scholarly journals Acrolein Contributes to Human Colorectal Tumorigenesis Through Activation of RAS/MAPK Pathway

2021 ◽  
Author(s):  
Hong-Chieh Tsai ◽  
Han-Hsing Tsou ◽  
Chun-Chi Lin ◽  
Shao-Chen Chen ◽  
Hsiao-Wei Cheng ◽  
...  
Keyword(s):  
Microarray Analysis ◽  
Cdna Microarray ◽  
Oncogenic Transformation ◽  
3T3 Cells ◽  
Cdna Microarray Analysis ◽  
Colon Tumorigenesis ◽  
Tumor Tissues ◽  
Chi Square Analysis ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

Abstract Background. Colorectal cancer (CRC) is one of the most well-known malignancies with high prevalence and poor 5-year survival. Previous studies have demonstrated that intake of food rich in fat, and with low fiber content (as known as high-fat diet, HFD) is capable of increasing the odds of developing CRC. Acrolein, an IARC group 2A carcinogen, can be formed by thermal treatment of animal and vegetable fats, carbohydrates and amino acids through Maillard reaction. Also, acrolein has been shown to be produced from microbial glycerol metabolism in human gut. Consequently, humans are at risk of acrolein exposure through consumption of foods rich in fat. However, whether acrolein contributes to HFD-induced CRC tumorigenesis remains elusive.Methods. The effect of acrolein in oncogenic transformation was analyzed using NIH/3T3 cells with xenograft tumorigenesis mice models. Furthermore, cDNA microarray analysis with Ingenuity Pathway Analysis (IPA) was performed in acrolein-transformed NIH/3T3 cells. Finally, acrolein-induced DNA damages (Acr-dG) were analyzed in tumor tissues and normal epithelial of CRC patients using immunohistochemical analysis. The levels of Acr-dG adducts were associated with tumor characteristics and CRC patients’ survival using Chi-Square analysis and Kaplan Meier survival analysis, respectively.Results. In this present study, we found that acrolein induced oncogenic transformation including faster cell cycling, proliferation, soft agar formation, sphere formation, cell migration in NIH/3T3 cells. Using xenograft tumorigenicity assays, the acrolein-transformed NIH3T3 clone formed tumors whereas no tumors were observed in mice inoculated with NIH3T3 parental cells. In addition, RAS/MAPK pathway contributing to colon tumorigenesis was activated in NIH/3T3 Acr-clone using cDNA microarray analysis with IPA. Finally, Acr-dG adducts were higher in CRC tumor tissues compared to normal epithelial cells in CRC patients. Intriguingly, CRC patients with higher Acr-dG adducts have better prognosis. Conclusions. Taken together, this is the first study to demonstrate that acrolein is important in oncogenic transformation through activating RAS/MAPK signaling pathway contributing to colon tumorigenesis. Thus, acrolein might be a novel target for early detection, prevention and treatment of tumors in the future.

scholarly journals Insulin and IGF-1 Induce Different Patterns of Gene Expression in Mouse Fibroblast NIH-3T3 Cells: Identification by cDNA Microarray Analysis

Endocrinology ◽  
2001 ◽  
Vol 142 (11) ◽  
pp. 4969-4975 ◽  
Author(s):  
Joelle Dupont ◽  
Javed Khan ◽  
Bao-He Qu ◽  
Paul Metzler ◽  
Lee Helman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Microarray Analysis ◽  
Cdna Microarray ◽  
Mouse Fibroblast ◽  
3T3 Cells ◽  
Cdna Microarray Analysis ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

Oncogenic Transformation of NIH 3T3 Fibroblasts by BCR-ABL Oncoprotein Requires the IL-3 Receptor.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3370-3370
Author(s):  
Wenjing Tao ◽  
Hui Lin ◽  
Tong Sun ◽  
Ajoy K. Samanta ◽  
Ralph B. Arlinghaus
Keyword(s):  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Cell System ◽  
Receptor Expression ◽  
Oncogenic Transformation ◽  
3T3 Cells ◽  
Lymphoid Leukemia ◽  
3T3 Fibroblasts ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

