Proteins Lamin A and SUN1 are exclusively decreased in nuclear grade 4 clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) nuclear grade is associated with patient prognosis. Currently, the World Health Organization (WHO)/International Society of Urologic Pathologists (ISUP) grading system is used to evaluate nuclear and cellular morphology. The present study aimed to investigate the relationship between nuclear envelope-associated protein expression and nuclear grade. A total of 199 patients diagnosed with ccRCC were included in the study. Following immunohistochemical staining for Lamin A, Lamin B1, Lamin B2, Emerin, SUN1, SUN2, Nesprin-1, Nesprin-2 and Nesprin-3, their expression levels were evaluated. Comparing the nuclear grade with the mean nuclear area and perimeter revealed a significant increase across each grade from G1 to G3. However, the difference between G3 and G4 was not significant, indicating that nuclear morphology in G4 may be influenced by another factor. Comparison of Lamin expression across nuclear grades showed that only Lamin A was significantly decreased in G4 cases. Furthermore, the positive rates of Lamin B1 and Lamin B2, as well as nuclear grade, did not differ significantly between the grades. Next, the association between changes in Emerin, SUN and Nesprin expression and nuclear grade was examined; notably, only SUN1 showed significant changes in G4, whereas no significant differences were observed between nuclear grade and the other proteins. Therefore, reduced Lamin A and SUN1 expression may cause morphological changes in the nucleus and cells, leading to a shift toward G4. The total volumes of the nucleus and nucleoli showed an isometric relationship. Thus, evaluating the nucleolus using nuclear grade classification in G1-G3 ccRCC is essentially equivalent to evaluating the size of the nucleus. In conclusion, in the WHO/ISUP grading system, G1, G2 and G3 rely solely on nucleolar size as an indicator. However, in G4, both nuclear and cell morphology may be considered as indicators, since changes in nuclear envelope-associated proteins were only detected in this grade.