Background Among the most aggressive and rapidly lethal types of lung cancer, lung adenocarcinoma is the most common type. Exosomes, as a hot area, play an influential role in cancer. By using proteomics analysis, we aimed to identify potential markers of lung adenocarcinoma in serum. Methods In our study, we used the ultracentrifugation method to isolate serum exosomes. The Liquid chromatography-mass spectrometry (LC–MS) and bioinformatics analysis were used to identify potential serum exosomal proteins with altered expression among patients with advanced lung adenocarcinoma, early lung adenocarcinoma, and healthy controls. A western blot (WB) was performed to confirm the above differential expression levels in a separate serum sample-isolated exosome, and immunohistochemistry (IHC) staining was conducted to detect expression levels of the above differential proteins of serum exosomes in lung adenocarcinoma tissues and adjacent tissues. Furthermore, we compared different expression models of the above differential proteins in serum and exosomes. Result According to the ITGAM (Integrin alpha M chain) and CLU (Clusterin) were differentially expressed in serum exosomes among different groups as well as tumor tissues and adjacent tissues. ITGAM was significantly and specifically enriched in exosomes. As compared to serum, CLU did not appear to be significantly enriched in exosomes. ITGAM and CLU were identified as serum exosomal protein markers of lung adenocarcinoma. Conclusions This study can provide novel ideas and a research basis for targeting lung adenocarcinoma treatment as a preliminary study.
Rationale:The current molecular classification of small cell lung cancer (SCLC) based on expression of four lineage transcription factors still leaves its major subtype SCLC-A as a heterogeneous group, necessitating more precise characterization of lineage subclasses.Objectives: To refine the current SCLC classification with epigenomic profiles and to identify features of the re-defined SCLC subtypes. Methods:We performed unsupervised clustering of epigenomic profiles on 25 SCLC cell lines.Functional significance was evaluated by cell growth, apoptosis and xenograft using CRISPR-Cas9-mediated deletion. The specific cistromic profiles by ChIP-seq and its functional transcriptional partners using co-immunoprecipitation followed by mass spectrometry were determined. Rb1 fl/fl Trp53 fl/fl and Rb1 fl/fl Trp53 fl/fl Nkx2-1 fl/fl mouse models were engineered to explore the function of Nkx2-1 in tumor initiation and differentiation. H3K27ac profiles were analyzed to reveal 6 human SCLC specimen and 20 mice tumors epigenomic landscapes. Measurements and Main Results:We identified an epigenomic subclusters of the major SCLC-A subtype, named SCLC-Aα and SCLC-Aσ. SCLC-Aα was characterized by the presence of a super-enhancer at the NKX2-1 locus, which was observed in human SCLC specimens and a murine SCLC model. We found NKX2-1, a dual lung and neural lineage factor, is uniquely relevant in SCLC-Aα. We further found maintenance of this neural identity in SCLC-Aα is mediated by collaborative transcriptional activity with another neuronal transcriptional factor SOX1. Conclusions:We comprehensively describe an additional epigenomic heterogeneity of the major SCLC-A subtype, and define SCLC-Aα subtype by the core regulatory circuitry representing NKX2-1 and SOX1 super-enhancers and their functional collaborations to maintain neuronal linage state. (Word count 250
RationaleThe current molecular classification of small cell lung cancer (SCLC) based on expression of four lineage transcription factors still leaves its major subtype SCLC-A as a heterogeneous group, necessitating more precise characterization of lineage subclasses.ObjectivesTo refine the current SCLC classification with epigenomic profiles and to identify features of the re-defined SCLC subtypes.MethodsWe performed unsupervised clustering of epigenomic profiles on 25 SCLC cell lines. Functional significance was evaluated by cell growth, apoptosis and xenograft using CRISPR-Cas9-mediated deletion. The specific cistromic profiles by ChIP-seq and its functional transcriptional partners using co-immunoprecipitation followed by mass spectrometry were determined. Rb1fl/flTrp53fl/fl and Rb1fl/flTrp53fl/flNkx2-1fl/fl mouse models were engineered to explore the function of Nkx2-1 in tumor initiation and differentiation. H3K27ac profiles were analyzed to reveal 6 human SCLC specimen and 20 mice tumors epigenomic landscapes.Measurements and Main ResultsWe identified an epigenomic subclusters of the major SCLC-A subtype, named SCLC-A1 and SCLC-A2. SCLC-A1 was characterized by the presence of a super-enhancer at the NKX2-1 locus, which was observed in human SCLC specimens and a murine SCLC model. We found NKX2-1, a dual lung and neural lineage factor, is uniquely relevant in SCLC-A1. We further found maintenance of this neural identity in SCLC-A1 is mediated by collaborative transcriptional activity with another neuronal transcriptional factor SOX1.ConclusionsWe comprehensively describe an additional epigenomic heterogeneity of the major SCLC-A subtype, and define SCLC-A1 subtype by the core regulatory circuitry representing NKX2-1 and SOX1 super-enhancers and their functional collaborations to maintain neuronal linage state.
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