Leukemia Inhibitory Factor Promotes Tumor Growth and Metastasis in Human Osteosarcoma via Activating STAT3

APMIS. 2015 Oct;123(10):837-46. doi: 10.1111/apm.12427. Epub 2015 Aug 14.

Abstract

The leukemia inhibitory factor (LIF) has been demonstrated to be an oncogene and participated in multiple procedures during the initiation and progression of many human malignancies. However, the role of LIF in osteosarcoma is still largely unknown. Here, we performed a series of in vitro and in vivo experiments to investigate the expression and biological functions of LIF in osteosarcoma. Compared to that in the non-cancerous tissues, LIF was significantly overexpressed in a panel of 68 osteosarcoma samples (p < 0.0001). Moreover, the overexpression of LIF was significantly correlated with advanced tumor stage, larger tumor size, and shorter overall survival. In addition, knockdown of LIF notably suppressed the proliferation and invasion of osteosarcoma via blocking the STAT3 signal pathway; in contrast, treatment with the recombinant LIF protein significantly promoted the growth and invasion of osteosarcoma through enhancing the phosphorylation of STAT3, which can be partially neutralized by the STAT3 inhibitor, HO-3867. In conclusion, we demonstrated that LIF was frequently overexpressed in osteosarcoma, which could promote the growth and invasion through activating the STAT3 pathway. Our findings proposed that LIF might be a potent therapeutic target for osteosarcoma.

Keywords: Osteosarcoma; STAT3; invasion; leukemia inhibitory factor; proliferation.

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Bone Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Child
  • Child, Preschool
  • Disease Models, Animal
  • Enzyme Activation
  • Female
  • Humans
  • Leukemia Inhibitory Factor / biosynthesis
  • Leukemia Inhibitory Factor / genetics*
  • Leukemia Inhibitory Factor / metabolism*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Invasiveness / genetics
  • Neoplasm Metastasis / pathology
  • Neoplasm Transplantation
  • Osteosarcoma / pathology*
  • Phosphorylation
  • Piperidones / pharmacology
  • RNA Interference
  • RNA, Small Interfering
  • STAT3 Transcription Factor / antagonists & inhibitors
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction
  • Transplantation, Heterologous
  • Young Adult

Substances

  • (3,5-bis((4-fluorophenyl)methylidene)-1-((1-hydroxy-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl)methyl)piperidin-4-one)
  • LIF protein, human
  • Leukemia Inhibitory Factor
  • Piperidones
  • RNA, Small Interfering
  • STAT3 Transcription Factor
  • STAT3 protein, human