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Autophagy and nuclear morphometry are associated with histopathologic features in esophageal squamous cell carcinoma

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Abstract

Less than 15% of patients with esophageal squamous cell carcinoma (ESCC) survive 5 years after diagnosis. A better understanding of the biology of these tumors and the development of clinical biomarkers is needed. Autophagy is a physiological mechanism involved in the turnover of cellular components that plays a key role in cancer. This study evaluated the differential levels of three key regulators of autophagy (SQSTM1, MAP1LC3B, and BECN1) in patients with ESCC, associating autophagy with histopathologic features, including the grade of differentiation, mitotic rate, inflammation score, and the intensity of tumor-infiltrating lymphocytes. Nuclear morphometry of the tumor parenchyma was also assessed, associating it with autophagy and histopathology. All three markers significantly increased in patients with ESCC compared to the control group. Based on the mean expression of each protein in the control group, 57% of patients with ESCC had high levels of all three markers compared to control patients (14%). The most frequent profiles found in ESCC were BECNhigh/MAP1LC3high and BECNhigh/SQSTM1high. According to the TCGA database, we found that the main autophagy genes were upregulated in ESCC. Moreover, high levels of autophagy markers were associated with a poor prognosis. Considering nuclear morphometry, ESCC samples showed a significant reduction in nuclear area, which was strongly negatively correlated with autophagy. Finally, the percentage of normal nuclei was associated with tumor differentiation, while poorly differentiated tumors showed lower SQSTM1 levels. ESCC progression may involve increased autophagy and changes in nuclear structure, associated with clinically relevant histopathological features.

Key messages

  • Autophagy markers are co-increased in primary ESCC.

  • Autophagy negatively correlates with nuclear morphometry in ESCC parenchyma.

  • Autophagy and nuclear morphometry are associated with histopathological features.

  • Autophagy is increased in ESCC-TCGA database and associated with poor prognosis.

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Data availability

Immunohistochemistry generated in this study is not publicly available due to ethical privacy, but can be obtained from the corresponding author upon reasonable request.

Abbreviations

AutoIndex:

Autophagic Index

ATG:

Autophagy genes or proteins

BECN1:

Beclin-1

ESCC:

Esophageal squamous cell carcinoma

EC:

Esophageal carcinoma

MAP1LC3A/B/C (LC3A/B/C):

Microtubule-associated protein 1 light chain 3 (isoforms A, B, and C)

NMA:

Nuclear morphometric analysis

tNMA:

Nuclear morphometric analysis in tissue

NII:

Nuclear irregularity index

N nuclei:

Normal nuclei

OST:

Overall survival time

SQSTM1:

Sequestosome 1

SR nuclei:

Small and regular nuclei

TCGA:

The Cancer Genome Atlas

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Acknowledgements

We thank the Research and Event Incentive Fund (FIPE) of the Hospital de Clínicas of Porto Alegre (HCPA) for funding this study and the statistical analysis service of the Hospital de Clínicas de Porto Alegre for helping with the project.

Funding

This study was funded by the Research and Event Incentive Fund (FIPE) of the Hospital de Clínicas of Porto Alegre (HCPA), project no. 16–0233.

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Authors and Affiliations

  1. Graduate Program in Gastroenterology and Hepatology, Faculty of Medical Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil

    Ricardo Iserhard, Antonio Barros Lopes, Patrícia Luciana da Costa Lopez & Eduardo Cremonese Filippi-Chiela

  2. Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil

    Emily Ferreira Salles Pilar, Francine Hehn de Oliveira, Paula Ferst, Fernanda Visioli, Antonio Barros Lopes, Patrícia Luciana da Costa Lopez & Eduardo Cremonese Filippi-Chiela

  3. Department of Genetics, UFRGS, Porto Alegre, Rio Grande do Sul, Brazil

    Sidia Maria Callegari-Jacques

  4. Graduate Program in Dentistry, School of Dental Sciences, UFRGS, Porto Alegre, Rio Grande do Sul, Brazil

    Fernanda Visioli

  5. Center for Biotechnology, UFRGS, Porto Alegre, Rio Grande do Sul, Brazil

    Eduardo Cremonese Filippi-Chiela

  6. Department of Morphological Sciences, UFRGS, Porto Alegre, Rio Grande do Sul, Brazil

    Eduardo Cremonese Filippi-Chiela

  7. Hospital de Clínicas de Porto Alegre - Experimental Research Center, Rua Ramiro Barcelos, Porto Alegre, RS, 2350, 90035-903, Brazil

    Eduardo Cremonese Filippi-Chiela

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  1. Ricardo Iserhard
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Contributions

RI, EFSP, and ECFC contributed to the study conception and design. RI, PF, PLDCL, and SMCJ performed material preparation and data collection and analysis. FH and FV performed histopathological analysis. RI and ECFC wrote the first draft of the manuscript, and all authors commented on previous versions of the article. ADBL reviewed and tabulated patients’ medical records in the Hospital de Clínicas de Porto Alegre system and also reviewed the manuscript. All authors read and approved the final version.

Corresponding author

Correspondence to Eduardo Cremonese Filippi-Chiela.

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Ethics approval and consent to participate

All procedures performed in this study, from sample recruitment and use, as well as access to clinical information were approved by the Ethical Committee of the Hospital de Clinicas de Porto Alegre under the Certificate of Presentation for Ethical Appreciation (CAAE): 57102216.0.0000.5327. The risk of breach of confidentiality was controlled by signing the term of responsibility for the use of biological material, in which the researchers undertake not to use references that identify the study patients.

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Iserhard, R., Pilar, E.F.S., de Oliveira, F.H. et al. Autophagy and nuclear morphometry are associated with histopathologic features in esophageal squamous cell carcinoma. J Mol Med 102, 39–52 (2024). https://doi.org/10.1007/s00109-023-02387-4

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