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IF=14.97|| strong ice helps to characterize tumor specific transcripts expressed in HCV at high frequencies. Time: 2019-12-09

As a complex heterogeneous disease, malignant tumors involve genetic and epigenetic changes, leading to the formation of more complex and diverse transcriptome. In the process of tumorigenesis and development, cancer cells produce some tumor specific transcripts. (Tumor-Specific Transcripts , TSTs) It can affect cell proliferation and tumor formation. TSTs It has become a sign of malignancy. Therefore, the study of tumor specific transcription factors and their potential role in tumor progression is of great value for tumor diagnosis and intervention.

2019 Six month Seven Day, Tumour Hospital Affiliated to Shanghai Fudan University Huang Sheng Lin Research group and He Xiang Fire Research Group Cooperative study of hepatocellular carcinoma ( HCC Widespread in TSTs The study was identified and characterized by the help of the alternative ice splicing analysis coupled with transcriptome sequencing. HCC Medium and high frequency expression TSTs It also describes its role in clinical diagnosis and treatment. The research results are based on "Tumor-specific Transcripts are Frequently Expressed in Hepatocellular Carcinoma with Clinical Implication and Potential Potential" Published in the title Hepatology "( IF=14.971 In the journal.


Experimental design:


Main findings:

Next, the Xiaobian will be from the following Four Let's introduce the results of this article.

One Identification and characterization of liver cancer tissues TSTs

The study analyzed normal tissues and liver cancer tissues. RNA Sequencing data was found. Four hundred and seventy individual TSTs In which the long chain is not annotated RNA occupy 72.9% Nearly half TSTs From the intergenic region, it consists of long terminal repeats. LTR A new transcription initiation site is generated.

union TCGA Data analysis found that TSTs There was a positive correlation between the expression frequency and cell proliferation, dry and non integer multiple variation, but little correlation with tumor development stage, patient gender and various risk factors. One )

chart One Identification and characterization of hepatocellular carcinoma TSTs

Two High frequency expression TSTs May lead to HCC Poor prognosis

As shown in Figure 2, TSTs The expression level was divided into two types: TST-high Subtype (accounting for the total number of patients) 23% Sum TST-low The survival rate and disease free survival time of two subtypes were observed. TST-high The prognosis and disease-free survival of the subtypes decreased significantly. It is associated with poor prognosis.

By differentially expressed genes. KEGG Analysis found TST-high The cell cycle, metabolic pathways and carcinogenic signaling pathways of the subtypes are evidently enriched. TST-high Subtypes are invasive malignant tumors with proliferative capacity.

Figure 2   The presence of TSTs in hepatocellular carcinoma is associated with poor prognosis.

Three A new type of functional screening was obtained. TST And characterize it.

Researchers further use small interferences. RNA ( SiRNAs Yes. TSTs Functional screening was carried out to discover a new type. TST (known as TST1 Silence can significantly inhibit cell proliferation, and QRT-PCR Analysis found TST1 It is mainly expressed in liver cancer tissues. 41.7% ) By inhibiting TST1 The tumorigenicity of cells decreased significantly, and the weight and volume of tumor decreased. In general, TST1 It has the ability of cell proliferation and tumor formation (Fig. 3).

Figure 3    Functional screening and identification of a new TST -- TST1

adopt RNA Co immunoprecipitation ISH Experimental proof TST1 They are mainly distributed in cytoplasm. Screening and TST1 Combined MiRNA as well as RNA-Seq Data analysis found TST1 Can be directly associated with MiR-500a-3p Combination promotes cell proliferation (Fig. 4).

Figure 4 TST1 promotes cell proliferation through direct regulation of miR-500a-3p.

As shown in Figure 5, research findings TST1 Subject to DNA Methylation and retinoic acid ( RA Drug related regulation LTR12C The promoter is produced. RA and Tamibarotene (retinoic acid compounds) can be passed with RA Response element sequence combined with direct inhibition TST1 It can effectively inhibit cell proliferation and tumor formation. Tamibarotene Probably right. TST1 The expression of HCC patients has therapeutic effect.

Figure 5   TST1 is produced by long terminal repeat promoter controlled by DNA methylation and retinoic acid.

Four Detected in blood extracellular vesicles. TSTs (including TST1 )

Through analysis Seventy-one example HCC Extracapsular vesicles in patients' blood ( EVs )的 RNA Sequencing data found 56% Of HCC The patient is in the blood. EVs Detected in TSTs In particular TST1 (proportion) 32.5% ) But not detected in healthy patients. TST1 Combine HCC Postoperative patients TST1 A significant decrease in blood loss was observed. EVs in TSTs The level of expression can be used to predict the prognosis of patients (Fig. 6).

Figure 6   TSTs was detected in the blood extracellular vesicles of HCC patients.

To sum up, the study has been identified. HCC Medium and high frequency expression TSTs It is helpful to understand the complex heterogeneity of tumor tissue transcriptome and characterize the new type. TST1 The potential function and clinical application of the new strategy were studied, which lay the foundation for the development of new strategies for cancer diagnosis and treatment.


Link: Https://doi.org/10.1002/hep.30805

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