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Application of GATA4 inhibitor in inhibition of NF-[kappa]B/STAT3 signal channel

A signaling pathway and inhibitor technology, applied in the field of GATA4 inhibitor, inhibiting NF-κB/STAT3 signaling pathway, which can solve problems such as unreported

Inactive Publication Date: 2021-04-06
SHANGHAI FIRST PEOPLES HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] There is no report about the use of the GATA4 inhibitor of the present invention in inhibiting the NF-κB / STAT3 signaling pathway

Method used

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  • Application of GATA4 inhibitor in inhibition of NF-[kappa]B/STAT3 signal channel
  • Application of GATA4 inhibitor in inhibition of NF-[kappa]B/STAT3 signal channel
  • Application of GATA4 inhibitor in inhibition of NF-[kappa]B/STAT3 signal channel

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Embodiment 1 Pre-experiment

[0030] First, in order to explore the changes in protein expression during the transformation of pancreatitis to pancreatic cancer, we conducted a 4-target iTRAQ experiment, including 2 pancreatitis samples and 2 pancreatic cancer samples. Using T test, false positive rate FDR (False discovery rate) and the multiple of expression difference to screen, we got a total of 87 differentially expressed proteins, of which 58 were up-regulated and 29 were down-regulated (left heat map) (fold change Twice, FDR Image 6 ).

[0031] Next, we downloaded the human pancreatic cancer RNA-seq dataset from the TCGA database (The Cancer Genome Atlas, https: / / tcga-data.nci.nih.gov / tcga / , currently the largest tumor genome database), sorted and selected Among the 141 cases with complete clinical parameters and survival data, the Pearson correlation coefficient between GATA4 and other genes was calculated, and the genes with a coefficient greater than 0.6 were ...

Embodiment 2

[0033] Example 2 Cell experiment

[0034] 1 method

[0035] (1) Add different concentrations of lipopolysaccharide LPS (0, 50, 100 ng / ml) to the macrophage culture medium that induces THP-1 differentiation, overexpress NF-κB and Reg3β in the cells, and observe whether the interference with GATA4 can be rescued Resulting phenotype;

[0036] (2) Silence NF-κB and Reg3β in cell lines, and observe whether the phenotype caused by overexpression of GATA4 can be rescued;

[0037] (3) RT-PCR and WB were performed to detect the levels of GATA4, NF-κB, SASP, Reg3β and STAT3 in the cells at the same time, and to observe whether the expression of NF-κB and Reg3β was correlated with GATA4.

[0038] 2 results

[0039] The expressions of NF-κB and Reg3β were correlated with GATA4.

Embodiment 3

[0040] Embodiment 3 animal model experiments

[0041] 1 method

[0042] (1) Establishment of an orthotopic pancreatic cancer model in SCID mice to study the effect of GATA4 on pancreatic tumorigenesis and downstream signaling pathways:

[0043] 1) Construction of an orthotopic pancreatic cancer model in SCID mice: pancreatic cancer cells (cells marked with luciferase gene) in the GATA4 interference group, overexpression group, and control group were orthotopically injected into the pancreas of SCID mice to establish pancreatic cancer In situ model, 6 rats in each group. The expression of luciferase was detected by the CaliperIVIS imaging system every two weeks to observe the tumor status of each group;

[0044] 2) Specimen preparation: SCID mice were killed within a certain period of time, tumor tissue and venous blood were taken, blood was tested for CA199 concentration, tumor weight and size were measured, RNA and protein were extracted, and some tissues were fixed in form...

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Abstract

The invention relates to an application of a GATA4 inhibitor in inhibiting an NF-[kappa]B / STAT3 signal channel, and according to earlier-stage research, USP28 regulates the stability of MYC through deubiquitination so as to promote up-regulation of the expression quantity of MYC; then a GATA4 promoter region is demethylated, so the expression of GATA4 is up-regulated; The process of 'inflammatory cancer transformation' of pancreas is promoted by activating two inflammation-related signal channels, namely NF-[kappa]B / SASP and Reg3[beta] / STAT3. The application has the advantages that the transcription factor GATA4 is taken as an entry point, the discussion that USP28 / MYC / GATA4 signal axis promotes pancreas inflammatory cancer transformation is taken as the center, the formation cause of pancreas cancer is understood from the new perspective of transformation, and a new method and thought are provided for preventing and treating pancreas cancer.

Description

technical field [0001] The invention relates to the technical field of molecular diagnosis, in particular to the use of GATA4 inhibitors in inhibiting NF-κB / STAT3 signaling pathway. Background technique [0002] Pancreatic ductal adenocarcinoma (PDAC) has a high degree of malignancy, difficult early diagnosis, and poor curative effect of existing treatment methods. Therefore, its mortality rate is high and its prognosis is extremely poor. Its five-year survival rate is only 5%. Although the introduction and application of new diagnostic and treatment methods have brought the morbidity and mortality of other cancers under control, the morbidity and mortality of pancreatic cancer continue to rise. In 2012, PDAC ranked first in the mortality rate of malignant tumors in the United States. 4, and by 2030 it is predicted to rise to the 2nd place. It is of great scientific significance and clinical value to deeply study the initiating link of the pathogenesis of pancreatic cancer,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K31/7088A61P1/18A61P35/00
CPCA61K45/00A61K31/7088A61P1/18A61P35/00
Inventor 杨丽娟蒋魏亮陈聪颖黄丽沈杰
Owner SHANGHAI FIRST PEOPLES HOSPITAL
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