Metallothioneins and Megalin Expression Profiling in Premalignant and Malignant Oral Squamous Epithelial Lesions
1
Department of Oral Surgery, Clinical Hospital Center Rijeka, Krešimirova ul. 40, 51000 Rijeka, Croatia
2
Department of Pathology, Clinical Hospital Center Rijeka, Krešimirova ul. 42, 51000 Rijeka, Croatia
3
Faculty of Dental Medicine, University of Rijeka, Krešimirova ul. 40, 51000 Rijeka, Croatia
4
Department of Physiology and Immunology, Faculty of Medicine, University of Rijeka, Ul. Braće Branchetta 20, 51000 Rijeka, Croatia
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2021, 13(18), 4530; https://doi.org/10.3390/cancers13184530
Submission received: 16 June 2021
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Revised: 3 September 2021
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Accepted: 7 September 2021
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Published: 9 September 2021
(This article belongs to the Section Molecular Cancer Biology)
Simple Summary
Interactions of metallothioneins with the multiligand receptor megalin have been found to promote cell survival and proliferation after noxious stimuli in non-malignant tissues. However, the relationship between these proteins and their interaction remains to be addressed in malignancies and premalignant lesions. In this retrospective study, we compared the expression profiles of metallothioneins and megalin in different histological grades of oral squamous cell carcinoma, oral leukoplakia, and oral lichen planus. The data obtained show a gradual increase of both proteins concomitantly with the gaining of more malignant features, as well as their co-expression and direct interaction in carcinomatous tissue. The results point to the pro-oncogenic role of the metallothionein-megalin functional axis, which may impact tumor phenotype and behavior.
Abstract
This study aimed to assess the relationship and possible interactions between metallothioneins (MTs) and megalin (LRP-2) in different grades of oral squamous cell carcinoma (OSCC) and premalignant lesions of the oral mucosa (oral leukoplakia and oral lichen planus). The study included archived samples of 114 patients and control subjects. Protein expression was examined by immunohistochemistry and immunofluorescence, and staining quantification was performed by ImageJ software. Protein interaction in cancer tissue was tested and visualized by proximity ligation assay. Mann-Whitney and Kruskal-Wallis tests were used to determine the significance of differences between each group, whereas Pearson correlation coefficient was performed to test correlation. Expression of both proteins differed significantly between each group showing the same pattern of gradual increasing from oral lichen planus to poorly differentiated OSCC. Moreover, MTs and megalin were found to co-express and interact in cancer tissue, and their expression positively correlated within the overall study group. Findings of prominent nuclear and chromosomal megalin expression suggest that it undergoes regulated intramembrane proteolysis upon MTs binding, indicating its ability to directly affect gene expression and cellular division in cancer tissue. The data obtained point to the onco-driving potential of MTs-megalin interaction.
