Transmembrane and Immunoglobulin Domain Containing 1, a Putative Tumor Suppressor, Induces G2/M Cell Cycle Checkpoint Arrest in Colon Cancer Cells
Open accessPublished version of a preprint
Abstract
Colorectal cancer (CRC) is a leading nonfamilial cause of cancer mortality among men and women. Although various genetic and epigenetic mechanisms have been identified, the full molecular mechanisms deriving CRC tumorigenesis are not fully understood. This study demonstrates that cell adhesion molecule transmembrane and immunoglobulin domain containing 1 (TMIGD1) are highly expressed in mouse and human normal intestinal epithelial cells. TMIGD1 knockout mice were developed, and the loss of TMIGD1 in mice was shown to result in the development of adenomas in small intestine and colon. In addition, the loss of TMIGD1 significantly impaired intestinal epithelium brush border membrane, junctional polarity, and maturation. Mechanistically, TMIGD1 inhibits tumor cell proliferation and cell migration, arrests cell cycle at the G2/M phase, and induces expression of p 21CIP1 (cyclin-dependent kinase inhibitor 1), and p 27KIP1 (cyclin-dependent kinase inhibitor 1B) expression, key cell cycle inhibitor proteins involved in the regulation of the cell cycle. Moreover, TMIGD1 is shown to be progressively down-regulated in sporadic human CRC, and its downregulation correlates with poor overall survival. The findings herein identify TMIGD1 as a novel tumor suppressor gene and provide new insights into the pathogenesis of colorectal cancer and a novel potential therapeutic target.
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?
TMIGD1 is predominantly expressed by proximal tubule kidney epithelial cells and by intestinal epithelial cells.
“TMIGD1 is predominantly expressed by proximal tubule kidney epithelial cells23–25 and by intestinal epithelial cells26–28.”
From Membrane recruitment of the polarity protein Scribble by the cell adhesion receptor TMIGD1 (2023) · cites this paper as [27]
Inactivation of the Tmigd1 gene in mice results in a grossly altered morphology of intestinal tissues associated with intestinal adenoma formation and enhanced proliferative activity in intestinal crypts.
“In further support of a role of TMIGD1 as tumor suppressor, inactivation of the Tmigd1 gene in mice results in a grossly altered morphology of intestinal tissues associated with intestinal adenoma formation and enhanced proliferative activity in intestinal crypts27.”
From Membrane recruitment of the polarity protein Scribble by the cell adhesion receptor TMIGD1 (2023) · cites this paper as [27]
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
Comprehensive molecular characterization of human colon and rectal cancer
The Cancer Genome Atlas Network (2012) · Nature · doi:10.1038/nature11252 · Cited by 8,499 · see citing works
The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity
Barretina, J., Caponigro, G., Stransky, N., Venkatesan, K., Margolin, A. A., Kim, S., Wilson, C. J., Lehár, J., Kryukov, G. V., Sonkin, D., et al. (2012) · Nature · doi:10.1038/nature11003 · Cited by 7,950 · see citing works
TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells
Li, T., Fan, J., Wang, B., Traugh, N. C., Chen, Q., Liu, J. S., Li, B., & Liu, X. S. (2017) · Cancer Research · doi:10.1158/0008-5472.can-17-0307 · Cited by 5,914 · see citing works
