m6A-modified circSTX6 as a key regulator of cervical cancer malignancy via SPI1 and IL6/JAK2/STAT3 pathways

Oncogene. 2025 Apr;44(14):968-982. doi: 10.1038/s41388-024-03260-5. Epub 2025 Jan 15.

Abstract

In recent years, circRNAs have garnered increasing attention for their role in cervical cancer. However, the functions of many newly identified circRNAs remain unclear and require further exploration. In this study, we investigated the expression and oncogenic potential of the novel circRNA circSTX6 in cervical cancer. Our findings revealed that circSTX6 is highly expressed in cervical cancer (CC) and is significantly associated with poor patient prognosis, promoting cell survival, proliferation, invasion, and migration. Mechanistically, circSTX6 enhances the stability of the transcription factor SPI1 by binding to it, thereby upregulating IL6 transcription and activating the JAK2/STAT3 signaling pathway. Additionally, METTL3-mediated N6-methyladenosine (m6A) modification stabilizes circSTX6 through recognition by YTHDC1, forming a positive feedback regulatory loop among METTL3, circSTX6, and SPI1. These findings not only deepen our understanding of the biological mechanisms underlying CC but also highlight circSTX6 as a potential target for molecular therapies.

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / metabolism
  • Animals
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Interleukin-6* / genetics
  • Interleukin-6* / metabolism
  • Janus Kinase 2 / genetics
  • Janus Kinase 2 / metabolism
  • Methyltransferases / genetics
  • Methyltransferases / metabolism
  • Mice
  • Prognosis
  • Proto-Oncogene Proteins c-ets* / genetics
  • Proto-Oncogene Proteins c-ets* / metabolism
  • RNA, Circular* / genetics
  • RNA, Circular* / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / genetics
  • Uterine Cervical Neoplasms* / genetics
  • Uterine Cervical Neoplasms* / metabolism
  • Uterine Cervical Neoplasms* / pathology

Substances

  • STAT3 Transcription Factor
  • RNA, Circular
  • Interleukin-6
  • STAT3 protein, human
  • JAK2 protein, human
  • Janus Kinase 2
  • N-methyladenosine
  • IL6 protein, human
  • Adenosine
  • METTL3 protein, human
  • Methyltransferases
  • Proto-Oncogene Proteins c-ets