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INFORMATION OF RESEARCH RESULTS

1. General information

• Project title: Study of the effect of All trans retinoic acid on gene expression in signaling pathways in gastric cancer stem cell
• Code number: B2017-TNA-48
• Coordinator: Assoc. Prof. Luu Thi Binh
• Implementing institution: Thai Nguyen University
• Duration: From January 2017- December 2018

2. Objectives

• Culture cancer stem cells from gastric cancer cell lines in cultural medium without fetal bovine serum.
• Assess the inhibition of the in vitro tumorsphere formation from gastric cancer stem cells.
• Indicate the effect of retinoic acid on gene expression in different molecular signaling pathways of gastric cancer stem cells.

3. Creativeness and innovativeness

Retinoic acid has been used in the treatment of leukemia. We have recently shown it has the ability to inhibit stomach cancer in vitro culture and in tumor transplant mice. However, effect of All trans retinoic acid (ATRA) on the molecular signaling pathways of gastric cancer stem cellsremains known. Therefore, the results of this project contribute to clarify the molecular mechanism of ATRA-mediated gastric cancer inhibition.

4. Researh results

1. Results of Gastric cancer stem cell (CSC) culture and CSC treatment with ATRA in 3D culture condition. Gastric cancer stem cell culture is performed on non-adhering surfaces and media containing FGF, EGF, insulin growth substances. In this culture, the cancer stem cells create tumorspheres. However, other cells quickly die after a few cell division under these conditions. Tumorspheres after 5 days of culture treated with ATRA resulted in a decrease in the number and size of tumorspheres.
2. Results of total RNA extraction from the tumorsphere: Total RNA was extracted from tumorspheres by Trizol method. Results of fluorescence absorption spectra of total RNA samples showed that the total RNA obtained has very good purity. All 260/280 parameters are greater than 1.9. In addition, the RNA of the samples collected was high in concentration and used to synthesize into cDNA for realtime PCR analysis in the next study. Treatment of tumorphere with ATRAdown-regulated a series of key genes in the cell apopotis signaling pathway. In particular, ATRA reduced the expression of apoptosis-inhibiting genes such as AKT1, BAD, NUP62, BCL2, PIK3R2, MAPK1. In contrast, ATRA down-regulated expression of genes that promotes apoptosis including CASP9, FOXO3, IL2, and P53.
3. Assess the impact of ATRA on the expression of genes in the apoptosis signaling pathway. Treatment of tumorphere with ATRA down-regulated a series of key gene in the apopotis signaling pathway in gastric cancer stem cells. In particular, ATRA decreased the expression of genes inhibiting apoptosis such as AKT1, BAD, NUP62, BCL2, PIK3R2, MAPK1. In contrast, ATRA modulated the expression of a genes that promotes apoptosis including CASP9, FOXO3, IL2, and P53.
4. Assess the impact of ATRA on the expression of genes in EGF signaling pathway, JAK / STAT signaling pathway: This study show that ATRA inhibited the expression of various genes in the EGF, and JAK / STAT signaling pathway.In which, key genes such as GAB2, NUP62 and RPS6KA5 were reduced expression levels from 1.5 to 2 times compared to the control. The remaining genes such as GAB1, STAT1, STAT2, NUP62, SRC were not almost changed in expression level.   
5. Assess the impact of ATRA on the expression of genes involved in cell renewal and stem cell markers: ATRA down regulated expression of genes that control cell renewal, in which the levelof KLF4 expression decreased by 2 times, DNMT1 decreased by 4 times and SOX2 decreased by 5 times compared to the control. Only LIN28A expression was not changedin expression level. ATRA reduced the expression of ITGB1 and CD24 genes by 2 times, and 3 times for the CD90 and MUC1 genes. However, BMI1 expression level was almost unchanged and ATAXIN1 expression level increased significantly, approximately 1.8 times compared to untreated cells.
6. 6./. Assess the impact of ATRA on the gene expression in senessence pathway: ATRA inhibited the transcription of genes encoding cyclins 4 to 5 times more than the control. Similarly, the expression level of the genes coding for cell cycle proteins including CHEK1 and CHEK2 decreased from 2.5 to 3 times. In particular, the genes encoding the key proteins of the cellular senessence pathway including p53, P21 and GADD45A expressed 1.5, 2.5 and 4 times in comparison with the control.

5. Products

5.1. Sicientific products

1. Ngo Thu Ha, Luu Thi Binh, Le Thi Thanh Huong, Mai Van Linh,  Nguyen Dac Trung, Nguyen Phu Hung (2017), “All-trans Retinoic Acid Effect on the Apoptosis Gene Expression of Gastric Cancer Cell”, VNU Journal of Science: Natural Sciences and Technology, 33 (1S), pp. 138-143, DOI: 10.25073/2588-1140/vnunst.4540
2. Mai Van Linh, Ngo Thu Ha, Le Thi Thanh Huong, Lưu Thi Binh, Nguyen Phu Hung (2018), “All-trans retinoic acid effects on the EGF and JAK/STAT signaling pathways in gastric cancer stem cells”, Journal of Vietnam medicine, 469, pp.156-158.
3. Le Thi Thanh Huong, Luu Thi Binh, Diep Thi Huong Giang, Nguyen Phu Hung (2017), “Inhibition of All-Trans Retinoic Acid on the Expression of the Genes Envoled in Self-Renewal and Notch Signaling Pathway in Gastric Cancer Cells”, VNU Journal of Science: Natural Sciences and Technology, 34 (4), pp.30-36. DOI doi: .
4. Luu Thi Binh, Le Thi Thanh Huong, Nguyen Trung Thanh, Nguyen Phu Hung (2019), “All trans retinoic acid regulates expression of genes invoved in cell senescence pathway in gastric cancer cell line MKN45”, VNU Journal of Science: Natural Sciences and Technology, completed review, posted in Q4.

5.2. Training products

1. Diep Thi Huong Giang (2019), Study the effect of All trans retinoic acid on the senessence of gastric cancer cells MKN45, Master thesis of Applied Biology, Thai Nguyen university of sciences.
2. Mai Van Linh (2019), Study the effect of All trans retinoic acid on EGF and JAK/STAT signaling pathways in gastric cancer cell MKN45, Master thesis in Applied Biology, Thai Nguyen University of Sciences.

6. Transfer alternatives, application institution, impacts and benefits of research results

• This is a basic research project.
• Impact and benefits of the research results: These research results contribute to clarify the molecular mechanism of cancer suppression by ATRA. These are additional evidences to prove ATRA is a potential substance in the treatment of gastric cancer.