Abstract Bcr-Abl is a leukemia-inducing protein, which causes oncogenic transformation of myeloid progenitors in Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) and lymphoid progenitors in Ph+ acute lymphoid leukemia (ALL). Oncogenic transformation of hematopoietic cells by the Bcr-Abl oncoprotein directly involves the activation Jak2 tyrosine kinase and the Stat5 transcription factor. Both proteins are normally linked to the IL-3/GM-CSF receptors for growth and survival. Since fibroblastic cells are not targets of BCR-ABL induced oncogenesis, we determined whether forced expression of the IL-3 receptor would allow oncogenic transformation of NIH 3T3 fibroblasts known to be resistant to transformation by BCR-ABL. NIH 3T3 cells transduced with the human IL-3 receptor a and b chains were highly susceptible to oncogenic transformation by expression of BCR-ABL. Forced expression of both receptor chains but not either one alone allowed efficient foci formation of NIH 3T3 cells expressing BCR-ABL, and these cells formed colonies in soft agar whereas BCR-ABL positive NIH 3T3 cells lacking IL-3 receptor expression did not. The Bcr-Abl kinase inhibitor imatinib mesylate (1 mM) and the Jak kinase inhibitor AG490 (10 mM) strongly inhibited agar colony formation. A small molecule inhibitor of Jak2 kinase, 1,2,3,4,5,6-hexabromocyclohexane reported to be specific for Jak2 (Sandberg et al. J. Med. Chem, 2005)-significantly reduced the phosphorylation of Gab2 at the YxxM motif, which is needed for activation of the PI-3 kinase and Akt, two proteins that are part of the Bcr-Abl/Jak2 Network (Samanta et al. Cancer Res, 2006). These findings indicate that Bcr-Abl oncoprotein requires the IL-3 receptor/Jak2/Stat5 pathways for oncogenic transformation of NIH 3T3 fibroblasts, and may explain partially why Bcr-Abl oncogenesis is restricted to hematopoietic malignancies. Furthermore, this cell system in fibroblastic and other cell lineages will provide a model to probe the detailed steps that require IL-3 receptor and Jak2 for Bcr-Abl induced leukemia.

scholarly journals Inhibition of v-src-induced transformation by a GTPase-activating protein

1991 ◽  
Vol 11 (5) ◽  
pp. 2812-2818 ◽  
Author(s):  
M Nori ◽  
U S Vogel ◽  
J B Gibbs ◽  
M J Weber
Keyword(s):  
Active Form ◽  
Signalling Pathway ◽  
Oncogenic Transformation ◽  
Gtpase Activating Protein ◽  
3T3 Cells ◽  
Inactive Form ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

Previous work has shown that microinjection into cells of antibodies against p21ras blocks transformation by src, suggesting that oncogenic transformation by pp60v-src is dependent on p21ras. The activity of p21ras itself is regulated by its cyclic association with GDP-GTP, where p21ras-GTP is the active form and p21ras-GDP is the inactive form. A GTPase-activating protein (GAP) mediates the inactivation of p21ras by facilitating the conversion of the active p21ras-GTP to the inactive p21ras-GDP. This predicts that overexpression of GAP would inactivate p21ras and block transformation of cells by src. In this paper, we confirm this prediction. We report that overexpression of GAP in NIH 3T3 cells blocks transformation by pp60v-src but not by v-ras. Susceptibility to transformation by v-src is restored when GAP expression is lowered to levels comparable to that in control cells. These results support the suggestion that p21ras plays a central role in the signalling pathway used by pp60v-src.

scholarly journals Inhibition of v-src-induced transformation by a GTPase-activating protein.

1991 ◽  
Vol 11 (5) ◽  
pp. 2812-2818 ◽  
Author(s):  
M Nori ◽  
U S Vogel ◽  
J B Gibbs ◽  
M J Weber
Keyword(s):  
Active Form ◽  
Signalling Pathway ◽  
Oncogenic Transformation ◽  
Gtpase Activating Protein ◽  
3T3 Cells ◽  
Inactive Form ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

Previous work has shown that microinjection into cells of antibodies against p21ras blocks transformation by src, suggesting that oncogenic transformation by pp60v-src is dependent on p21ras. The activity of p21ras itself is regulated by its cyclic association with GDP-GTP, where p21ras-GTP is the active form and p21ras-GDP is the inactive form. A GTPase-activating protein (GAP) mediates the inactivation of p21ras by facilitating the conversion of the active p21ras-GTP to the inactive p21ras-GDP. This predicts that overexpression of GAP would inactivate p21ras and block transformation of cells by src. In this paper, we confirm this prediction. We report that overexpression of GAP in NIH 3T3 cells blocks transformation by pp60v-src but not by v-ras. Susceptibility to transformation by v-src is restored when GAP expression is lowered to levels comparable to that in control cells. These results support the suggestion that p21ras plays a central role in the signalling pathway used by pp60v-src.

scholarly journals Resistance to oncogenic transformation in revertant R1 of human ras-transformed NIH 3T3 cells.

