CD109 mediates tumorigenicity and cancer aggressiveness via regulation of EGFR and STAT3 signalling in cervical squamous cell carcinoma

Br J Cancer. 2020 Sep;123(5):833-843. doi: 10.1038/s41416-020-0922-7. Epub 2020 Jun 8.

Abstract

Background: CD109 was involved in the tumorigenesis and progression of various cancers via TGF-β1 signalling and STAT3 activation. As CD109 is strongly expressed in cervical squamous cell carcinoma, this study was conducted to investigate its functional characteristics in cervical cancer.

Methods: CD109 expression was examined by immunohistochemistry (IHC) with cervical tissue microarray. The effects of CD109 expression were examined on migration, cell proliferation, spheroid formation and soft-agar colony-formation assay. Meanwhile, cervical cancer cell lines with high CD109 expression were chosen for the functional study using siRNA knockdown and CRISPR/Cas9 knockout.

Results: IHC demonstrated an upregulation of CD109 in the cell membrane of cervical squamous cell carcinoma. CD109( + ) cells isolated by flow-cytometric sorting displayed enhanced migration, cell proliferation, sphere-forming and anchorage-independent cell growth ability. In contrast, silencing of CD109 expression could reverse the in vitro and in vivo tumorigenic and aggressive properties. Furthermore, CD109 induced EGFR-mediated STAT3 phosphorylation known to be responsible for cell migration, proliferation and maintenance of CSC phenotype.

Conclusion: Abundant CD109( + ) populations in cervical cancer cells potentially contributed to carcinogenesis and aggressiveness, whereas silencing of CD109 expression could reverse those properties. CD109 mediates cervical tumorigenicity and aggressiveness via CD109/EGFR/STAT3 signalling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / biosynthesis
  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Base Sequence
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • ErbB Receptors / metabolism
  • Female
  • GPI-Linked Proteins / biosynthesis
  • GPI-Linked Proteins / genetics
  • GPI-Linked Proteins / metabolism
  • Gene Knockout Techniques
  • Heterografts
  • Humans
  • Immunohistochemistry
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Phosphorylation
  • RNA, Small Interfering / administration & dosage
  • RNA, Small Interfering / genetics
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction
  • Uterine Cervical Neoplasms / genetics
  • Uterine Cervical Neoplasms / metabolism*
  • Uterine Cervical Neoplasms / pathology

Substances

  • Antigens, CD
  • CD109 protein, human
  • GPI-Linked Proteins
  • Neoplasm Proteins
  • RNA, Small Interfering
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • EGFR protein, human
  • ErbB Receptors