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ORAOV1-B Promotes OSCC Metastasis via the NF-κB-TNFα Loop.

X Luo1, Y Jiang1, F Chen1,2

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A novel long noncoding RNA, ORAOV1-B, promotes oral cancer metastasis by stabilizing Hsp90 and activating the NF-κB-TNFα pathway. This discovery offers a potential new target for oral squamous cell carcinoma (OSCC) treatment.

Keywords:
RNAalternative splicingepithelial-mesenchymal transitionlong noncodingmolecular chaperones

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Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Metastasis is a key indicator of poor prognosis in oral squamous cell carcinoma (OSCC).
  • Understanding the regulators of OSCC metastasis is crucial for developing effective treatment strategies.
  • Long noncoding RNAs (lncRNAs) are emerging as significant modulators of cancer metastasis, but their specific roles in OSCC require further elucidation.

Purpose of the Study:

  • To identify and characterize novel regulators of OSCC metastasis.
  • To investigate the role of a newly identified lncRNA, ORAOV1-B, in OSCC invasion and migration.
  • To elucidate the molecular mechanisms by which ORAOV1-B promotes OSCC metastasis.

Main Methods:

  • Identification and validation of ORAOV1-B as an alternative splice variant of ORAOV1.
  • Assessment of OSCC cell invasion and migration in vitro.
  • RNA pulldown assays and mass spectrometry to identify direct binding targets of ORAOV1-B.
  • Analysis of the NF-κB pathway activation and downstream targets, including TNFα.
  • In vivo studies using orthotopic and metastatic models to evaluate ORAOV1-B's role in metastasis.

Main Results:

  • ORAOV1-B was identified as a novel lncRNA correlated with OSCC lymph node metastasis.
  • Overexpression of ORAOV1-B significantly increased OSCC cell invasion and migration.
  • ORAOV1-B directly binds to and stabilizes Hsp90, activating the NF-κB pathway and inducing TNFα.
  • TNFα was essential for ORAOV1-B-mediated metastatic ability, enhancing epithelial-mesenchymal transition.
  • ORAOV1-B significantly promoted lung metastasis in vivo.

Conclusions:

  • The novel lncRNA ORAOV1-B potentiates OSCC invasion and metastasis by interacting with Hsp90 and activating the NF-κB-TNFα signaling loop.
  • ORAOV1-B represents a potential therapeutic target for intervention in OSCC metastasis.
  • These findings highlight the significance of the 11q13 gene locus and the ORAOV1 family in OSCC progression.