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Alternative ANKHD1 transcript promotes proliferation and inhibits migration in uterine corpus endometrial carcinoma.

ABSTRACT: Alternative splicing (AS) is common in gene expression, and abnormal splicing often results in several cancers. Overall survival-associated splicing events (OS-SEs) have been used to predict prognosis in cancer. The aim of this study was to investigate the presence and function of OS-SEs in uterine corpus endometrial carcinoma (UCEC). Based on TCGA and TCGASpliceSeq databases, gene expression and the AS data of UCEC samples were retrieved. An alternate terminator of ANKHD1 transcripts named ANKHD1-BP3 was found to be significantly related to metastasis and OS in UCEC and significantly associated with HSPB1. The upregulated expression of HSPB1 induced downregulation of ANKHD1-BP3 and promoted tumor metastasis. These findings indicate that HSPB1, a splicing factor, regulates the expression of ANKHD1-BP3 to promote metastasis in UCEC.

SUBMITTER: Sun W

PROVIDER: S-EPMC9519915 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Alternative ANKHD1 transcript promotes proliferation and inhibits migration in uterine corpus endometrial carcinoma.

Sun Wenhuizi W Huang Runzhi R Li Zhenyu Z Zhu Yaru Y Bai Yan Y Wu Siyu S Wang Jingshuai J Xiao Yan Y Xian Shuyuan S Tong Xiaowen X Zhang Jie J Guo Yi Y Ouyang Yiqin Y

NPJ genomic medicine 20220929 1

Alternative splicing (AS) is common in gene expression, and abnormal splicing often results in several cancers. Overall survival-associated splicing events (OS-SEs) have been used to predict prognosis in cancer. The aim of this study was to investigate the presence and function of OS-SEs in uterine corpus endometrial carcinoma (UCEC). Based on TCGA and TCGASpliceSeq databases, gene expression and the AS data of UCEC samples were retrieved. An alternate terminator of ANKHD1 transcripts named ANKH ...[more]

PMID: 36171217

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Project description:Phosphoserine aminotransferase 1 (PSAT1) has been associated with the occurrence and development of various carcinomas; however, its function in uterine corpus endometrial carcinoma (UCEC) is unknown. We aimed to explore the relationship between PSAT1 and UCEC using The Cancer Genome Atlas database and functional experiments. PSAT1 expression levels in UCEC were employed using the paired sample t-test, Wilcoxon rank-sum test, the Clinical Proteomic Tumor Analysis Consortium database, and the Human Protein Atlas database, while survival curves were constructed using the Kaplan-Meier plotter. We performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis to explore the possible functions and related pathways of PSAT1. Furthermore, single-sample gene set enrichment analysis was performed to detect the relationship between PSAT1 and tumor immune infiltration. StarBase and quantitative PCR were used to predict and verify the interactions between miRNAs and PSAT1. The Cell Counting Kit-8, EdU assay, clone formation assay, western blotting and flow cytometry were used to evaluate cell proliferation. Finally, Transwell and Wound healing assays were used to assess cell invasion and migration. Our study found that PSAT1 was significantly overexpressed in UCEC, and this high expression was associated with a worse prognosis. A high level of PSAT1 expression was associated with a late clinical stage and, histological type. In addition, the results of GO and KEGG enrichment analysis showed that PSAT1 was mainly involved in the regulation of cell growth, immune system and cell cycle in UCEC. In addition, PSAT1 expression was positively correlated with Th2 cells and negatively correlated with Th17 cells. Furthermore, we also found that miR-195-5P negatively regulated the expression of PSAT1 in UCEC. Finally, the knockdown of PSAT1 resulted in the inhibition of cell proliferation, migration, and invasion in vitro. Overall, PSAT1 was identified as a potential target for the diagnosis and immunotherapy of UCEC.