Estimating the world cancer burden: Globocan 2000
Parkin, D. M., Bray, F., Ferlay, J., & Pisani, P. (2001) · International Journal of Cancer · doi:10.1002/ijc.1440 · Cited by 3,718 · see citing works
Cell Adhesion: The Molecular Basis of Tissue Architecture and Morphogenesis
Gumbiner, B. M. (1996) · Cell · doi:10.1016/s0092-8674(00)81279-9 · Cited by 3,471 · see citing works
Comprehensive analyses of tumor immunity: implications for cancer immunotherapy
Li, B., Severson, E. A., Pignon, J., Zhao, H., Li, T., Novak, J. S. S., Jiang, P., Shen, H., Aster, J. C., Rodig, S. J., et al. (2016) · Genome biology · doi:10.1186/s13059-016-1028-7 · Cited by 2,419 · see citing works
Lynch, H. T., & de la Chapelle, A. (2003) · New England Journal of Medicine · doi:10.1056/nejmra012242 · Cited by 2,201 · see citing works
Genevestigator V3: A Reference Expression Database for the Meta‐Analysis of Transcriptomes
Hrúz, T., Laule, O., Szabo, G., Wessendorp, F., Stefan Bleuler, A., Oertle, L., Widmayer, P., Gruissem, W., & Philip Zimmermann, B. (2008) · Advances in Bioinformatics · doi:10.1155/2008/420747 · Cited by 1,910 · see citing works
Molecular Genetics of Colorectal Cancer
Fearon, E. R. (2011) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-011110-130235 · Cited by 1,805 · see citing works
Tight Junctions and Cell Polarity
Shin, K., Fogg, V. C., & Margolis, B. L. (2006) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.22.010305.104219 · Cited by 745 · see citing works
Wnt/β-Catenin Is Essential for Intestinal Homeostasis and Maintenance of Intestinal Stem Cells
Fevr, T., Robine, S., Louvard, D., & Huelsken, J. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01034-07 · Cited by 650 · see citing works
An Intestine-Specific Homeobox Gene Regulates Proliferation and Differentiation
Suh, E. R., & Traber, P. G. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.2.619 · Cited by 487 · see citing works
p21 and p27: roles in carcinogenesis and drug resistance
Abukhdeir, A. M., & Park, B. H. (2008) · Expert Reviews in Molecular Medicine · doi:10.1017/s1462399408000744 · Cited by 465 · see citing works
Multiple Roles of APC and its Therapeutic Implications in Colorectal Cancer
Zhang, L., & Shay, J. W. (2016) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djw332 · Cited by 451 · see citing works
Establishment of Intestinal Identity and Epithelial-Mesenchymal Signaling by Cdx2
Gao, N., White, P., & Kaestner, K. H. (2009) · Developmental Cell · doi:10.1016/j.devcel.2009.02.010 · Cited by 370 · see citing works
Loss of Apc+ in intestinal adenomas from Min mice.
Luongo, C., Moser, A. R., Gledhill, S., & Dove, W. F. (1994) · PubMed · Cited by 369 · see citing works
The molecular genetics of colorectal cancer
Ewing, I., Hurley, J. J., Josephides, E., & Millar, A. (2013) · Frontline Gastroenterology · doi:10.1136/flgastro-2013-100329 · Cited by 250 · see citing works
A Key Role for E-cadherin in Intestinal Homeostasis and Paneth Cell Maturation
Schneider, M. R., Dahlhoff, M., Horst, D. A., Hirschi, B., Trülzsch, K., Müller‐Höcker, J., Vogelmann, R., Allgäuer, M., Gerhard, M., Steininger, S., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0014325 · Cited by 206 · see citing works
Molecular genetics of colorectal cancer.
