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Nischarin expression may have differing roles in male and female melanoma patients

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Abstract

Due to the development of resistance to previously effective therapies, there is a constant need for novel treatment modalities for metastatic melanoma. Nischarin (NISCH) is a druggable scaffolding protein reported as a tumor suppressor and a positive prognostic marker in breast and ovarian cancers through regulation of cancer cell survival, motility and invasion. The aim of this study was to examine the expression and potential role of nischarin in melanoma. We found that nischarin expression was decreased in melanoma tissues compared to the uninvolved skin, and this was attributed to the presence of microdeletions and hyper-methylation of the NISCH promoter in the tumor tissue. In addition to the previously reported cytoplasmic and membranous localization, we observed nischarin in the nuclei in melanoma patients’ tissues. NISCH expression in primary melanoma had favorable prognostic value for female patients, but, unexpectedly, high NISCH expression predicted worse prognosis for males. Gene set enrichment analysis suggested significant sex-related disparities in predicted association of NISCH with several signaling pathways, as well as with different tumor immune infiltrate composition in male and female patients. Taken together, our results imply that nischarin may have a role in melanoma progression, but that fine-tuning of the pathways it regulates is sex-dependent.

Key messages

  • Nischarin is a tumor suppressor whose role has not been investigated in melanoma.

  • Nischarin expression was downregulated in melanoma tissue compared to the normal skin.

  • Nischarin had the opposite prognostic value in male and female melanoma patients.

  • Nischarin association with signaling pathways differed in females and males. Our findings challenge the current view of nischarin as a universal tumor suppressor.

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Availability of data and materials

The datasets analyzed during the current study are available at the following web links: (1) NCBI GEO repository: GSE3189, GSE46517, GSE86355; (2) Broad Institute GDAC Firehose; (3) cBioPortal: TCGA SKCM, DFCI dataset; (4) The Human Protein Atlas: skin, melanoma samples; (5) Mexpress.

Abbreviations

ACTB:

Beta actin

CNA:

Copy-number alteration

DFCI:

Dana-Farber Cancer Institute

FDA:

Food and Drug Administration

FDR:

False discovery rate

FFPE:

Formalin-fixed and paraffin-embedded

GEO:

Gene Expression Omnibus

GSEA:

Gene set enrichment analysis

H&E :

Hematoxylin and eosin

HPA:

Human Protein Atlas

IORS:

Institute for Oncology and Radiology of Serbia

IR1:

Imidazoline receptor 1

IRAS:

Imidazoline receptor antisera selected

LRR:

Leucine-rich repeat

LOH:

Loss of heterozygosity

MSP:

Methylation specific PCR

NCBI:

National Center for Biotechnology Information

NER:

Nucleotide excision repair

NES:

Normalized enrichment score

NISCH:

Nischarin

SKCM:

Skin cutaneous melanoma

TCA:

Tricarboxylic acid

TCGA:

The Cancer Genome Atlas

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Acknowledgements

The results shown here are in part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga.

Funding

This study was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia (Agreement No. 451-03-68/2022-14/200043 and 451-03-68/2022-14/200015). JG is supported by Horizon 2020 MSC grant agreement No. 891135.

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Author notes

  1. Marija Ostojić and Marko Jevrić contributed equally to this work.

Authors and Affiliations

  1. Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, Belgrade, 11000, Serbia

    Marija Ostojić, Kristina Živić, Miljana Tanić, Milena Čavić, Tatjana Srdić-Rajić & Jelena Grahovac

  2. Department of Surgery, Institute for Oncology and Radiology of Serbia, Pasterova 14, Belgrade, 11000, Serbia

    Marko Jevrić

  3. Department of Molecular Oncology, Institute for Medical Research, Dr Subotića 4, Belgrade, 11000, Serbia

    Olivera Mitrović-Ajtić

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  1. Marija Ostojić
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Contributions

Marija Ostojić, Marko Jevrić, Tatjana Srdić-Rajić and Jelena Grahovac contributed to the study conception and design. Material preparation, data collection and analysis were performed by Marija Ostojić, Marko Jevrić, Olivera Mitrović-Ajtić, Kristina Živić, Miljana Tanić, Milena Čavić, and Jelena Grahovac. Tatjana Srdić-Rajić and Jelena Grahovac secured the acquisition of funds for the study. The first draft of the manuscript was written by Marija Ostojić and Jelena Grahovac, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Tatjana Srdić-Rajić or Jelena Grahovac.

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The study was approved by the Ethics Committee of the Institute for Oncology and Radiology of Serbia (Approval No5549-01, from 11.12.2017) and was performed in accordance with the Helsinki Declaration of 1975, as revised in 2013.

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Ostojić, M., Jevrić, M., Mitrović-Ajtić, O. et al. Nischarin expression may have differing roles in male and female melanoma patients. J Mol Med 101, 1001–1014 (2023). https://doi.org/10.1007/s00109-023-02339-y

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