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Objectives: This study aimed to establish a neural‐related gene risk score (NRGRS) for the prediction of head and neck squamous cell carcinoma prognosis and explore its predictive value on the benefit of immune checkpoint inhibitor therapy. Methods: Based on the transcriptome data of HNSCC patients (n = 546) from The Cancer Genome Atlas database, 37 neural‐related hub genes were identified by weighted gene co‐expression network analysis. Four genes (ITGA5, PYGM, GNG7 and ATP2A3) were identified to construct NRGRS using Lasso‐Cox regression method based on the derivation cohort and validated in the Gene Expression Omnibus cohort (n = 109). The survival analysis was performed to validate the prognostic value of NRGRS and immune characteristics in NRGRS‐defined subgroups were analyzed. Results: NRGRS‐high patients had a worse overall survival than NRGRS‐low patients. Tumors with high NRGRS were more likely to have high infiltration of naive CD4+ T cells, M0, M2 macrophages and resting mast cells, which illustrated suppressive immunity and less benefit from immunotherapy therapy. Conclusion: NRGRS strongly correlates with survival and is a promising biomarker to predict immunotherapy benefits for head and neck cancer patients. This study provides evidence for the potential correlation between neural‐related transcriptome alteration and immune activity. [ABSTRACT FROM AUTHOR]

Tumors usually display fetal‐like characteristics, and many oncofetal proteins have been identified. However, fetal‐like reprogramming of RNA splicing in hepatocellular carcinoma (HCC) is poorly understood. Here, it is demonstrated that the expression of epithelial splicing regulatory protein 2 (ESRP2), an RNA splicing factor, is suppressed in fetal hepatocytes and HCC, in parallel with tumor progression. By combining RNA‐Seq with splicing analysis, it is identified that ESRP2 controls the fetal‐to‐adult switch of multiple splice isoforms in HCC. Functionally, ESRP2 suppressed cell proliferation and migration by specifically switching the alternative splicing (AS) of the TAK1 gene and restraining the expression of the fetal and oncogenic isoform, TAK1_ΔE12. Notably, aberrant TAK1 splicing led to the activation of p38MAPK signaling and predicted poor prognosis in HCC patients. Further investigation revealed that TAK1_ΔE12 protein interacted closely with TAB3 and formed liquid condensation in HCC cells, resulting in p38MAPK activation, enhanced cell migration, and accelerated tumorigenesis. Loss of ESRP2 sensitized HCC cells to TAK1 kinase inhibitor (TAK1i), promoting pyroptotic cell death and CD8+ T cell infiltration. Combining TAK1i with immune checkpoint therapy achieved potent tumor regression in mice. Overall, the findings reveal a previously unexplored onco‐fetal reprogramming of RNA splicing and provide novel therapeutic avenues for HCC. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Esophageal cancer is currently the eighth most common tumor in the world and a leading cause of cancer death. SULT2B1 plays crucial roles in tumorigenesis. The purpose of this study is to explore the role of SULT2B1 in esophageal squamous cell carcinoma (ESCC).The expression of SULT2B1 and its clinicopathological characteristics were evaluated in ESCC cohorts. Bisulfite genomic sequencing and methylation specific PCR were used to detect the promoter hypermethylation of the SULT2B1 gene. The effects of SULT2B1 on the biological characters of ESCC cells were identified on functional assays. Subcutaneous xenograft models revealed the role of SULT2B1 in vivo with tumor growth. RNA‐Seq analysis and qRT‐PCR were performed to recognize the targeted effect of SULT2B1 on PER1.SULT2B1 was not expressed or at a low level in most patients with ESCC or in ESCC cell lines, and this was accompanied by poor clinical prognosis. Furthermore, the downregulation of SULT2B1 occurred in promoter hypermethylation. According to the functional results, overexpression of SULT2B1 could inhibit tumoral proliferation in vitro and retard tumor growth in vivo, whereas SULT2B1 knockdown could accelerate ESCC progression. Mechanistically, SULT2B1 targeted PER1 at the mRNA level during post‐transcriptional regulation. Finally, PER1 was verified as a suppressor and poor‐prognosis factor in ESCC.SULT2B1 loss is a consequence owing to its ability to promote hypermethylation. In addition, it serves as a suppressor and poor‐prognosis factor because of the post‐transcriptional regulation of PER1 in ESCC. [ABSTRACT FROM AUTHOR]