Comprehensive Exploration of SERPINA1 and Alternative Splicing Events within the Goblets in Colorectal Cancer: Implications for Mucin Secretion and Prognosis

Introduction: Colorectal cancer (CRC), has been diagnosed as a malignant tumor with high morbidity and mortality rate. Goblet cells play a significant role in CRC development by secreting mucins, while the mechanisms and critical targets are largely veiled.

Methods: The single-cell dataset was obtained to acquire differentially expressed genes (DEGs) in goblets, and further the key prognostic genes and splicing events in CRC patients were screened, on which basis an integrated prognostic model was constructed. The selected critical gene and splicing events were validated using HT-29 and NCM460 cell lines. Furthermore, the NMF method was employed for new goblet subtype identification. Meanwhile, the CRC smart-seq data was also employed to further investigate the splicing event landscape in goblets

Results: 6 key prognostic genes and 10 key splicing events were obtained after selection, and subsequently integrated to establish a combined prognostic model. Through comprehensive exploration in both transcriptomic analysis and in vitro experiments in cell line level, the SERPINA1 and the corresponding splicing event SERPINA1/ES/29130 were identified as the significant gene and splicing events regulating prognosis of CRC in goblet. A novel goblet subtype, SERPINA1+ goblet was identified, and its protective impact was comprehensively investigated by single- cell and spatial transcriptomic analysis. Additionally, the splicing event landscape of goblet CRC were also explored by smart-seq analysis, with obviously upregulated exon skipping and translation process

Conclusion: Generally, our study constructed an integrated prognostic model related to goblets in CRC, and identified the crucial role of SEPRINA1+ goblets in CRC progression, providing a novel target to CRC clinical treatment