RAP80 regulates epithelial–mesenchymal transition related with metastasis and malignancy of cancer
Open accessAbstract
Epithelial–mesenchymal transition (EMT) has been closely related with invasive and metastatic properties of cancer. Recently, the convergence of DNA damage response and EMT in cancer development has received a great amount of scientific attention. Here, we showed that EMT is induced by the downregulation of RAP 80, a well‐known regulator for DNA damage response. The knockdown of RAP 80 leads to EMT‐like morphological changes and the increase of tumor sphere formation in non‐adhesive culture. Mechanistically, RAP 80 controls a reciprocal regulatory axis of ZEB 1 (for EMT activation) and miR200c (for EMT inhibition). The downregulation of RAP 80 increases ZEB 1 protein and decreases miR200c expression to activate EMT signaling in the form of drastic inhibitions of E‐cadherin, p16 and p21 expression. Using in vivo metastasis analysis, RAP 80 knockdown cells are shown to dramatically metastasize into the lung and generate more malignant phenotype compared to controls. Interestingly, the expression level of RAP 80 was positively correlated with the survival rate in lung adenocarcinoma and breast cancer patients. These findings indicate that RAP 80 is a critical gatekeeper in impeding EMT‐induced metastasis and malignant phenotypes of cancer as well as preserving DNA integrity.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
MDM2 and UIMC1 are highly expressed in the testis and have been implicated in cancer.
“Both genes are highly expressed in the testis (http://www.gtexportal.org/) and have been implicated in cancer62, 63.”
From Distinct selective forces and Neanderthal introgression shaped genetic diversity at genes involved in neurodevelopmental disorders (2017) · cites this paper as [63]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells
Mani, S. A., Guo, W., Liao, M.-J., Eaton, E. N., Ayyanan, A., Zhou, A. Y., Brooks, M. W., Reinhard, F., Zhang, C. C., Shipitsin, M. V., et al. (2008) · Cell · doi:10.1016/j.cell.2008.03.027 · Cited by 8,679 · see citing works
Molecular mechanisms of epithelial–mesenchymal transition
Lamouille, S., Xu, J., & Derynck, R. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3758 · Cited by 8,091 · see citing works
Glioma stem cells promote radioresistance by preferential activation of the DNA damage response
Bao, S., Wu, Q., McLendon, R. E., Hao, Y., Shi, Q., Hjelmeland, A. B., Dewhirst, M. W., Bigner, D. D., & Rich, J. N. (2006) · Nature · doi:10.1038/nature05236 · Cited by 6,397 · see citing works
DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis
Bartkova, J., Hořejší, Z., Koed, K., Krämer, A., Tort, F., Zieger, K., Guldberg, P., Sehested, M., Nesland, J. M., Lukas, C., et al. (2005) · Nature · doi:10.1038/nature03482 · Cited by 2,688 · see citing works
Role of cell shape in growth control
Folkman, J., & Moscona, A. (1978) · Nature · doi:10.1038/273345a0 · Cited by 2,422 · see citing works
Park, S.-M., Gaur, A. B., Lengyel, E., & Peter, M. E. (2008) · Genes & Development · doi:10.1101/gad.1640608 · Cited by 2,272 · see citing works
Self-citationActivation of the DNA damage checkpoint and genomic instability in human precancerous lesions
