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Use of DLC3 for preparation of drug for targeted treatment of gastric cancer

A targeted therapy and drug technology, applied in the field of gene and protein function and application, can solve the problem that the relationship between metabolic stress is not completely clear

Inactive Publication Date: 2019-05-17
NANFANG HOSPITAL OF SOUTHERN MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the relationship between metabolic stress and EMT is not fully understood, and it is necessary to further explore the regulatory network between them

Method used

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  • Use of DLC3 for preparation of drug for targeted treatment of gastric cancer
  • Use of DLC3 for preparation of drug for targeted treatment of gastric cancer
  • Use of DLC3 for preparation of drug for targeted treatment of gastric cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0109] Example 1: Low expression of DLC3 promotes the proliferation and migration of gastric cancer cells

[0110] In order to clarify the role of DLC3 in gastric cancer cells, the inventors used human MKN45 gastric cancer cells to construct gastric cancer cell models with DLC3 overexpression and silencing. Overexpression of DLC3 significantly inhibited gastric cancer cell viability ( figure 1 A), DNA synthesis ( figure 1 B) and clonogenicity ( figure 1 C). In contrast, inhibition of DLC3 expression significantly promoted the above biological processes. It shows that DLC3 negatively regulates the proliferation ability of gastric cancer cells.

[0111] Unexpectedly, the inventors also found that DLC3 can also affect the morphology of gastric cancer cells. When DCL3 was overexpressed, the cells shrunk into small balls, and the ratio of cell long diameter to short diameter decreased significantly ( figure 1 D). On the contrary, when DLC3 was silenced, the cells became long...

Embodiment 2

[0113] Example 2: Animal experiments prove that low expression of DLC3 promotes gastric cancer metastasis and affects glucose metabolism

[0114] On the basis of the cell model, the inventor further carried out the verification of animal experiments. Gastric cancer xenografts were inoculated subcutaneously in nude mice ( figure 2 A), silencing DLC3 significantly inhibited the growth rate of gastric cancer xenografts ( figure 2 B). On the 34th day, the xenograft tumors were taken for measurement, regardless of size and weight ( figure 2 C), or tissue Ki-67 expression ( figure 2 D), the growth of silenced DLC3 was significantly stronger than that of the control group.

[0115] In terms of metastatic ability, the inventors carried out tail vein injection of lung metastases model and spleen injection of liver metastases model for verification. Tumor cells were injected through the tail vein of nude mice, and it was found that the number of metastases in the MACC1 silencin...

Embodiment 3

[0116] Example 3: DLC3 / MACC1 Axis Jointly Affects the Prognosis of Gastric Cancer

[0117] In order to understand the relationship between DLC3 and MACC1, the inventors performed bioinformatics analysis. The results of TCGA gastric cancer data analysis showed that there was a significant negative correlation between DLC3 and MACC1 ( image 3 A). The inventors further collected clinical patient specimens after radical gastrectomy for stage I-III gastric cancer in Nanfang Hospital for detection, and the results of immunohistochemical analysis also indicated that MACC1 and DLC3 showed a negative correlation in protein expression ( image 3 B), and as the disease stage increases, the proportion of patients with negative DLC3 also gradually increases ( image 3 C). In DLC3 negative patients, the proportion of MACC1 positive expression was higher ( image 3 D), and the risk of relapse was higher in DLC3-negative and MACC1-positive patients ( image 3 E and F). In terms of surv...

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Abstract

The invention belongs to the field of function and application of genes and proteins, and relates to novel use of deleted in liver cancer genes 3 (DLC3), in particular to the use of the DLC3 for preparation of a drug for targeted treatment of gastric cancer. The use of the drug for modulating the DLC3 for the preparation of the drug for the targeted treatment of the gastric cancer is provided. Further, the drug for modulating the DLC3 is lovastatin or other statins. The role of the DLC3 in promoting gastric cancer metastasis from clinical phenomena and cell functions to molecular mechanism, and the mechanism of the gastric cancer metastasis is discussed by using the DLC3 as a node. Results prove that the lipid-lowering drug lovastatin regulates the DLC3 / MACC1 axis to inhibit the gastric cancer progression. Therefore, the DLC3 can be used as a new therapeutic target for the gastric cancer, and the drug for the targeted treatment of the gastric cancer can be prepared. The existing lovastatin and other statins have the potential to be further developed as the drug for the targeted treatment of the gastric cancer.

Description

technical field [0001] The invention belongs to the field of functions and applications of genes and proteins, and relates to the new application of deletion gene 3 (DLC3) in liver cancer, in particular to the application of DLC3 in the preparation of drugs for targeted treatment of gastric cancer. Background technique [0002] Liver cancer deletion gene 3 (deleted in liver cancer-3, DLC3) DLC3 is a member of the DLC family. The DLC family is considered as a class of tumor suppressor genes, but one of its members, DLC3, is rarely studied. Theoretically, DLC3 has a domain that can inactivate Rho GTPase, and the activation of Rho GTPase can trigger a series of downstream signals to promote the epithelial-mesenchymal transition (EMT) of tumor cells. Previous literature has also reported that the expression of DLC3 is down-regulated in a variety of tumors, thereby activating RhoA. However, neither the clinical prognostic significance of DLC3 in gastric cancer nor the relations...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61K31/366A61P35/00
Inventor 廖旺军林立石敏潘常惬刘彦潭张俊浩
Owner NANFANG HOSPITAL OF SOUTHERN MEDICAL UNIV
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