Project description:Background:Uterine corpus endometrial carcinoma (UCEC) is a clinically heterogeneous disease, and this heterogeneity is associated with tumor development, clinical characteristics, and prognostic outcomes. Mutant-allele tumor heterogeneity (MATH) is a novel, non-biased, quantitative measure to assess intra-tumor heterogeneity based on next-generation sequencing data. We aimed to explore the use of MATH as a measure for tumor heterogeneity and its prognostic role in UCEC patients. Methods:We calculated MATH scores from the available data of 560 UCEC patients from The Cancer Genome Atlas (TCGA) and investigated their correlations with clinical characteristics, genetic alterations, and overall survival. Predictive accuracy was quantified using the area under the receiver operating characteristic curve (AUC) and the index of concordance (C-index). Results:In total, 242 MATH scores were obtained from the UCEC cohort. MATH scores were significantly related to age, race, cancer type, clinical stage, histological grade, molecular type, targeted molecular therapy, and hormonal therapy. Furthermore, the genomic pattern on the basis of MATH scores showed that mutation rates of TP53 (tumor protein p53) and ARID1A (AT-rich interaction domain 1A) were independently associated with MATH scores. Correlation analysis revealed a significantly positive association of MATH scores with the fraction of somatic copy number alteration (SCNA). Importantly, a high MATH score was significantly associated with shorter overall survival [hazard ratio (HR), 2.342; 95% confidence interval (CI), 1.110-4.942]. Multivariate Cox regression combined with stratified analysis revealed that the MATH score is an independent prognostic factor in UCEC patients under 60 years old, and predictive quantification showed the MATH score had an AUC of 0.756 and a C-index of 0.845. Conclusions:Our results suggest that MATH, a practical and useful way to measure intra-tumor heterogeneity, may serve as a significant biomarker for the prognosis of patients with UCEC, enabling more accurate prediction of clinical outcomes.

Project description:Necroptosis is a recently identified caspase-independent form of cell death which plays a significant role in the onset and progression of cancer. MicroRNAs (miRNAs) are vital for the development of uterine corpus endometrial carcinoma (UCEC) because they are an important regulatory component in necroptosis. This study developed a new necroptosis-related miRNAs profile to predict the prognosis of patients with UCEC. The TCGA-UCEC cohort's RNA sequencing data, consisting of 534 tumor samples and 33 normal samples, was downloaded. Ten differentially expressed miRNAs related to necroptosis were identified. A prediction model for necroptosis-related miRNAs was then created through COX regression and nomograms analysis. Clinical and pathological parameters were integrated to construct a nomogram and evaluate the model. Prognosis-related miRNAs were further used to predict target genes, and functional analysis was conducted to explore the potential mechanisms of these target genes. Subsequently, immune infiltration analysis was performed using transcriptome data to identify immune genes associated with prognosis, and the expression levels of target gene was validated using UCEC tissues. We identified 7 up-regulated miRNAs (hsa-miR-577, hsa-miR-7-5p, hsa-miR-210-3p, hsa-miR-210-5p, hsa-miR-200a-5p, hsa-miR-141-3p, hsa-miR-425-5p) and 3 down-regulated miRNAs (hsa-miR-7-2-3p, hsa-miR-383-5p, hsa-miR-29a-3p). The risk signature was based on univariate and multivariate COX analyses, constructed using 2 independent prognostic factors and miRNAs (hsa-miR-425-5p, hsa-miR-7-5p) associated with necroptosis. Nomograms demonstrated the prognostic value of risk level, age, FIGO stage, and histological type. Kaplan-Meier analysis revealed significant differences in overall survival (OS) outcomes associated with the expression of hsa-miR-425-5p (P < 0.001) and hsa-miR-7-5p (P = 0.015). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) investigations indicated that these miRNAs play crucial roles in tumor development, metastasis, and prognosis. Immune infiltration analysis showed decreased infiltration of CD8+ T cells, CD8+ T cells, NK cells, and M1 macrophages in normal tissues. Subsequently, a necroptosis-related immune gene significantly associated with prognosis (THRB) was identified, western blot and immunohistochemical staining confirmed the differential expression of THRB in normal endometrial tissues and tumor. Our findings demonstrate a close association between necroptosis and UCEC. The two necroptosis-related miRNAs used in this study may serve as valuable prognostic markers for UCEC patients, and are associated with immune cell infiltration. This suggests that necroptosis may be involved in the development of UCEC through its interaction with immune responses.

Dataset Information

Alternative ANKHD1 transcript promotes proliferation and inhibits migration in uterine corpus endometrial carcinoma.

Publications

Alternative ANKHD1 transcript promotes proliferation and inhibits migration in uterine corpus endometrial carcinoma.

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