Gorgoulis, V. G., Vassiliou, L.-V. F., Karakaidos, P., Zacharatos, P., Kotsinas, A., Liloglou, T., Venere, M., DiTullio, R. A., Kastrinakis, N. G., Levy, B., et al. (2005) · Nature · doi:10.1038/nature03485 · Cited by 2,009 · see citing works
Exploring the role of cancer stem cells in radioresistance
Baumann, M. A., Krause, M., & Hill, R. P. (2008) · Nature reviews. Cancer · doi:10.1038/nrc2419 · Cited by 817 · see citing works
Abraxas and RAP80 Form a BRCA1 Protein Complex Required for the DNA Damage Response
Wang, B., Matsuoka, S., Ballif, B. A., Zhang, D., Smogorzewska, A., Gygi, S. P., & Elledge, S. J. (2007) · Science · doi:10.1126/science.1139476 · Cited by 695 · see citing works
RAP80 Targets BRCA1 to Specific Ubiquitin Structures at DNA Damage Sites
Sobhian, B., Shao, G., Lilli, D. R., Culhane, A. C., Moreau, L. A., Xia, B., Livingston, D. M., & Greenberg, R. A. (2007) · Science · doi:10.1126/science.1139516 · Cited by 672 · see citing works
Lukas, J., Lukas, C., & Bartek, J. (2011) · Nature Cell Biology · doi:10.1038/ncb2344 · Cited by 645 · see citing works
Ubiquitin-Binding Protein RAP80 Mediates BRCA1-Dependent DNA Damage Response
Kim, H., Chen, J., & Yu, X. (2007) · Science · doi:10.1126/science.1139621 · Cited by 540 · see citing works
Self-citationATM-mediated stabilization of ZEB1 promotes DNA damage response and radioresistance through CHK1
Zhang, P., Wei, Y., Wang, L., Debeb, B. G., Yuan, Y., Zhang, J., Yuan, J., Wang, M., Chen, D., Sun, Y., et al. (2014) · Nature Cell Biology · doi:10.1038/ncb3013 · Cited by 454 · see citing works
Zeb1 links epithelial-mesenchymal transition and cellular senescence
Liu, Y., El‐Naggar, S., Darling, D. S., Higashi, Y., & Dean, D. C. (2008) · Development · doi:10.1242/dev.007047 · Cited by 304 · see citing works
CCDC98 is a BRCA1-BRCT domain-binding protein involved in the DNA damage response
Kim, H., Huang, J., & Chen, J. (2007) · Nature Structural & Molecular Biology · doi:10.1038/nsmb1277 · Cited by 212 · see citing works
Self-citationWang, B., Hurov, K., Hofmann, K., & Elledge, S. J. (2009) · Genes & Development · doi:10.1101/gad.1770309 · Cited by 172 · see citing works
Yan, J., Kim, Y. S., Yang, X.-P., Li, L., Liao, G., Xia, F., & Jetten, A. M. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-0924 · Cited by 170 · see citing works
Guha, M., Srinivasan, S., Ruthel, G. T., Kashina, A., Carstens, R. P., Mendoza, A., Khanna, C., Winkle, T. V., & Avadhani, N. G. (2013) · Oncogene · doi:10.1038/onc.2013.467 · Cited by 154 · see citing works
MERIT40 controls BRCA1–Rap80 complex integrity and recruitment to DNA double-strand breaksPreprint
Shao, G., Patterson-Fortin, J., Messick, T. E., Feng, D., Shanbhag, N. M., Wang, Y., & Greenberg, R. A. (2009) · Genes & Development · doi:10.1101/gad.1739609 · Cited by 154 · see citing works
Takeyama, Y., Sato, M., Horio, M., et al. (2010) · Cancer Letters · doi:10.1016/j.canlet.2010.04.008 · Cited by 153 · see citing works
CCDC98 targets BRCA1 to DNA damage sites
Liu, Z., Wu, J., & Yu, X. (2007) · Nature Structural & Molecular Biology · doi:10.1038/nsmb1279 · Cited by 148 · see citing works
DNA Damage in Cancer Therapeutics: A Boon or a Curse?
