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Updated: May 26, 2025
Author Spotlight: Unveiling the Role of TMOD3 in Platinum Resistance and Immune Infiltration in Ovarian Cancer
Published on: August 2, 2024
Bioinformatics-driven Identification of lncRNA LINC02381 in Mediating Cisplatin Resistance via IL-12 Induced Wnt/TCF7
Zeinab Karbalaei Pazoki1, Mostafa Hosseini2, Shiva Irani3
1Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran. zkarbalaeip@gmail.com.
Abstract:
Cisplatin resistance presents a considerable hurdle in the treatment of ovarian cancer, significantly impacting patient outcomes and limiting the effectiveness of chemotherapy. This study employs advanced bioinformatics techniques-including RNA sequencing (RNA-seq), DNA sequencing (DNA-seq), and chromatin immunoprecipitation sequencing (ChIP-seq)-to elucidate the molecular mechanisms underlying this resistance, with a particular focus on the long non-coding RNA (lncRNA) LINC02381. Our findings reveal that LINC02381 is significantly upregulated in ovarian cancer cells exhibiting resistance to cisplatin, suggesting its pivotal role in mediating this phenomenon. We further demonstrate that cytokines, particularly interleukin-12 (IL-12), secreted by immune cells within the tumor microenvironment, activate the Wnt signaling pathway. This activation leads to the binding of the transcription factor TCF7 to the promoter region of LINC02381, resulting in enhanced expression of this lncRNA. Notably, this interaction establishes a positive feedback loop in which LINC02381 not only promotes its own expression but also amplifies Wnt signaling activity. This cascade ultimately drives the upregulation of ATP-binding cassette (ABC) transporters, which are crucial for the efflux of cisplatin from cancer cells. Thus, the drug's intracellular concentration is reduced, and cell survival under chemotherapy pressure is facilitated. These insights uncover a novel mechanism of cisplatin resistance driven by the IL-12/Wnt/TCF7/LINC02381 axis, highlighting the complex interplay between immune signaling and drug resistance in ovarian cancer. Our findings suggest that targeting this regulatory pathway may offer promising therapeutic strategies to overcome chemotherapy resistance, paving the way for improved treatment outcomes in patients with ovarian cancer. Future research should focus on validating these mechanisms and exploring potential interventions that disrupt this feedback loop.
Insights
A novel mechanism of cisplatin resistance in ovarian cancer involves the long non-coding RNA LINC02381, activated by immune signaling (interleukin-12) and Wnt pathway. This pathway promotes drug efflux, reducing chemotherapy effectiveness.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Cisplatin resistance is a major challenge in ovarian cancer treatment.
- Understanding the molecular basis of this resistance is crucial for developing effective therapies.
Purpose of the Study:
- To elucidate the molecular mechanisms of cisplatin resistance in ovarian cancer.
- To investigate the role of long non-coding RNA LINC02381 in this process.
Main Methods:
- RNA sequencing (RNA-seq), DNA sequencing (DNA-seq), and chromatin immunoprecipitation sequencing (ChIP-seq) were employed.
- Bioinformatic analyses were used to identify key regulatory pathways and molecules.
Main Results:
- LINC02381 is significantly upregulated in cisplatin-resistant ovarian cancer cells.
- Interleukin-12 (IL-12) activates the Wnt signaling pathway, leading to TCF7 binding and increased LINC02381 expression.
- This creates a positive feedback loop that upregulates ATP-binding cassette (ABC) transporters, causing cisplatin efflux and resistance.
Conclusions:
- A novel IL-12/Wnt/TCF7/LINC02381 axis drives cisplatin resistance in ovarian cancer.
- Targeting this pathway presents a potential therapeutic strategy to overcome chemoresistance.