Bogaert, J. A., & Prenen, H. (2014) · Europe PMC (PubMed Central) · Cited by 183 · see citing works
A genetic study of the role of the Wnt/β-catenin signalling in Paneth cell differentiation
Andreu, P., Peignon, G., Slomianny, C., Taketo, M. M., Colnot, S., Robine, S., Lamarque, D., Laurent‐Puig, P., Perret, C., & Romagnolo, B. (2008) · Developmental Biology · doi:10.1016/j.ydbio.2008.09.027 · Cited by 124 · see citing works
Non-traditional roles for the Adenomatous Polyposis Coli (APC) tumor suppressor protein
Hanson, C. A., & Miller, J. R. (2005) · Gene · doi:10.1016/j.gene.2005.07.024 · Cited by 122 · see citing works
The adenomatous polyposis coli protein: in the limelight out at the edge
Dikovskaya, D., Zumbrunn, J., Penman, G. A., & Näthke, I. S. (2001) · Trends in Cell Biology · doi:10.1016/s0962-8924(01)02069-4 · Cited by 80 · see citing works
Identification of IGPR-1 as a novel adhesion molecule involved in angiogenesis
Rahimi, N., Rezazadeh, K., Mahoney, J. E., Hartsough, E. J., & Meyer, R. (2012) · Molecular Biology of the Cell · doi:10.1091/mbc.e11-11-0934 · Cited by 65 · see citing works
Self-citationCdx2 Levels Modulate Intestinal Epithelium Maturity and Paneth Cell Development
Crissey, M. A. S., Guo, R., Funakoshi, S., Kong, J., Liu, J. J., & Lynch, J. P. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.11.033 · Cited by 58 · see citing works
Woolf, N., Pearson, B. E., Bondzie, P. A., Meyer, R., Lavaei, M., Belkina, A. C., Chitalia, V. C., & Rahimi, N. (2017) · Oncogenesis · doi:10.1038/oncsis.2017.77 · Cited by 50 · see citing works
Self-citationCattaneo, E., Laczko, E., Buffoli, F., Zorzi, F., Bianco, M. A., Menigatti, M., Bartosova, Z., Haider, R., Helmchen, B., Sabates‐Bellver, J., et al. (2011) · EMBO Molecular Medicine · doi:10.1002/emmm.201100141 · Cited by 44 · see citing works
Molecular genetics of colorectal cancer
Clarens, D. C.-B. (2004) · Revista Española de Enfermedades Digestivas · doi:10.4321/s1130-01082004000100007 · Cited by 43 · see citing works
TMIGD1 Is a Novel Adhesion Molecule That Protects Epithelial Cells from Oxidative Cell Injury
Arafa, E., Bondzie, P. A., Rezazadeh, K., Meyer, R. D., Hartsough, E., Henderson, J. M., Schwartz, J. H., Chitalia, V., & Rahimi, N. (2015) · The American Journal of Pathology · doi:10.1016/j.ajpath.2015.06.006 · Cited by 40 · see citing works
Self-citationIyer, S. V., Ranjan, A., Elias, H. K., Parrales, A., Sasaki, H., Roy, B. C., Umar, S., Tawfik, O. W., & Iwakuma, T. (2016) · Nature Communications · doi:10.1038/ncomms13561 · Cited by 38 · see citing works
IGPR-1 Is Required for Endothelial Cell–Cell Adhesion and Barrier Function
Wang, Y. H. W., Meyer, R., Bondzie, P. A., Jiang, Y., Rahimi, I., Rezazadeh, K., Mehta, M. N., Laver, N., Costello, C. E., & Rahimi, N. (2016) · Journal of Molecular Biology · doi:10.1016/j.jmb.2016.11.003 · Cited by 32 · see citing works
Self-citationTMIGD1 acts as a tumor suppressor through regulation of p21Cip1/p27Kip1 in renal cancer
Meyer, R. D., Zou, X., Ali, M., Ersoy, E., Bondzie, P. A., Lavaei, M., Alexandrov, I., Henderson, J., & Rahimi, N. (2018) · Oncotarget · doi:10.18632/oncotarget.23822 · Cited by 24 · see citing works
Self-citationZabana, Y., Lorén, V., Domènech, E., Aterido, A., Garcia-Jaraquemada, A., Julià, A., Vicario, M., Pedrosa, E., Ferreiro, M., Troya, J., et al. (2020) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00027.2020 · Cited by 24 · see citing works
