ITPR1-AS1 promotes small cell lung cancer metastasis by facilitating P21HRAS splicing and stabilizing DDX3X to activate the cRaf-MEK-ERK cascade

Cancer Lett. 2023 Nov 28:577:216426. doi: 10.1016/j.canlet.2023.216426. Epub 2023 Oct 9.

Abstract

The mechanisms underlying the involvement of long non-coding RNAs (lncRNAs) in the metastasis of small cell lung cancer (SCLC) remain largely unknown. Here, we identified that the lncRNA ITPR1-AS1 was upregulated in SCLC and lymph node metastasis tissues and positively correlated with SCLC malignant features. The overexpression of ITPR1-AS1 in SCLC was an independent risk factor for the overall survival of patients with SCLC. Our data confirmed that ITPR1-AS1 induces SCLC cell metastasis both in vitro and in vivo. Mechanistically, ITPR1-AS1 acts as a scaffold to enhance the interaction between SRC-associated in mitosis 68 kDa and heterogeneous nuclear ribonucleoprotein A1, which facilitates the alternative splicing of the H-Ras proto-oncogene (HRAS) pre-mRNA (P21HRAS). Moreover, we observed that ITPR1-AS1 could associate in a complex with and maintain the stability of DEAD-box polypeptide 3 (DDX3X), which inhibited the latter's ubiquitination and degradation. Our data provide evidence that ITPR1-AS1 activates the cRaf-MEK-ERK cascade by upregulating P21HRAS production and stabilizing DDX3X, to promote SCLC metastasis.

Keywords: Alternative splicing; Long non-coding RNAs; Metastasis; Scaffold; Small cell lung cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation / genetics
  • DEAD-box RNA Helicases / genetics
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Inositol 1,4,5-Trisphosphate Receptors / genetics
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism
  • Lung Neoplasms* / metabolism
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Neoplasm Metastasis
  • Proto-Oncogene Proteins c-raf / metabolism
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • RNA, Long Noncoding* / genetics
  • Small Cell Lung Carcinoma* / genetics

Substances

  • DDX3X protein, human
  • DEAD-box RNA Helicases
  • HRAS protein, human
  • Inositol 1,4,5-Trisphosphate Receptors
  • ITPR1 protein, human
  • Mitogen-Activated Protein Kinase Kinases
  • Proto-Oncogene Proteins p21(ras)
  • RNA, Long Noncoding
  • Proto-Oncogene Proteins c-raf