RESUMO
CONTEXT: Papillary thyroid microcarcinoma (PTMC) is the most common type of thyroid cancer. It has been shown that lymph node metastasis is associated with poor prognosis in patients with PTMC. OBJECTIVE: We aim to characterize the PTMC transcriptome landscape and identify the candidate transcripts that are associated with lateral neck lymph node metastasis of PTMC. METHODS: We performed full-length transcriptome sequencing in 64 PTMC samples. Standard bioinformatic pipelines were applied to characterize and annotate the full-length expression profiles of 2 PTMC subtypes. Functional open reading frame (ORF) annotation of the known and novel transcripts were predicted by HMMER, DeepLoc, and DeepTMHMM tools. Candidate transcripts associated with the pN1b subtype were identified after transcript quantification and differential gene expression analyses. RESULTS: We found that skipping exons accounted for the more than 27.82% of the alternative splicing events. At least 42.56% of the discovered transcripts were novel isoforms of annotated genes. A total of 39 193 ORFs in novel transcripts and 18 596 ORFs in known transcripts were identified. Distribution patterns of the characterized transcripts in functional domain, subcellular localization, and transmembrane structure were predicted. In total, 1033 and 1204 differentially expressed genes were identified in the pN0 and pN1b groups, respectively. Moreover, novel isoforms of FRMD3, NOD1, and SHROOM4 were highlighted for their association with pN1b subtype. CONCLUSION: Our data provided the global transcriptome landscape of PTMC and also revealed the novel isoforms that associated with PTMC aggressiveness.
RESUMO
Previous studies have suggested the role of CD4+Foxp3+ regulatory T cells (Tregs) in protection against kidney ischemia reperfusion injury via their immunosuppressive properties. Unfortunately, the associated mechanisms of Tregs in kidney ischemia reperfusion injury have not been fully elucidated. Semaphorin 4A (Sema4A) is essential for maintaining the immunosuppressive capacity of Tregs in tumors. However, whether Sema4A can alleviate kidney ischemia reperfusion injury through Tregs has not yet been demonstrated. Here, we investigated the effect and mechanism of Sema4A on the development of kidney ischemia reperfusion injury. Administration of recombinant human Sema4A-Fc chimera protein prior to ischemia reperfusion injury promoted the expansion and function of Tregs and decreased the accumulation of neutrophils and proinflammatory macrophages thereby attenuating functional and histological injury of the injured kidneys. Depletion of Tregs abrogated the protective effect of Sema4A on kidney ischemia reperfusion injury, suggesting Tregs as the main target cell type for Sema4A in the development of this injury. Mechanistically, Sema4A bound to neuropilin 1 (Nrp1), a cell surface receptor for Sema4A and other ligands and a key regulator of Tregs, which then promoted recruitment of phosphatase and tensin homologue and suppressed the Akt-mTOR pathway in Foxp3Cre mice but not in Nrp1f/fFoxp3Cre mice. Consistently, Treg-specific deletion of Nrp1 blocked the effect of Sema4A on the expansion and function of Treg cells. Thus, our results demonstrate that the Sema4A-Nrp1 axis alleviates the development of ischemia reperfusion injury by promoting the stability and function of Tregs in mouse kidneys.
