HNF4α is a therapeutic target that links AMPK to WNT signalling in early-stage gastric cancer
Open accessAbstract
BACKGROUND: Worldwide, gastric cancer (GC) is the fourth most common malignancy and the most common cancer in East Asia. Development of targeted therapies for this disease has focused on a few known oncogenes but has had limited effects. OBJECTIVE: To determine oncogenic mechanisms and novel therapeutic targets specific for GC by identifying commonly dysregulated genes from the tumours of both Asian-Pacific and Caucasian patients. METHODS: We generated transcriptomic profiles of 22 Caucasian GC tumours and their matched non-cancerous samples and performed an integrative analysis across different GC gene expression datasets. We examined the inhibition of commonly overexpressed oncogenes and their constituent signalling pathways by RNAi and/or pharmacological inhibition. RESULTS: Hepatocyte nuclear factor-4α (HNF4α) upregulation was a key signalling event in gastric tumours from both Caucasian and Asian patients, and HNF4α antagonism was antineoplastic. Perturbation experiments in GC tumour cell lines and xenograft models further demonstrated that HNF4α is downregulated by AMPKα signalling and the AMPK agonist metformin; blockade of HNF4α activity resulted in cyclin downregulation, cell cycle arrest and tumour growth inhibition. HNF4α also regulated WNT signalling through its target gene WNT5A, a potential prognostic marker of diffuse type gastric tumours. CONCLUSIONS: Our results indicate that HNF4α is a targetable oncoprotein in GC, is regulated by AMPK signalling through AMPKα and resides upstream of WNT signalling. HNF4α may regulate 'metabolic switch' characteristic of a general malignant phenotype and its target WNT5A has potential prognostic values. The AMPKα-HNF4α-WNT5A signalling cascade represents a potentially targetable pathway for drug development.
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?
Metformin reduces hepatocyte nuclear factor 4α levels via activation of AMPKα, which subsequently modulates the WNT signaling pathway.
“Chang et al., for example, demonstrated that metformin reduced hepatocyte nuclear factor 4α (HNF4α) levels via activation of AMPKα, which subsequently modulated the WNT signaling pathway.199”
From Drug repurposing for cancer therapy (2024) · cites this paper as [199]
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
Jemal, A., Bray, F., Ferlay, J., Ward, E., & Forman, D. (2011) · CA A Cancer Journal for Clinicians · doi:10.3322/caac.20107 · Cited by 54,708 · see citing works
Analyzing real-time PCR data by the comparative CT method
Schmittgen, T. D., & Livak, K. J. (2008) · Nature Protocols · doi:10.1038/nprot.2008.73 · Cited by 26,190 · see citing works
Global Cancer Statistics, 2002
Parkin, D. M., Bray, F., Ferlay, J., & Pisani, P. (2005) · CA A Cancer Journal for Clinicians · doi:10.3322/canjclin.55.2.74 · Cited by 18,573 · see citing works
Bang, Y.-J., Van Cutsem, E., Feyereislova, A., Chung, H. C., Shen, L., Sawaki, A., Lordick, F., Ohtsu, A., Omuro, Y., Satoh, T., et al. (2010) · The Lancet · doi:10.1016/s0140-6736(10)61121-x · Cited by 7,302 · see citing works
Targeting HIF-1 for cancer therapy
Semenza, G. L. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1187 · Cited by 6,717 · see citing works
Suerbaum, S., & Michetti, P. (2002) · New England Journal of Medicine · doi:10.1056/nejmra020542 · Cited by 2,984 · see citing works
The LKB1-AMPK pathway: metabolism and growth control in tumour suppression
Shackelford, D. B., & Shaw, R. J. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2676 · Cited by 1,943 · see citing works
