DDIT4 promotes gastric cancer proliferation and tumorigenesis through the p53 and MAPK pathways
Open accessAbstract
Background: Gastric cancer (GC) is one of the most common malignancies worldwide, particularly in China. DNA damage‐inducible transcript 4 (DDIT4) is a mammalian target of rapamycin inhibitor and is induced by various cellular stresses; however, its critical role in GC remains poorly understood. The present study aimed to investigate the potential relationship and the underlying mechanism between DDIT4 and GC development. Methods: We used western blotting, real‐time polymerase chain reaction, and immunohistochemical or immunofluorescence to determine DDIT4 expression in GC cells and tissues. High‐content screening, cell counting kit‐8 assays, colony formation, and in vivo tumorigenesis assays were performed to evaluate cell proliferation. Flow cytometry was used to investigate cell apoptosis and cell cycle distribution. Results: DDIT4 was upregulated in GC cells and tissue. Furthermore, downregulating DDIT4 in GC cells inhibited proliferation both in vitro and in vivo and increased 5‐fluorouracil‐induced apoptosis and cell cycle arrest. In contrast, ectopic expression of DDIT4 in normal gastric epithelial cells promoted proliferation and attenuated chemosensitivity. Further analysis indicated that the mitogen‐activated protein kinase and p53 signaling pathways were involved in the suppression of proliferation, and increased chemosensitivity upon DDIT4 downregulation. Conclusion: DDIT4 promotes GC proliferation and tumorigenesis, providing new insights into the role of DDIT4 in the tumorigenesis of human GC.
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Quantitative proteomic analysis of protein expression changes conferred by asukamycin treatment in 231MFP cells showed many known p53 transcriptional targets upregulated, including GADD45A, GADD45B, ANKRD1, HMOX1, ATF3, PMAIP1, DDIT4, DNAJB9, and PLK2.
“quantitative proteomic analysis of protein expression changes conferred by asukamycin treatment in 231MFP cells showed many known p53 transcriptional targets upregulated in expression, including GADD45A, GADD45B, ANKRD1, HMOX1, ATF3, PMAIP1, DDIT4, DNAJB9, and PLK2 (Extended Data Figure 9) 31–37.”
From Manumycin polyketides act as molecular glues between UBR7 and P53 (2020) · cites this paper as [34]
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Cites
Coussens, L. M., & Werb, Z. (2002) · Nature · doi:10.1038/nature01322 · Cited by 15,111 · see citing works
Comprehensive molecular characterization of gastric adenocarcinoma
The Cancer Genome Atlas Research Network (2014) · Nature · doi:10.1038/nature13480 · Cited by 6,498 · see citing works
Tumor suppressor p53 is a direct transcriptional activator of the human bax gene
Toshiyuki, M., & Reed, J. C. (1995) · Cell · doi:10.1016/0092-8674(95)90412-3 · Cited by 4,063 · see citing works
Proliferation, cell cycle and apoptosis in cancer
Evan, G. I., & Vousden, K. H. (2001) · Nature · doi:10.1038/35077213 · Cited by 3,383 · see citing works
Signal integration by JNK and p38 MAPK pathways in cancer development
Wagner, E. F., & Nebreda, Á. R. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2694 · Cited by 2,583 · see citing works
Genomic instability — an evolving hallmark of cancer
Negrini, S., Gorgoulis, V. G., & Halazonetis, T. D. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2858 · Cited by 2,397 · see citing works