1989 ◽  
Vol 9 (5) ◽  
pp. 2258-2263 ◽  
Author(s):  
N Kuzumaki ◽  
Y Ogiso ◽  
A Oda ◽  
H Fujita ◽  
H Suzuki ◽  
...  
Keyword(s):  
Simian Virus 40 ◽  
Soft Agar ◽  
Simian Virus ◽  
T Antigen ◽  
Oncogenic Transformation ◽  
3T3 Cells ◽  
Cellular Mechanisms ◽  
Ras Gene ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

A flat revertant, R1, was isolated from human activated c-Ha-ras-1 (hu-ac-Ha-ras) gene-transformed NIH 3T3 cells (EJ-NIH 3T3) treated with mutagens. R1 contained unchanged transfected hu-ac-Ha-ras DNA and expressed high levels of hu-ac-Ha-ras-specific mRNA and p21 protein. Transfection experiments revealed that NIH 3T3 cells could be transformed by DNA from R1 cells but R1 cells could not be retransformed by Kirsten sarcoma virus, DNA from EJ-NIH 3T3 cells, hu-ac-Ha-ras, v-src, v-mos, simian virus 40 large T antigen, or polyomavirus middle T antigen. Somatic cell hybridization studies showed that R1 was not retransformed by fusion with NIH 3T3 cells and suppressed anchorage independence of EJ-NIH 3T3 and hu-ac-Ha-ras gene-transformed rat W31 cells in soft agar. These results suggest that the reversion and resistance to several oncogenes in R1 is due not to cellular defects in the production of the transformed phenotype but rather to enhancement of cellular mechanisms that suppress oncogenic transformation.

Analysis of Ras-induced oncogenic transformation of NIH-3T3 cells using differential-display 2-DE proteomics

2007 ◽  
Vol 28 (12) ◽  
pp. 1997-2008 ◽  
Author(s):  
Hong Ji ◽  
Robert L. Moritz ◽  
Yu-Sam Kim ◽  
Hong-Jian Zhu ◽  
Richard J. Simpson
Keyword(s):  
Differential Display ◽  
Oncogenic Transformation ◽  
3T3 Cells ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

scholarly journals Resistance to oncogenic transformation in revertant R1 of human ras-transformed NIH 3T3 cells

1989 ◽  
Vol 9 (5) ◽  
pp. 2258-2263
Author(s):  
N Kuzumaki ◽  
Y Ogiso ◽  
A Oda ◽  
H Fujita ◽  
H Suzuki ◽  
...  
Keyword(s):  
Simian Virus 40 ◽  
Soft Agar ◽  
Simian Virus ◽  
T Antigen ◽  
Oncogenic Transformation ◽  
3T3 Cells ◽  
Cellular Mechanisms ◽  
Ras Gene ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

A flat revertant, R1, was isolated from human activated c-Ha-ras-1 (hu-ac-Ha-ras) gene-transformed NIH 3T3 cells (EJ-NIH 3T3) treated with mutagens. R1 contained unchanged transfected hu-ac-Ha-ras DNA and expressed high levels of hu-ac-Ha-ras-specific mRNA and p21 protein. Transfection experiments revealed that NIH 3T3 cells could be transformed by DNA from R1 cells but R1 cells could not be retransformed by Kirsten sarcoma virus, DNA from EJ-NIH 3T3 cells, hu-ac-Ha-ras, v-src, v-mos, simian virus 40 large T antigen, or polyomavirus middle T antigen. Somatic cell hybridization studies showed that R1 was not retransformed by fusion with NIH 3T3 cells and suppressed anchorage independence of EJ-NIH 3T3 and hu-ac-Ha-ras gene-transformed rat W31 cells in soft agar. These results suggest that the reversion and resistance to several oncogenes in R1 is due not to cellular defects in the production of the transformed phenotype but rather to enhancement of cellular mechanisms that suppress oncogenic transformation.

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