LKB1 is the upstream kinase in the AMP-activated protein kinase cascade
Woods, A., Johnstone, S. R., Dickerson, K., Leiper, F. C., Fryer, L. G. D., Neumann, D., Schlattner, U., Wallimann, T., Carlson, M., & Carling, D. (2003) · Current Biology · doi:10.1016/j.cub.2003.10.031 · Cited by 1,650 · see citing works
Cancer Statistics in Korea: Incidence, Mortality, Survival and Prevalence in 2010
Jung, K., Won, Y., Kong, H., Oh, C.-M., Seo, H., & Lee, J.-S. (2013) · Cancer research and treatment : official journal of Korean Cancer Association · doi:10.4143/crt.2013.45.1.1 · Cited by 1,086 · see citing works
Self-citationGene Expression Signature–Based Prognostic Risk Score in Gastric Cancer
Choi, Y., Lim, J. Y., Cheong, J., Park, Y., Yoon, S.-L., Kim, S. M., Kim, S.-B., Kim, H., Hong, S. W., Park, Y. N., et al. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-2180 · Cited by 350 · see citing works
Hnf4: A Central Regulator of Hepatocyte Differentiation and Function
Watt, A. J., Garrison, W. D., & Duncan, S. A. (2003) · Hepatology · doi:10.1053/jhep.2003.50273 · Cited by 307 · see citing works
Hallstrom, T. C., Mori, S., & Nevins, J. R. (2008) · Cancer Cell · doi:10.1016/j.ccr.2007.11.031 · Cited by 249 · see citing works
The Antidiabetic Drug Metformin Inhibits Gastric Cancer Cell Proliferation In Vitro and In Vivo
Kato, K., Gong, J., Iwama, H., Kitanaka, A., Tani, J., Miyoshi, H., Nomura, K., Mimura, S., Kobayashi, M., Aritomo, Y., et al. (2012) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-11-0594 · Cited by 226 · see citing works
Epstein-Barr Virus (EBV)-associated Gastric Carcinoma
Iizasa, H., Nanbo, A., Nishikawa, J., Jinushi, M., & Yoshiyama, H. (2012) · Viruses · doi:10.3390/v4123420 · Cited by 225 · see citing works
Hong, Y. H., Varanasi, U. S., Yang, W., & Leff, T. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m304112200 · Cited by 220 · see citing works
Wainberg, Z. A., Anghel, A., Desai, A. J., Ayala, R., Luo, T., Safran, B., Fejzo, M. S., Hecht, J. R., Slamon, D. J., & Finn, R. S. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-1112 · Cited by 214 · see citing works
Diabetes, cancer, and metformin: connections of metabolism and cell proliferation
Gallagher, E. J., & LeRoith, D. (2011) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2011.06285.x · Cited by 206 · see citing works
Cui, J., Chen, Y., Chou, W., Sun, L., Chen, L., Suo, J., Ni, Z., Zhang, M., Kong, X., Hoffman, L. L., et al. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq960 · Cited by 199 · see citing works
Kim, J., Hoffman, J. P., Alpaugh, R. K., Rhim, A. D., Reichert, M., Stanger, B. Z., Furth, E. E., Sepulveda, A. R., Yuan, C., Won, K., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.05.036 · Cited by 188 · see citing works
Tanaka, T., Jiang, S. S., Hotta, H., Takano, K., Iwanari, H., Sumi, K., Daigo, K., Ohashi, R., Sugai, M., Ikegame, C., et al. (2006) · The Journal of Pathology · doi:10.1002/path.1928 · Cited by 183 · see citing works
Wnt Signaling Regulates Hepatic Metabolism
Liu, H., Fergusson, M. M., Wu, J., Rovira, I. I., Liu, J., Gavrilova, O., Lü, T., Bao, J., Han, D., Sack, M. N., et al. (2011) · Science Signaling · doi:10.1126/scisignal.2001249 · Cited by 173 · see citing works
Cattin, A.-L., Beyec, J. L., Barreau, F., Saint-Just, S., Houllier, A., Gonzalez, F. J., Robine, S., Pinçon‐Raymond, M., Cardot, P., Lacasa, M., et al. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.00939-09 · Cited by 157 · see citing works
HNF4α—role in drug metabolism and potential drug target?