Epidemiology of gastric cancer
Crew, K. D., & Neugut, A. I. (2006) · World Journal of Gastroenterology · doi:10.3748/wjg.v12.i3.354 · Cited by 2,118 · see citing works
Mice Lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control
Deng, C., Zhang, P., Wade Harper, J., Elledge, S. J., & Leder, P. (1995) · Cell · doi:10.1016/0092-8674(95)90039-x · Cited by 2,113 · see citing works
Principles of cancer therapy: oncogene and non-oncogene addiction
Luo, J., Solimini, N. L., & Elledge, S. J. (2009) · Cell · doi:10.1016/j.cell.2009.02.024 · Cited by 1,765 · see citing works
The importance of intrinsic disorder for protein phosphorylation
Iakoucheva, L. M. (2004) · Nucleic Acids Research · doi:10.1093/nar/gkh253 · Cited by 1,429 · see citing works
A role for ATR in the DNA damage-induced phosphorylation of p53
Tibbetts, R. S., Brumbaugh, K. M., Williams, J. M., Sarkaria, J. N., Cliby, W. A., Shieh, S.-Y., Taya, Y., Prives, C., & Abraham, R. T. (1999) · Genes & Development · doi:10.1101/gad.13.2.152 · Cited by 1,046 · see citing works
DeYoung, M. P., Horak, P., Sofer, A., Sgroi, D., & Ellisen, L. W. (2008) · Genes & Development · doi:10.1101/gad.1617608 · Cited by 710 · see citing works
Ellisen, L. W., Ramsayer, K. D., Johannessen, C. M., Yang, A., Beppu, H., Minda, K., Oliner, J. D., McKeon, F., & Haber, D. A. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00706-2 · Cited by 474 · see citing works
Yoshida, T., Mett, I. L., Bhunia, A. K., Bowman, J. C., Perez, M. J., Zhang, L., Gandjeva, A., Zhen, L., Chukwueke, U. N., Mao, T., et al. (2010) · Nature Medicine · doi:10.1038/nm.2157 · Cited by 234 · see citing works
Negative feedback control of HIF-1 through REDD1-regulated ROS suppresses tumorigenesis
Horak, P., Crawford, A. R., Vadysirisack, D. D., Nash, Z. M., DeYoung, M. P., Sgroi, D. C., & Ellisen, L. W. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0907705107 · Cited by 201 · see citing works
Hwang‐Verslues, W. W., Chang, P.-H., Wei, P.-C., Yang, C.-Y., Huang, C.-K., Kuo, W.-H., Shew, J.-Y., Chang, K.-J., Lee, E.-H., & Lee, W.-H. (2011) · Oncogene · doi:10.1038/onc.2010.618 · Cited by 199 · see citing works
REDD1 enhances protein phosphatase 2A-mediated dephosphorylation of Akt to repress mTORC1 signaling
Dennis, M. D., Coleman, C. S., Berg, A., Jefferson, L. S., & Kimball, S. R. (2014) · Science Signaling · doi:10.1126/scisignal.2005103 · Cited by 159 · see citing works
Inflammation, DNA Damage, Helicobacter pylori and Gastric Tumorigenesis
Kalisperati, P., Spanou, E., Pateras, I. S., Korkolopoulou, P. A., Varvarigou, A. A., Karavokyros, I., Gorgoulis, V. G., Vlachoyiannopoulos, P. G., & Sougioultzis, S. (2017) · Frontiers in Genetics · doi:10.3389/fgene.2017.00020 · Cited by 108 · see citing works
Wang, Y., Han, E. S., Xing, Q., et al. (2014) · Cancer Letters · doi:10.1016/j.canlet.2014.12.033 · Cited by 97 · see citing works
Molitoris, J. K., McColl, K. S., Swerdlow, S., Matsuyama, M., Lam, M., Finkel, T. H., Matsuyama, S., & Distelhorst, C. W. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.245423 · Cited by 96 · see citing works
Pinto, J. A., Rolfo, C. D., Raez, L. E., Prado-Mantilla, A., Araujo, J. M., Bravo, L., Fajardo, W., Morante, Z., Aguilar, A., Neciosup, S. P., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-01207-3 · Cited by 83 · see citing works