Suppressive roles of A3AR and TMIGD3 i1 in osteosarcoma malignancy
Ranjan, A., Iyer, S. V., & Iwakuma, T. (2017) · Cell Cycle · doi:10.1080/15384101.2017.1308153 · Cited by 11 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Ma, W., Zhou, Y., Lou, W., Wang, B., Li, B., Liu, X., Yang, J., Yang, B. Y., Liu, J., & Di, D. (2022) · Food Bioscience · doi:10.1016/j.fbio.2022.101664 · Cited by 37 · see citing works
Zhou, L., Zhu, L., Wu, X., Hu, S., Zhang, S., Ning, M., Yu, J. Q., & Chen, M. (2023) · BMC Medicine · doi:10.1186/s12916-023-02989-2 · Cited by 24 · see citing works
Intestinal brush border formation requires a TMIGD1-based intermicrovillar adhesion complex
Hartmann, C., Thüring, E.-M., Greune, L., Michels, B. E., Pajonczyk, D., Leußink, S., Brinkmann, F., Glaesner-Ebnet, M., Wardelmann, E., Zobel, T., et al. (2022) · Science Signaling · doi:10.1126/scisignal.abm2449 · Cited by 19 · see citing works
Rahimi, N., Ho, R. X.-Y., Chandler, K. B., Cena, K. O. C. D. L., Amraei, R., Mitchel, A. J., Engblom, N., & Costello, C. E. (2021) · Journal of Biomedical Science · doi:10.1186/s12929-021-00757-z · Cited by 15 · see citing works
Self-citationTMIGD1: Emerging functions of a tumor supressor and adhesion receptor
Thüring, E.-M., Hartmann, C., Schwietzer, Y. A., & Ebnet, K. (2023) · Oncogene · doi:10.1038/s41388-023-02696-5 · Cited by 11 · see citing works
Identification of four novel hub genes as monitoring biomarkers for colorectal cancer
Luo, D., Yang, J., Liu, J., Yong, X., & Wang, Z. (2022) · Hereditas · doi:10.1186/s41065-021-00216-7 · Cited by 10 · see citing works
Membrane recruitment of the polarity protein Scribble by the cell adhesion receptor TMIGD1
Thüring, E.-M., Hartmann, C., Maddumage, J. C., Javorsky, A., Michels, B. E., Gerke, V., Banks, L., Humbert, P. O., Kvansakul, M., & Ebnet, K. (2023) · Communications Biology · doi:10.1038/s42003-023-05088-3 · Cited by 7 · see citing works
The Role of TMIGD1 as a Tumor Suppressor in Colorectal Cancer
Mu, L., Wang, Y., Hu, Y., Shi, C., Alman, B. A., Zhang, C., & She, J. (2022) · Genetic Testing and Molecular Biomarkers · doi:10.1089/gtmb.2021.0169 · Cited by 7 · see citing works
Wahiduzzaman, M., Liu, Y., Huang, T., Wei, W., & Li, Y. (2022) · Biosafety and Health · doi:10.1016/j.bsheal.2022.03.001 · Cited by 6 · see citing works
Jalali, P., Aliyari, S., Etesami, M., Niasar, M. S., Taher, S., Kavousi, K., Mojarad, E. N., & Salehi, Z. (2024) · Clinical and Experimental Medicine · doi:10.1007/s10238-024-01512-y · Cited by 4 · see citing works
Alterations in Gene Pair Correlations as Potential Diagnostic Markers for Colon Cancer
Yang, B. Y., & Sakharkar, M. K. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232012463 · Cited by 3 · see citing works
Cheng, Y., He, X., Wang, L., Xu, Y., Shen, M., Zhang, W., Xia, Y., Zhang, J., Zhang, M., Wang, Y., et al. (2023) · PubMed Central · doi:10.12122/j.issn.1673-4254.2023.04.06 · Cited by 2 · see citing works
A Comprehensive Analysis of LYAR in Colorectal Cancer: Prognostic Marker and Therapeutic Target
Wen, J., Fang, Y., Li, D., Tang, Y.-L., Huang, H., Liu, L., Zeng, J., Dang, Y., Pan, Y.-F., Zeng, D.-T., et al. (2024) · Cancer Biotherapy and Radiopharmaceuticals · doi:10.1089/cbr.2023.0181 · Cited by 1 · see citing works