Hwang‐Verslues, W. W., & Sladek, F. M. (2010) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2010.08.010 · Cited by 147 · see citing works
Torres-Padilla, M. E., Fougère-Deschatrette, C., & Weiss, M. C. (2001) · Mechanisms of Development · doi:10.1016/s0925-4773(01)00521-4 · Cited by 96 · see citing works
Kim, Y. H., Liang, H., Liu, X., Lee, J., Choi, Y., Cheong, J., Kim, H., Li, M., Downey, T. J., Dyer, M. D., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-3870 · Cited by 91 · see citing works
Self-citationGastric cancer,helicobacter pyloriinfection and other risk factors
Fuccio, L. (2010) · World Journal of Gastrointestinal Oncology · doi:10.4251/wjgo.v2.i9.342 · Cited by 84 · see citing works
Okines, A. F. C., & Cunningham, D. (2010) · European Journal of Cancer · doi:10.1016/j.ejca.2010.05.003 · Cited by 76 · see citing works
PATHOME: an algorithm for accurately detecting differentially expressed subpathways
Nam, S., Chang, H., Kim, K.-T., Kook, M., Hong, D., Kwon, C. H., Jung, H.-Y., Park, H. S., Powis, G., Liang, H., et al. (2014) · Oncogene · doi:10.1038/onc.2014.80 · Cited by 66 · see citing works
Self-citationTrend in gastric cancer: 35 years of surgical experience in Japan
Yamashita, K. (2011) · World Journal of Gastroenterology · doi:10.3748/wjg.v17.i29.3390 · Cited by 63 · see citing works
Gastric cancer in the era of molecularly targeted agents: current drug development strategies
Arkenau, H. (2009) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-009-0583-7 · Cited by 62 · see citing works
Esophagogastric cancer: Targeted agents
Ku, G. Y., & Ilson, D. H. (2010) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2009.12.009 · Cited by 59 · see citing works
Kim, Y. H., Coon, A., Baker, A. F., & Powis, G. (2011) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-010-1500-0 · Cited by 45 · see citing works
Self-citationIdentifying molecular drivers of gastric cancer through next-generation sequencing
Liang, H., & Kim, Y. H. (2012) · Cancer Letters · doi:10.1016/j.canlet.2012.11.029 · Cited by 42 · see citing works
Self-citationHNF4α: A New Biomarker in Colon Cancer?
Chellappa, K., Robertson, G. R., & Sladek, F. M. (2012) · Biomarkers in Medicine · doi:10.2217/bmm.12.23 · Cited by 35 · see citing works
cAMP-mediated regulation of HNF-4α depends on the level of coactivator PGC-1α
Dankel, S. N., Hoang, T., Flågeng, M. H., Sagen, J. V., & Mellgren, G. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2010.05.008 · Cited by 27 · see citing works
Uozaki, H., Barua, R. R., Sun, M., Ushiku, T., Hino, R., Shinozaki‐Ushiku, A., Sakatani, T., & Fukayama, M. (2011) · Europe PMC (PubMed Central) · Cited by 20 · see citing works
Ribeiro, A., Archer, A., Beyec, J. L., Cattin, A.-L., Saint-Just, S., Pinçon‐Raymond, M., Chambaz, J., Lacasa, M., & Cardot, P. (2007) · Recent Patents on Endocrine Metabolic & Immune Drug Discovery · doi:10.2174/187221407780832000 · Cited by 13 · see citing works
Early Gastric Cancer and Dysplasia
Tamura, W., & Fukami, N. (2012) · Gastrointestinal Endoscopy Clinics of North America · doi:10.1016/j.giec.2012.10.011 · Cited by 13 · see citing works
Flagged first, then by citations
1 of the 39 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Drug repurposing for cancer therapy
Xia, Y., Sun, M., Huang, H., & Jin, W.-L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01808-1 · Cited by 443 · see citing works
“199 A different study reported that metformin inhibited HNF4G activity via AMPK-driven phosphorylation and ubiquitin-mediated degradation, which suppressed the invasive abilities and metastasis of SMAD4-de fi cient pancreatic ductal adenocarcinoma cells.”
