Abstract
The relationship between autophagy and tumour is well studied, but tumour cell morphological changes associated with autophagy defects are rarely reported, especially in renal cell carcinoma (RCC). We collected 10 renal tumour samples with characteristic eosinophilic cytoplasmic inclusions (ECIs) and found that the ECIs were majorly composed of sequestosome 1/P62, neighbor of BRCA1 gene 1 (NBR1), PEX14, and CATALASE1 (CAT1). Further, transmission electron microscopy analysis revealed that ECIs were aggregates of proteinaceous material and peroxisomes. These results confirmed that ECIs in RCCs were the products of autophagy defects. The presence of ECIs was correlated with high Fuhrman grade components of RCCs. Whole-exome sequencing (WES) and Sanger sequencing confirmed that tumours with ECIs showed somatic mutations or high frequency of genetic variations in autophagy-related (ATG) genes, such as ATG7, ATG5, and ATG10. These results indicate that nucleotide changes in ATG genes are associated with autophagy defect, ECI formation, and even tumour grade in RCCs.
Highlights
Renal cell carcinoma (RCC) accounts for 2–3% of all malignant diseases in adults[1]
We investigated 10 rare cases of renal cell carcinoma (RCC) with characteristic eosinophilic cytoplasmic inclusions (ECIs) and found that the ATG proteins sequestosome 1/P62, neighbor of BRCA1 gene 1 (NBR1), beclin 1 (BECN1), autophagy-related gene 5 (ATG5) and LC3 are located in ECIs, and that peroxisomes are distributed within ECIs too
The GM130 protein and NBR1 co-existed in ECIs (Fig. 4J). These results indicate that the single membrane-bound electron-dense structures within the ECIs were peroxisomes, and that NBR1 present in ECIs mainly played a role in the recruitment of peroxisomes to the inclusion bodies
Summary
Renal cell carcinoma (RCC) accounts for 2–3% of all malignant diseases in adults[1]. RCCs with eosinophilic cytoplasmic inclusions (ECIs) are rarely reported[2,3,4,5,6,7,8]. The role of autophagy-related (ATG) gene mutations in cancers is not so well studied[17], and the mutation profile of ATG genes associated with RCC, in particular, needs further investigation[18]. Tumour subtype ccRCC ccRCC ccRCC ccRCC ccRCC ccRCC ccRCC ccRCC PRCC MTSCC characteristic morphological features of renal cancer related to autophagy defects and the relationship between genetic variations of ATG genes and tumour cell morphological changes in RCCs. We investigated 10 rare cases of RCCs with characteristic ECIs and found that the ATG proteins sequestosome 1/P62, neighbor of BRCA1 gene 1 (NBR1), BECN1, ATG5 and LC3 are located in ECIs, and that peroxisomes are distributed within ECIs too. The results indicate that autophagy dysfunction in RCCs is related to ECI pathogenesis and tumour grade
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