Su, Y., & Tonghua, C. (2021) · Research Square · doi:10.21203/rs.3.rs-200275/v1
Ebnet, K., Thüring, E.-M., Hartmann, C., Maddumage, J. C., Javorsky, A., Michels, B. E., Gerke, V., Banks, L., Humbert, P. O., & Kvansakul, M. (2023) · Research Square · doi:10.21203/rs.3.rs-2639220/v1
Zavarzadeh, P. G., Abedi, Z., Abbasi, A., MotieGhader, H., & Masoudi‐Nejad, A. (2024) · Research Square · doi:10.21203/rs.3.rs-2210142/v1
Zhou, L., Zhu, L., Wu, X., Hu, S., Zhang, S., Ning, M., Yu, J. Q., & Chen, M. (2023) · Figshare · doi:10.6084/m9.figshare.23884295
Zhou, L., Zhu, L., Wu, X., Hu, S., Zhang, S., Ning, M., Yu, J. Q., & Chen, M. (2023) · Figshare · doi:10.6084/m9.figshare.23884292
Rahimi, N., Potluri, S., & Chitalia, V. C. (2025) · Biochemistry · doi:10.1021/acs.biochem.5c00393
Self-citationZhou, L., Zhu, L., Wu, X., Hu, S., Zhang, S., Ning, M., Yu, J., & Chen, M. (2023) · Figshare · doi:10.6084/m9.figshare.23884301
Rahimi, N., Ho, R. X.-Y., Chandler, K. B., Cena, K. O. C. D. L., Amraei, R., Mitchel, A. J., Engblom, N., & Costello, C. E. (2021) · Figshare · doi:10.6084/m9.figshare.16599449
Self-citationZhou, L., Zhu, L., Wu, X., Hu, S., Zhang, S., Ning, M., Yu, J., & Chen, M. (2023) · Figshare · doi:10.6084/m9.figshare.23884289
Human TMIGD1 Promoter Exhibits Robust Activity in Prokaryotic Cells
Meyer, R., Yamamoto, K., Whelpley, B., Dempsey, D. R., & Rahimi, N. (2025) · Biochemistry · doi:10.1021/acs.biochem.5c00615
Self-citationDynamic gut responses to sepsis uncovered by multi-omics profiling in a rodent model
Lei, J., Qi, J., Zhai, J., Chen, Z., Li, N., Zhang, Y., Yuan, Y., & Sun, C. (2026) · Communications Biology · doi:10.1038/s42003-026-09940-0
Abdullah‐Zawawi, M., Tan, S. C., Jalal, M. I. A., Shahri, N. A. A. M., Mokhtar, M. F. M., & Jamal, R. (2026) · Heliyon · doi:10.1016/j.heliyon.2026.e45374
- Authors
- De La Cena, K. O. C., Ho, R. X.-Y., Amraei, R., Woolf, N., Tashjian, J. Y., Zhao, Q., Richards, S., Walker, J., Huang, J., Chitalia, V. C., & Rahimi, N.
- Affiliations
- Boston University (US)
- Boston Medical Center (US)
- Corresponding author
- Rahimi, Nader
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2021-01
- Volume
- 191
- Issue
- 1
- Pages
- 157-167
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC7788663
- OpenAlex
- W3096133051
- Cited by
- 23
- References
- 33
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 7 · 2022: 6 · 2021: 3
- FWCI
- 1.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Boston University
- National Institutes of Health (R21CA193958, R21CA191970, R01 HL132325, RO1CA175382)
- Clinical and Translational Science Institute, University of Pittsburgh (1UL1TR001430)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- tumor suppressor, colorectal cancer, G2/M cell cycle arrest, p21, p27, adhesion molecules, intestinal epithelial cells, adenoma, cell migration, cell proliferation, brush border membrane, prognostic factors, therapeutic target
- MeSH terms
- Adenoma, Animals, Cell Movement, Cell Transformation, Neoplastic, Colonic Neoplasms, Humans, Membrane Glycoproteins, Genes, Tumor Suppressor, Mice, Knockout, Tumor Suppressor Proteins, Cell Proliferation, Mice, Cell Cycle Checkpoints, G2 Phase Cell Cycle Checkpoints
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
