RACK1 promotes the invasive activities and lymph node metastasis of cervical cancer via galectin-1

Cancer Lett. 2020 Jan 28:469:287-300. doi: 10.1016/j.canlet.2019.11.002. Epub 2019 Nov 6.

Abstract

Cervical cancer remains the first leading cause of cancer-related mortality among female reproductive system malignancies worldwide, and invasion and lymph node metastasis of cervical cancer represent the major reason for its poor prognosis. In this study, we found that RACK1 facilitated tumor cell invasion and lymphatic tube formation in vitro, as well as promoted lymphangiogenesis and lymph node metastasis in vivo in a galectin-1-dependent manner. Mechanism studies revealed that RACK1 promoted the expression and secretion of galectin-1 by reducing miR-1275 levels. Additionally, RACK1 also augmented galectin-1-induced downstream MEK/ERK, FAK, and AKT signaling via integrin-β1 in cervical cancer cells. Tissue microarray confirmed that RACK1 was upregulated in squamous intraepithelial lesion and cancer, and RACK1 was positively correlated with invasion/metastasis phenotype, galectin-1 expression, and unfavorable prognosis in cervical cancer cases. Human papillomavirus E6 oncogene contributes to increased expression of RACK1 via the enhancement of its O-GlcNAcylation and protein stability. Together, our results demonstrate that RACK1 stimulates tumor invasion and lymph node metastasis of cervical cancer via galectin-1 and imply that targeting RACK1/galectin-1 axis provides promising means for cervical cancer treatment.

Keywords: Human papillomavirus; Integrin-β1; Lymphangiogenesis; O-GlcNAcylation; miRNA-1275.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Female
  • Galectin 1 / genetics*
  • Humans
  • Lymph Nodes / metabolism
  • Lymph Nodes / pathology
  • Lymphangiogenesis / genetics
  • Lymphatic Metastasis / genetics*
  • Lymphatic Metastasis / pathology
  • Middle Aged
  • Neoplasm Invasiveness / genetics
  • Neoplasm Invasiveness / pathology
  • Neoplasm Proteins / genetics*
  • Prognosis
  • Receptors for Activated C Kinase / genetics*
  • Signal Transduction / genetics
  • Uterine Cervical Neoplasms / genetics*
  • Uterine Cervical Neoplasms / pathology

Substances

  • Galectin 1
  • Neoplasm Proteins
  • RACK1 protein, human
  • Receptors for Activated C Kinase