Abstract
AbstractClear cell renal cell carcinoma (ccRCC), as the most common histological subtype of kidney cancer, has been reported to originate primarily from proximal tubule (PT) cells in the kidney. However, the current research on its associated molecular mechanisms remains relatively limited. In our study, we analyzed multiple single-cell multi-omics datasets obtained from various research teams, revealing the significant role of the activator protein 1 (AP-1) in ccRCC tumorigenesis. The motif activity analysis of transcription factors (TFs) showed a predominant activation of AP-1 in ccRCC cancer cells compared to PT cells. Furthermore, our findings at single-cell resolution revealed a notable absence of AP-1 expression in PT cells when compared to ccRCC cancer cells. In bulk-RNA of discovery cohort, no differential expression of AP-1 was detected in normal kidney and ccRCC samples, which may be attributed to confounding effects in bulk-RNA sequencing. Meanwhile, spatial transcriptomics analysis demonstrated a broader expression range of the AP-1 compared to the ccRCC marker CA9. Moreover, we observed chromatin accessibility of the AP-1 in various cell-types, including PT cells, suggesting that the transcriptional expression of AP-1 in PT cells may be influenced by subsequent transcriptional modifications, reflecting the complex regulatory mechanism of AP-1 transcription. These findings provide important insights for a deeper understanding of the function and regulatory mechanisms of AP-1 in ccRCC, thereby establishing a theoretical foundation for future clinical research and the development of treatment strategies.
Funder
the Guangxi Natural Science Foundation
"Medical Excellence Award" Funded by the Creative Research Development Grant from the First Affiliated Hospital of Guangxi Medical University.
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology,Molecular Medicine
Reference11 articles.
1. Hsieh JJ, Purdue MP, Signoretti S, Swanton C, Albiges L, Schmidinger M, et al. Renal cell carcinoma. Nat Rev Dis Primers. 2017;3:17009.
2. Rathmell WK, Rumble RB, Van Veldhuizen PJ, Al-Ahmadie H, Emamekhoo H, Hauke RJ, et al. Management of metastatic clear cell renal cell carcinoma: ASCO guideline. J Clin Oncol. 2022;40(25):2957–95.
3. Kotecha RR, Motzer RJ, Voss MH. Towards individualized therapy for metastatic renal cell carcinoma. Nat Rev Clin Oncol. 2019;16(10):621–33.
4. Young MD, Mitchell TJ, Vieira Braga FA, Tran MGB, Stewart BJ, Ferdinand JR, et al. Single-cell transcriptomes from human kidneys reveal the cellular identity of renal tumors. Science. 2018;361(6402):594–9.
5. Zhang Y, Narayanan SP, Mannan R, Raskind G, Wang X, Vats P, et al. Single-cell analyses of renal cell cancers reveal insights into tumor microenvironment, cell of origin, and therapy response. Proc Natl Acad Sci U S A. 2021;118:24.