Yoshito Ihara

Impacts of cytoplasmic p53 aggregates on the prognosis and the transcriptome in lung squamous cell carcinoma

AbstractThe tumor suppressor TP53 gene, the most frequently mutated gene in human cancers, produces the product tumor protein p53, which plays an essential role in DNA damage. p53 protein mutations may contribute to tumorigenesis by loss of tumor suppressive functions and malignancy of cancer cells via gain‐of‐oncogenic functions. We previously reported that mutant p53 proteins form aggregates and that cytoplasmic p53 aggregates were associated with poor prognosis in human ovarian cancer. However, the prognostic impact of p53 aggregation in other tumors including lung squamous cell carcinoma (SCC) is poorly understood. Here, we demonstrated that lung SCC cases with cytoplasmic p53 aggregates had a significantly poor clinical prognosis. Analysis via patient‐derived tumor organoids (PDOs) established from lung SCC patients and possessing cytoplasmic p53 aggregates showed that eliminating cytoplasmic p53 aggregates suppressed cell proliferation. RNA sequencing and transcriptome analysis of p53 aggregate‐harboring PDOs indicated multiple candidate pathways involved in p53 aggregate oncogenic functions. With lung SCC‐derived cell lines, we found that cytoplasmic p53 aggregates contributed to cisplatin resistance. This study thus shows that p53 aggregates are a predictor of poor prognosis in lung SCC and suggests that detecting p53 aggregates via p53 conventional immunohistochemical analysis may aid patient selection for platinum‐based therapy.

Sulfated glycosaminoglycans mediate prion-like behavior of p53 aggregates

Significance Approximately 50 human diseases are associated with deposition of abnormally aggregated proteins that propagate in a prion-like manner. The tumor suppressor p53 forms amyloid-like aggregates; however, how p53 aggregates propagate remains unclear. Here, we identified heparan sulfate (HS), the common and major nonprotein component of in vivo deposits of various protein aggregates, as a mediator of prion-like propagation of p53 aggregates in cultured cells. Our immunohistochemical analysis showing codeposition of p53 and highly sulfated domains of HS in ovarian cancer tissues strongly support the role of HS-mediated propagation of p53 aggregates in cancer pathology. Accordingly, our results provide a mechanism of propagation of p53 aggregates that is mediated by HS. Elucidation of detailed biological relevance in cancer is warranted.