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PRRX1 promotes malignant properties in human osteosarcoma.

Ryoji Joko1, Daisuke Yamada2, Masahiro Nakamura3

  • 1Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan; Department Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.

Translational Oncology
|January 5, 2021
PubMed
Summary

Paired related homeobox 1 (PRRX1) promotes human osteosarcoma malignancy. PRRX1 expression correlates with poor prognosis and metastasis, and its inhibition suppresses tumor growth and increases chemo-sensitivity.

Keywords:
Connectivity map analysisDrug resistanceInvasionOsteosarcomaPRRX1Tumor malignancy

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Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Paired related homeobox 1 (PRRX1) is a marker for limb bud mesenchymal cells.
  • Deficiency of p53 or Rb in Prrx1-positive cells can induce osteosarcoma in mouse models.
  • The specific role of PRRX1 in human osteosarcoma remains largely undefined.

Purpose of the Study:

  • To investigate the regulatory role of PRRX1 in human osteosarcoma.
  • To assess the correlation between PRRX1 expression levels and patient prognosis, including metastasis.
  • To evaluate the therapeutic potential of targeting PRRX1 in osteosarcoma.

Main Methods:

  • PRRX1 immunostaining was performed on 35 human osteosarcoma specimens.
  • PRRX1 expression was analyzed in the 143B human osteosarcoma cell line.
  • PRRX1 knockdown was achieved to assess its effects on proliferation, invasion, and chemo-sensitivity.
  • In vivo studies involved subcutaneous transplantation of PRRX1-knockdown cells into nude mice.
  • Connectivity Map analysis identified potential therapeutic compounds, such as forskolin.

Main Results:

  • Higher PRRX1 expression in osteosarcoma patients correlated with poorer overall survival and increased lung metastasis.
  • PRRX1 was expressed in the highly metastatic 143B osteosarcoma cell line.
  • Downregulating PRRX1 reduced cell proliferation and invasion, and enhanced sensitivity to cisplatin and doxorubicin.
  • PRRX1 knockdown in vivo decreased tumor size and lung metastasis rates.
  • Forskolin mimicked the anti-tumor effects of PRRX1 knockdown, reducing proliferation and migration.

Conclusions:

  • PRRX1 significantly promotes tumor malignancy in human osteosarcoma.
  • PRRX1 expression serves as a potential prognostic biomarker for osteosarcoma.
  • Targeting PRRX1 or related pathways, like with forskolin, shows therapeutic promise for osteosarcoma treatment.