Yun, S.-M., Woo, S. H., Oh, S. T., Hong, S.-E., Choe, T., Ye, S., Kim, E., Seong, M. K., Kim, H., Noh, W. C., et al. (2015) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2015.11.016 · Cited by 67 · see citing works
Synergy between Androgen Receptor Antagonism and Inhibition of mTOR and HER2 in Breast Cancer
Gordon, M. A., D’Amato, N. C., Gu, H., et al. (2017) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-17-0111 · Cited by 59 · see citing works
Gastric cancer: current and evolving treatment landscape
Sun, W., & Yan, L. (2016) · 癌症：英文版 · doi:10.1186/s40880-016-0147-6 · Cited by 52 · see citing works
Barakat, D. J., Mendonca, J., Barberi, T. J., et al. (2016) · Cancer Letters · doi:10.1016/j.canlet.2016.03.005 · Cited by 51 · see citing works
Regulation of CHK1 by mTOR contributes to the evasion of DNA damage barrier of cancer cells
Zhou, X., Liu, W., Hu, X., Dorrance, A. M., Garzon, R., Houghton, P. J., & Shen, C. (2017) · Scientific Reports · doi:10.1038/s41598-017-01729-w · Cited by 46 · see citing works
Rehan, M. (2017) · Journal of Cellular Biochemistry · doi:10.1002/jcb.26117 · Cited by 39 · see citing works
REDD1 and p-AKT over-expression may predict poor prognosis in ovarian cancer.
Jia, W., Chang, B., Sun, L., Zhu, H., Pang, L., Lin, T., Zou, H., Du, J.-Z., Dong, Y., Yan, Q., et al. (2014) · PubMed Central · Cited by 36 · see citing works
Self-citationRedd1 inhibits the invasiveness of non-small cell lung cancer cells
Jin, H., Seo, S., Woo, S., Kim, Y., Hong, S., Yi, J.-Y., Noh, W.-C., Kim, E., Lee, J., Hong, S., et al. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.03.047 · Cited by 22 · see citing works
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Manumycin polyketides act as molecular glues between UBR7 and P53
Isobe, Y., Okumura, M., McGregor, L. M., Brittain, S. M., Jones, M. D., Liang, X., White, R., Forrester, W., McKenna, J. M., Tallarico, J. A., et al. (2020) · Nature Chemical Biology · doi:10.1038/s41589-020-0557-2 · Cited by 124 · see citing works
- Authors
- Du, F., Sun, L., Chu, Y., Li, T., Lei, C., Wang, X., Jiang, M., Min, Y., Lu, Y., Zhao, X., Nie, Y., & Fan, D.
- Affiliations
- National Clinical Research Center for Digestive Diseases (CN)
- Corresponding author
- Lu, Yuanyuan
- Zhao, Xiaodi
- Fan, Daiming
- Venue
- Cancer Communications
- Published
- 2018-07-05
- Volume
- 38
- Issue
- 1
- Pages
- 45-45
- ISSN
- 1000-467X (ISSN-L)
- 2523-3548
- PMC
- PMC6034313
- OpenAlex
- W2825767749
- Cited by
- 103
- References
- 29
- Citations by year
- 2026: 3 · 2025: 12 · 2024: 11 · 2023: 22 · 2022: 18 · 2021: 20 · 2020: 10 · 2019: 7
- FWCI
- 6.97
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- 癌症：英文版 (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (81430072, 81421003, 81602641, 81572929)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Gastric Cancer Management and Outcomes
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- DDIT4, gastric cancer, cell proliferation, carcinogenesis, p53 pathway, MAPK signaling, apoptosis, cell cycle arrest, mTOR inhibitors
- MeSH terms
- RNAi Therapeutics, Animals, Cell Line, Female, Humans, Male, Mice, Inbred BALB C, Mice, Nude, Middle Aged, Stomach Neoplasms, Transcription Factors, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, MAP Kinase Signaling System, Xenograft Model Antitumor Assays, RNA Interference, Cell Line, Tumor, Tumor Burden, Cell Proliferation, Carcinogenesis
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