Abstract Lung adenocarcinoma (LUAD) is the most common type of lung cancer and one of the malignancies with the highest incidence rate and mortality worldwide. Hypoxia is a typical feature of tumour microenvironment (TME), which affects the progression of LUAD from multiple molecular levels. However, the underlying molecular mechanisms behind LUAD hypoxia are not fully understood. In this study, we estimated the level of hypoxia by calculating a score based on 15 hypoxia genes. The hypoxia scores were relatively high in LUAD patients with poor prognosis and were bound up with tumour node metastasis (TNM) stage, tumour size, lymph node, age and gender. By comparison of high hypoxia score group and low hypoxia score group, 1820 differentially expressed genes were identified, among which up‐regulated genes were mainly about cell division and proliferation while down‐regulated genes were primarily involved in cilium‐related biological processes. Besides, LUAD patients with high hypoxia scores had higher frequencies of gene mutations, among which TP53 , TTN and MUC16 had the highest mutation rates. As for DNA methylation, 1015 differentially methylated probes‐related genes were found and may play potential roles in tumour‐related neurobiological processes and cell signal transduction. Finally, a prognostic model with 25 multi‐omics features was constructed and showed good predictive performance. The area under curve (AUC) values of 1‐, 3‐ and 5‐year survival reached 0.863, 0.826 and 0.846, respectively. Above all, our findings are helpful in understanding the impact and molecular mechanisms of hypoxia in LUAD.
Left-sided colon cancer (LCC) and right-sided colon cancer (RCC) have distinct characteristics in tumor immune microenvironment (TIME). Although existing studies have shown a strong association between gene mutations and TIME, whether the regulatory mechanisms between gene mutations and TIME are different between RCC and LCC is still unclear. In this study, we showed the fractions of CD8+ T cells were higher while those of regulatory T cells were lower in RCC. Besides, a stronger association between gene mutations and TIME was observed in RCC. Specifically, using multi-omics data, we demonstrated the mutations of most top mutated genes (TMGs) including BRAF, PCLO, MUC16, LRP2, ANK3, KMT2D, RYR2 made great contributions to elevated fraction of immune cells by up-regulating immune-related genes directly or indirectly through miRNA and DNA methylation, whereas the effects of APC, TP53 and KRAS mutations on TIME were reversed in RCC. Remarkably, we found the expression levels of several immune checkpoint molecules such as PD-1 and LAG3 were correlated with corresponding DNA methylation levels, which were associated with the mutations of TMGs in RCC. In contrast, the associations between gene mutations and TIME were less significant in LCC. Besides, survival analyses showed APC mutation had adverse impact on immunotherapy while patients with BRAF mutation were more suitable for immunotherapy in colon cancer. We hope that our results will provide a deeper insight into the sophisticated mechanism underlying the regulation between mutations and TIME, and thus boost the discovery of differential immunotherapeutic strategies for RCC and LCC.
Abstract Background: The tetratricopeptide repeat domain 39C ( TTC39C ) gene is a novel TTC genes, which mainly mediates the interaction between proteins. It has been shown to be involved in the progression of a variety of tumors. Here we aimed to identify the effect of TTC39C on lung adenocarcinoma, which can be used as potential intervention targets. Methods: Take samples from TCGA database for difference analysis of TTC39C. Transwell experiment was used to detect the ability of cell metastasis. Celigo and MTT assay detected the effect of TTC39C gene subtraction on cell proliferation. FACS was used to detect the effect of TTC39C gene subtraction on apoptosis. Clonal formation experiment was used to detect the effect of TTC39C gene subtraction on clonal ability. Transcriptomics, proteomics and metabolomics were used to study the possible enrichment pathway of TTC39C gene in the progression of lung adenocarcinoma. Results: TTC39C expression was significantly increased in lung adenocarcinoma. the proliferation, metastasis and cloning ability of human lung cancer cells were inhibited, while the apoptosis of cells increased significantly after TTC39C depletion. It is concluded that TTC39C may be involved in the progression of LUAD mainly through metabolic pathway and p53 pathway through transcriptomics combined with proteomics and metabolomics. Conclusion: In summary, TTC39C plays an important role in regulating the proliferation and metastasis of lung adenocarcinoma cells. The main pathways involved in TTC39C in lung adenocarcinoma mainly include energy metabolism and p53 pathway.
Brassica napus is one of the important oil crops grown worldwide, and oil quality improvement is a major goal in rapeseed breeding. Yellow seed is an excellent trait, which has great potential in improving seed quality and economic value. In this study, we created stable yellow seed mutants using a CRISPR/Cas9 system and obtained the yellow seed phenotype only when the four alleles of two BnTT2 homologues were knocked out, indicating that the two BnTT2 homologues had conserved but redundant functions in regulating seed color. Histochemical staining and flavonoid metabolic analysis proved that the BnTT2 mutation hindered the synthesis and accumulation of proanthocyanidins. Transcriptome analysis also showed that the BnTT2 mutation inhibited the expression of genes in the phenylpropanoid and flavonoid biosynthetic pathway, which might be regulated by the complex of BnTT2, BnTT8 and BnTTG1. In addition, the homozygous mutants of BnTT2 homologues increased oil content and improved fatty acid composition with higher linoleic acid (C18:2) and linolenic acid (C18:3), which could be used for the genetic improvement of rapeseed. Overall, this research showed that the BnTT2 mutation can be used for yellow seed breeding and oil improvement, which is of great significance in improving the economic value of rapeseeds.
DNA methylation, an important epigenetic modification, serves as a key function in the polyploidization of numerous crops. In this study, early generations of resynthesized Brassica napus (F1, S1–S3), ancestral parents B. rapa and B. oleracea were analyzed to characterize their DNA methylation status during polyploidization, applying DNA methylation-sensitive amplification polymorphism (MSAP) and high-performance liquid chromatography methods. In F1, 53.4% fragments were inherited from both A- and C-genomes. Besides, 5.04 and 8.87% fragments in F1 were inherited from A- and C- genome, respectively. 5.85 and 0.8% fragments were newly appeared and disappeared in resynthesized B. napus, respectively. 13.1% of these gene sites were identified with methylation changes in F1, namely, hypermethylation (7.86%) and hypomethylation (5.24%). The lowest methylation status was detected in F1 (38.7%) compared with in S1–S3. In S3, 40.32% genes were methylated according to MSAP analysis. Sequencing of methylated fragments indicated that genes involved in multiple biological processes were modified, including transcription factors, protein modification, and transporters. Expression ananlysis of DNA methyltransferase 1 and DNA methyltransferase chromomethylase 3 in different materials was consistent to the DNA methylation status. These results can generally facilitate dissection of how DNA methylation contributes to genetic stability and improvement of B. napus during polyploidization.
The type-B authentic response regulators (type-B ARRs) are positive regulators of cytokinin signaling and involved in plant growth and stress responses. In this study, we used bioinformatics, RNA-seq, and qPCR to study the phylogenetic and expression pattern of 35 type-B ARRs in Brassica napus. The BnARRs experienced gene expansion and loss during genome polyploidization and were classified into seven groups. Whole-genome duplication (WGD) and segmental duplication were the main forces driving type-B ARR expansion in B. napus. Several BnARRs with specific expression patterns during rapeseed development were identified, including BnARR12/14/18/23/33. Moreover, we found the type-B BnARRs were involved in rapeseed development and stress responses, through participating in cytokinin and ABA signaling pathways. This study revealed the origin, evolutionary history, and expression pattern of type-B ARRs in B. napus and will be helpful to the functional characterization of BnARRs.
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