LncCCLM inhibits lymphatic metastasis of cervical cancer by promoting STAU1-mediated IGF-1 mRNA degradation

Cancer Lett. 2021 Oct 10:518:169-179. doi: 10.1016/j.canlet.2021.07.005. Epub 2021 Jul 14.

Abstract

Cervical cancer (CC) patients with lymph node (LN) metastasis often have an extremely poor prognosis. However, the precise molecular mechanisms involved in LN metastasis of CC remain largely unknown. Herein, through RNA screening, we identified a novel long noncoding RNA (lncRNA), LncCCLM, that was downregulated in cervical cancer tissues and closely associated with lymphatic metastasis in cervical cancer patients. Gain-of-function and loss-of-function studies in CC cells demonstrated that LncCCLM inhibited cervical cancer-associated lymphangiogenesis, and CC cell migration and invasion in vitro and suppressed LN metastasis in vivo, but did not affect the growth of CC cells. Mechanistically, LncCCLM localized in the cytoplasm and interacted with staufen double-stranded RNA binding protein 1 (STAU1), promoting the binding of the STAU1 protein to the 3' untranslated region (3'UTR) of insulin-like growth factor 1 (IGF-1) mRNA, which accelerated the degradation of IGF-1 mRNA and decreased the IGF-1 protein level, ultimately reducing lymphangiogenesis and lymphatic metastasis in cervical cancer. Collectively, our findings suggest that LncCCLM acts as a tumor suppressor and may be used as a prognostic biomarker and therapeutic target for clinical intervention in LN-metastatic cervical cancer.

Keywords: Lymphangiogenesis; RNA-Binding protein; STAU1-Mediated mRNA degradation; lncRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers, Tumor / genetics
  • Cell Line
  • Cell Line, Tumor
  • Cytoskeletal Proteins / genetics*
  • Female
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Insulin-Like Growth Factor I / genetics*
  • Lymphangiogenesis / genetics
  • Lymphatic Metastasis / genetics*
  • Lymphatic Metastasis / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Prognosis
  • RNA Stability / genetics
  • RNA, Long Noncoding / genetics*
  • RNA, Messenger / genetics*
  • RNA-Binding Proteins / genetics*
  • Uterine Cervical Neoplasms / genetics*
  • Uterine Cervical Neoplasms / pathology

Substances

  • Biomarkers, Tumor
  • Cytoskeletal Proteins
  • IGF1 protein, human
  • RNA, Long Noncoding
  • RNA, Messenger
  • RNA-Binding Proteins
  • STAU1 protein, human
  • Insulin-Like Growth Factor I