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Focused cancer pathway analysis revealed unique therapeutic targets in retinoblastoma

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Abstract

Retinoblastoma (RB) is a pediatric cancer of the eye that occurs in 1/15000 live births worldwide. Albeit RB is initiated by the inactivation of RB1 gene, the disease progression relies largely on transcriptional alterations. Therefore, evaluating gene expression is vital to unveil the therapeutic targets in RB management. In this study, we employed an RT2 Profiler™ PCR array for a focused analysis of 84 cancer-specific genes in RB. An interaction network was built with gene expression data to identify the dysregulated pathways in RB. The key transcript alterations identified in 13 tumors by RT2 Profiler™ PCR array was further validated in 15 tumors by independent RT-qPCR. Out of 84 cancer-specific genes, 68 were dysregulated in RB tumors. Among the 68 genes, 23 were chosen for further analysis based on statistical significance and abundance across multiple tumors. Pathway analysis of altered genes showed the frequent perturbations of cell cycle, angiogenesis and apoptotic pathways in RB. Notably, upregulation of MCM2, MKI67, PGF, WEE1, CDC20 and downregulation of COX5A were found in all the tumors. Western blot confirmed the dysregulation of identified targets at protein levels as well. These alterations were more prominent in invasive RB, correlating with the disease pathogenesis. Our molecular analysis thus identified the potential therapeutic targets for improving retinoblastoma treatment. We also suggest that PCR array can be used as a tool for rapid and cost-effective gene expression analysis.

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The datasets generated during and/or analyzed during the current study are available from the corresponding author on request.

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Acknowledgements

We acknowledge all the RB patients and parents for their participation in this study. We duly acknowledge Senior Research fellowship for Rathinavel Sethu Nagarajan (2021-13793/SCR-BMS) from Indian Council for Medical Research and Junior and Senior Research Scholarship for Karuvel Kannan Saraswathi from Lady Tata Memorial Trust.

Funding

This work was supported by Science and Engineering Research Board, Department of Science and Technology, Government of India (EMR/2017/000285).

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Author notes

  1. Sekaran Balaji and Anindita Rao have contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Genetics, Aravind Medical Research Foundation, 1, Anna Nagar, Madurai, Tamil Nadu, 625 020, India

    Sekaran Balaji, Anindita Rao, Karuvel Kannan Saraswathi, Rathinavel Sethu Nagarajan & Ayyasamy Vanniarajan

  2. Department of Pathology, Aravind Eye Hospital, Madurai, Tamil Nadu, 625 020, India

    Radhakrishnan Santhi

  3. Department of Orbit, Oculoplasty and Ocular Oncology, Aravind Eye Hospital, Madurai, Tamil Nadu, 625 020, India

    Usha Kim

  4. Department of Immunology and Stem Cell Biology, Aravind Medical Research Foundation, Madurai, Tamil Nadu, 625 020, India

    Veerappan Muthukkaruppan

  5. Department of Molecular Biology, Aravind Medical Research Foundation - Affiliated to Alagappa University, Karaikudi, Tamil Nadu, 630003, India

    Karuvel Kannan Saraswathi, Rathinavel Sethu Nagarajan & Ayyasamy Vanniarajan

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  1. Sekaran Balaji
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Contributions

AV, UK and VM conceptualized the study. SB, AR, KKS, RSN and RS performed data curation and analysis. SB, AR, KKS, RSN and AV have written the manuscript. All the authors reviewed and accepted the final version of the manuscript.

Corresponding author

Correspondence to Ayyasamy Vanniarajan.

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We declared that none of the authors has financial and personal competing interests.

Ethical approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the Institutional Review Board of Aravind Medical Research Foundation (IRB2017009BAS).

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All tumor samples were collected with the informed consent from patient/family.

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Balaji, S., Rao, A., Saraswathi, K.K. et al. Focused cancer pathway analysis revealed unique therapeutic targets in retinoblastoma. Med Oncol 41, 168 (2024). https://doi.org/10.1007/s12032-024-02391-9

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