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Ryanodine receptor 2 promotes colorectal cancer metastasis by the ROS/BACH1 axis

Tianwei Chen1, Xilin Zhang2, Xufen Ding3

  • 1Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Molecular Oncology
|December 1, 2022
PubMed

Insights

Targeting ryanodine receptor 2 (RyR2) may treat KRAS-mutant metastatic colorectal cancer (mCRC). Upregulated RyR2 promotes metastasis via the RyR2/ROS/BACH1 axis, and inhibiting RyR2 with S107 shows therapeutic potential.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metastasis

Background:

  • KRAS-mutant metastatic colorectal cancer (mCRC) lacks targeted therapies due to obscure mechanisms.
  • Identifying novel therapeutic targets is crucial for improving patient outcomes in mCRC.

Purpose of the Study:

  • To identify a druggable gene target for KRAS-mutant mCRC.
  • To elucidate the functional role and mechanism of the candidate gene in cancer metastasis.
  • To evaluate the therapeutic potential of targeting the identified pathway.

Main Methods:

  • Bioinformatic analysis to identify candidate genes.
  • In vitro and in vivo experiments to assess cancer cell metastasis.
  • RyR2 knockdown and inhibition studies to analyze molecular mechanisms.
  • Analysis of patient cohorts to correlate gene expression with survival and clinical features.

Main Results:

  • Ryanodine receptor 2 (RyR2) expression is upregulated in KRAS-mutant mCRC and promotes metastasis.
  • The drug S107 inhibits RyR2-mediated cancer cell metastasis in vitro and in vivo.
  • High RyR2 expression correlates with poor survival and advanced disease features (serosa invasion, vascular tumor thrombus).
  • RyR2 regulates the RyR2/ROS/BACH1 axis, involving reactive oxygen species (ROS) and transcription factors Nrf2 and BACH1.

Conclusions:

  • The RyR2/ROS/BACH1 axis represents a potential therapeutic target for KRAS-mutant mCRC.
  • Inhibiting RyR2 with S107 demonstrates promise for treating metastatic colorectal cancer.
Keywords:
ROSRyR2colorectal cancermetastasis

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