrolase / genetics
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • Proteins / genetics
  • Proteins / physiology*
  • RNA, Small Interfering
  • Radiotherapy, Adjuvant
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / deficiency
  • Receptors, Transforming Growth Factor beta / genetics
  • Spheroids, Cellular
  • Taxoids / administration & dosage
  • Taxoids / pharmacology
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics

Substances

  • AGR2 protein, human
  • Apoptosis Regulatory Proteins
  • Mucoproteins
  • Neoplasm Proteins
  • Oncogene Proteins
  • Proteins
  • RNA, Small Interfering
  • Receptors, Transforming Growth Factor beta
  • Taxoids
  • Transcription Factors
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human
  • Tgfbr1 protein, mouse
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Pten protein, mouse
  • Cisplatin
  • Fluorouracil

Supplementary concepts

  • TPF protocol