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Stathmin 1 is highly expressed and associated with survival outcome in malignant adrenocortical tumours

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Adrenocortical carcinoma (ACC) is an aggressive endocrine cancer with few molecular predictors of malignancy and survival, especially in paediatric patients. Stathmin 1 (STMN1) regulates microtubule dynamics and has been involved in the malignant phenotype of cancer cells. Recently, it was reported that STMN1 is highly expressed in ACC patients, and STMN1 silencing reduces the clonogenicity and migration of ACC cell lines. However, the prognostic significance of STMN1 and its therapeutic potential remain undefined in ACC. In the present study, STMN1 mRNA levels were significantly higher (p < 0.05) in ACC patients, especially in an advanced stage, and correlated with BUB1B and PINK1 expression, the prognostic-related genes in ACC. In paediatric tumours, high STMN1 expression was observed in both adrenocortical carcinoma and adrenocortical adenoma patients. Among the adult malignant tumours, STMN1 level was an independent predictor of survival outcomes (overall survival: hazard ratio = 6.08, p = 0.002; disease-free survival: hazard ratio = 4.65, p < 0.0001). Paclitaxel, a microtubule-stabilizing drug, reduces the activation of STMN1 and significantly decreases cell migration and invasion in ACC cell lines and ACC cells from secondary cell culture (all p < 0.0001). In summary, STMN1 expression may be of great value to clinical and pathological findings in therapeutic trials and deserves future studies in ACC.

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Abbreviations

ACA:

Adrenocortical adenomas

ACC:

Adrenocortical carcinoma

BUB1B:

Budding uninhibited by benzimidazoles 1 homologue beta

FBS:

Foetal bovine serum

MTT:

Methylthiazoletetrazolium

PINK:

PTEN induced kinase 1

qPCR:

Quantitative PCR

STMN1:

Stathmin 1

TCGA:

The Cancer Genome Atlas.

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Acknowledgements

We are grateful to Cintia Fridman, Department of Legal Medicine and Medical Ethics, School of Medicine, University of São Paulo, for STR DNA profiling analysis in cell cultures. The authors would like to acknowledge all the research participants contributing to The Cancer Genome Atlas (TCGA) resource for providing high-quality data for analyses.

Funding

BSP and JLK are recipients of a scholarship from FAPESP (n° 2016/12381–7 / n° 2016/17285–6), the São Paulo State Research Foundation (FAPESP); BBC is the recipient of a scholarship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES); JAM-N received funding from FAPESP (n° 2017/24993–0) and from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); CFPL received funding from FAPESP (n° 2015/014199–9; 2018/19035–2) and from CNPq. This study was financed in part by CAPES- Finance Code 001.

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Author notes

  1. João Agostinho Machado-Neto and Claudimara Ferini Pacicco Lotfi contributed equally to this work.

Authors and Affiliations

  1. Department of Anatomy, Institute of Biomedical Science, University of São Paulo, Av. Prof. Lineu Prestes, 2415, São Paulo, SP, 05508-000, Brazil

    Bárbara dos Santos Passaia, Jean Lucas Kremer, Barbara Brito da Conceição & Claudimara Ferini Pacicco Lotfi

  2. Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil

    Keli Lima, Jean Carlos Lipreri da Silva & João Agostinho Machado-Neto

  3. Adrenal Unit, Hormone and Molecular Genetic Laboratory/LIM42, Hospital of Clinics, School of Medicine, University of São Paulo, São Paulo, Brazil

    Beatriz Marinho de Paula Mariani & Maria Candida Barisson Villares Fragoso

  4. Division of Anatomy Pathology, Laboratory of Liver Pathology/LIM14, Hospital of Clinics, School of Medicine, University of São Paulo, São Paulo, Brazil

    Maria Claudia Nogueira Zerbini

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  1. Bárbara dos Santos Passaia
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Contributions

BSP, KL, JLK, and BBC performed the experiments, data analysis and interpretation, and manuscript editing. BMPM processed patient samples and performed manuscript editing. JCLS performed multivariate statistical analysis, data interpretation, and manuscript editing. MCBVF provided the patient samples and clinical follow-up and performed manuscript editing. MCZ selected the patients and performed manuscript editing; JAMN and CFPL idealized the study, analysed the data and wrote the manuscript.

Corresponding author

Correspondence to Claudimara Ferini Pacicco Lotfi.

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Informed consent was obtained from all individual participants included in the study prior to sample collection, and the study was approved by the Institutional Review Board.

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The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

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Supplementary Figure 1

HighSTMN1expression negatively impacts disease-free survival in adrenocortical patients from the TCGA cohort. Kaplan–Meier analysis of disease-free survival according to STMN1 mRNA levels in the TCGA ACC cohort. Patients were dichotomized according to median gene expression for survival analysis. The p-values are indicated by the log-rank test. (PDF 91 kb)

Supplementary Figure 2

Representative images of STMN1 expression in carcinoma and adenoma secondary cell cultures and cell lines. Immunoperoxidase analysis of STMN1 expression in secondary cell culture from adrenocortical carcinoma ACC-T12 and adenoma ACA-T23 cells and the NCI-H295R cell line. Magnification 100x (upper) and 400x (above). (PDF 208 kb)

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dos Santos Passaia, B., Lima, K., Kremer, J.L. et al. Stathmin 1 is highly expressed and associated with survival outcome in malignant adrenocortical tumours. Invest New Drugs 38, 899–908 (2020). https://doi.org/10.1007/s10637-019-00846-9

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