Khanna, A. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-3247 · Cited by 140 · see citing works
Hypoxia-Regulated Delta-like 1 Homologue Enhances Cancer Cell Stemness and Tumorigenicity
Kim, Y., Lin, Q., Zelterman, D. A., & Yun, Z. (2009) · Cancer Research · doi:10.1158/0008-5472.can-09-1605 · Cited by 123 · see citing works
Emerging role of DUBs in tumor metastasis and apoptosis: Therapeutic implication
He, M., Zhou, Z., Wu, G. Y., Chen, Q., & Wan, Y. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.03.001 · Cited by 100 · see citing works
Yu, J., Sun, W., Hua, F., Xie, J., Lin, H., Zhou, D., & Hu, Z. (2015) · Cancer Letters · doi:10.1016/j.canlet.2015.05.029 · Cited by 93 · see citing works
DNA damage checkpoint recovery and cancer development
Wang, H., Zhang, X., Teng, L., & Legerski, R. J. (2015) · Experimental Cell Research · doi:10.1016/j.yexcr.2015.03.011 · Cited by 89 · see citing works
Janer, A., Antonická, H., Lalonde, E., Nishimura, T., Sasarman, F., Brown, G. K., Brown, R. M., Majewski, J., & Shoubridge, E. A. (2012) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2012.08.020 · Cited by 73 · see citing works
Nikkilä, J., Coleman, K. A., Morrissey, D., Pylkäs, K., Erkko, H., Messick, T. E., Karppinen, S.-M., Amelina, A., Winqvist, R., & Greenberg, R. A. (2009) · Oncogene · doi:10.1038/onc.2009.33 · Cited by 63 · see citing works
Modification ofBRCA1-Associated Breast and Ovarian Cancer Risk byBRCA1-Interacting Genes
Rebbeck, T. R., Mitra, N., Domchek, S. M., Wan, F., Friebel, T. M., Tran, T. V., Singer, C. F., Tea, M.-K. M., Blum, J. L., Tung, N., et al. (2011) · Cancer Research · doi:10.1158/0008-5472.can-11-0773 · Cited by 58 · see citing works
RAP80, a Novel Nuclear Protein That Interacts with the Retinoid-related Testis-associated Receptor
Yan, Z., Kim, Y. S., & Jetten, A. M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m203475200 · Cited by 50 · see citing works
RAP80 Is Critical in Maintaining Genomic Stability and Suppressing Tumor Development
Yin, Z., Menéndez, D., Resnick, M. A., French, J. E., Janardhan, K. S., & Jetten, A. M. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-1484 · Cited by 27 · see citing works
Mozzi, A., Forni, D., Cagliani, R., Pozzoli, U., Clerici, M., & Sironi, M. (2017) · Scientific Reports · doi:10.1038/s41598-017-06440-4 · Cited by 19 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [27]Yin Z, Menendez D, Resnick MA, French JE, Janardhan KS, Jetten AM. RAP80 is critical in maintaining genomic stability and suppressing tumor development. Cancer Res 2012; 72: 5081– 6. PMC3482830 22896338
Cited by
Sorted by citations
Mozzi, A., Forni, D., Cagliani, R., Pozzoli, U., Clerici, M., & Sironi, M. (2017) · Scientific Reports · doi:10.1038/s41598-017-06440-4 · Cited by 19 · see citing works
- Authors
- Park, S. Y., Korm, S., Chung, H. J., Choi, S. J., Jang, J., Cho, S., Lim, Y. T., Kim, H., & Lee, J.
- Affiliations
- Chungnam National University (KR)
- Sungkyunkwan University (KR)
- Corresponding author
- Kim, Hongtae
- Lee, Joo‐Yong
- Venue
- Cancer Science
- Publisher
- Wiley
- Published
- 2016-02-10
- Volume
- 107
- Issue
- 3
- Pages
- 267-273
- ISSN
- 1347-9032 (ISSN-L)
- 1349-7006
- PMC
- PMC4814264
- OpenAlex
- W2227664873
- Cited by
- 12
- References
- 32
- Citations by year
- 2025: 1 · 2022: 1 · 2021: 1 · 2020: 3 · 2019: 1 · 2017: 4 · 2016: 1
- FWCI
- 1.08
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cancer Science (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- National Research Foundation of Korea (NRF‐2012M3A9C6050087, 2013R1A6A9067028, 2013R1A1A2008576)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- RAP80, epithelial-mesenchymal transition, DNA damage response, metastasis, ZEB1, miR-200c, E-cadherin, p16, p21, lung adenocarcinoma, breast cancer, tumor sphere formation, DNA integrity, patient survival
- MeSH terms
- Zinc Finger E-box-Binding Homeobox 1, Adenocarcinoma of Lung, Adenocarcinoma, Animals, Breast Neoplasms, Carrier Proteins, DNA-Binding Proteins, Female, HeLa Cells, Humans, Lung Neoplasms, Male, Mice, Inbred BALB C, Mice, Nude, Neoplasm Transplantation, Nuclear Proteins, Transcription Factors, Homeodomain Proteins, Kaplan-Meier Estimate, Gene Knockdown Techniques, Histone Chaperones, Epithelial-Mesenchymal Transition
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
