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A Novel mRNA-Mediated and MicroRNA-Guided Approach to Specifically Eradicate Drug-Resistant Hepatocellular Carcinoma

Arun Kumar Selvam1, Rim Jawad1, Roberto Gramignoli1

  • 1Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Karolinska University Hospital, S-141 86 Stockholm, Sweden.

Antioxidants (Basel, Switzerland)
|August 6, 2021
PubMed

Insights

This study introduces a new treatment combining Se-methylselenocysteine (MSC) with tumor-specific Kynurenine aminotransferase 1 (KYAT1) induction for liver cancer. This approach enhances cancer cell killing while minimizing harm to healthy cells.

Area of Science:

  • Oncology
  • Hepatocellular Carcinoma Research
  • Drug Development

Background:

  • Visceral organ malignancies, including hepatocellular carcinoma (HCC), have a poor prognosis despite advances in treating other cancers.
  • Novel therapeutic strategies are essential for improving outcomes in patients with liver cancer.

Purpose of the Study:

  • To evaluate a novel therapeutic regimen for hepatocellular carcinoma (HCC) involving Se-methylselenocysteine (MSC) and tumor-specific Kynurenine aminotransferase 1 (KYAT1) induction.
  • To investigate methods for enhancing the specificity and efficacy of this treatment, minimizing off-target effects.

Main Methods:

  • Utilized vector-based and lipid nanoparticle-mediated mRNA delivery to induce KYAT1 expression in HCC cell lines.
  • Administered Se-methylselenocysteine (MSC) to KYAT1-overexpressing cells and assessed cytotoxicity, reactive oxygen species (ROS) formation, and off-target effects.
  • Incorporated microRNA (miR122) antisense-targeted sites to restrict cytotoxicity to HCC cells.
  • Investigated the role of alpha-ketoacid in enhancing MSC efficacy.

Main Results:

  • Co-treatment with MSC and KYAT1 overexpression significantly increased cytotoxicity in HCC cells via ROS generation compared to MSC alone.
  • The inclusion of miR122-targeted sites effectively limited cytotoxicity in HCC cells, demonstrating tumor-specific targeting.
  • High miR122 levels reduced KYAT1 expression, supporting miR-guided induction of cytotoxicity.
  • Alpha-ketoacid addition enhanced MSC's cytotoxic effect in HCC cells without impacting primary human hepatocytes.

Conclusions:

  • The proposed therapeutic regimen, combining MSC with KYAT1 induction and miR122-mediated targeting, shows significant potential for specifically and safely targeting liver tumors.
  • This approach offers a promising new strategy for treating currently untreatable hepatic tumors.
Keywords:
Se-methylselenocysteinealpha-keto acidhepatocellular carcinomakynurenine aminotransferases 1lipid nanoparticlemiRNA

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