Molecular classification of gastric cancer
Chia, N., & Tan, P. B. O. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw040 · Cited by 377 · see citing works
Ye, G., Yang, Q., Lei, X., Zhu, X., Li, F., He, J., Chen, H., Ling, R., Zhang, H., Lin, T., et al. (2020) · Theranostics · doi:10.7150/thno.46001 · Cited by 198 · see citing works
Gastric cancer – clinical and epidemiological aspects
Venerito, M., Link, A., Rokkas, T., & Malfertheiner, P. (2016) · Helicobacter · doi:10.1111/hel.12339 · Cited by 130 · see citing works
Ren, H., Hu, F., Wang, D., Kang, X., Feng, X., Zhang, L., Zhou, B., Liu, S., & Yuan, G. (2021) · Hepatology · doi:10.1002/hep.31773 · Cited by 95 · see citing works
Metformin reduces gastric cancer risk in patients with type 2 diabetes mellitus
Tseng, C. (2016) · Aging · doi:10.18632/aging.101019 · Cited by 82 · see citing works
Hu, Q., Li, L., Zou, X., Xu, L., & Yi, P. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.01150 · Cited by 82 · see citing works
Opposing roles of nuclear receptor HNF4α isoforms in colitis and colitis-associated colon cancer
Chellappa, K., Deol, P., Evans, J. R., Vuong, L. M., Chen, G., Briançon, N., Bolotin, E., Lytle, C. Y., Nair, M. G., & Sladek, F. M. (2016) · eLife · doi:10.7554/elife.10903 · Cited by 80 · see citing works
Role of hepatocyte nuclear factor 4-alpha in gastrointestinal and liver diseases
Yeh, M. M., Bosch, D. E., & Daoud, S. S. (2019) · World Journal of Gastroenterology · doi:10.3748/wjg.v25.i30.4074 · Cited by 78 · see citing works
Lv, D., Zhou, L., & Tang, H. (2021) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-00551-1 · Cited by 72 · see citing works
Multifaceted Role of AMPK in Viral Infections
Bhutta, M., Gallo, E. S., & Borenstein, R. (2021) · Cells · doi:10.3390/cells10051118 · Cited by 70 · see citing works
Deng, T., Shen, P., Li, A., Zhang, Z., Yang, H., Deng, X., Peng, X., Hu, Z., Tang, Z., Liu, J., et al. (2021) · Theranostics · doi:10.7150/thno.54961 · Cited by 65 · see citing works
Vuong, L. M., Chellappa, K., Dhahbi, J. M., Deans, J., Fang, B., Bolotin, E., Titova, N., Hoverter, N. P., Spindler, S. R., Waterman, M. L., et al. (2015) · Molecular and Cellular Biology · doi:10.1128/mcb.00030-15 · Cited by 64 · see citing works
Lü, J., Chen, Z., Zhao, H., Dong, H., Zhu, L., Zhang, Y., Wang, J., Zhu, H., Cui, Q., Qi, C., et al. (2020) · Journal of Translational Medicine · doi:10.1186/s12967-020-02268-1 · Cited by 63 · see citing works
Qamra, A., Xing, M., Padmanabhan, N., Kwok, J. J. T., Zhang, S., Xu, C., Leong, Y. S., Lim, A. P. L., Tang, Q., Ooi, W. F., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-1022 · Cited by 62 · see citing works
Self-citationThe role of TRPV1 ion channels in the suppression of gastric cancer development
Gao, N., Yang, F., Chen, S., Wan, H., Zhao, X., & Dong, H. F. (2020) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-020-01707-7 · Cited by 61 · see citing works
Metformin: A Dual-Role Player in Cancer Treatment and Prevention
Galal, M. A., Al-Rimawi, M., Hajeer, A., Dahman, H., Alouch, S. S., & Aljada, A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25074083 · Cited by 68 · see citing works
Li, L., Li, Y., Huang, Y., Ouyang, Y., Zhu, Y., Wang, Y., Guo, X., Yuan, Y., & Gong, K. (2018) · Cancer Science · doi:10.1111/cas.13801 · Cited by 57 · see citing works
Joo, M., Park, A., Kim, K., Son, W., Lee, H. S., Lim, G., Lee, J., Lee, D. H., An, J., Kim, J. H., et al. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20246276 · Cited by 57 · see citing works
Self-citationControl of Cell Identity by the Nuclear Receptor HNF4 in Organ Pathophysiology
Dubois, V., Staels, B., Lefebvre, P., Verzi, M., & Eeckhoute, J. (2020) · Cells · doi:10.3390/cells9102185 · Cited by 63 · see citing works
Pan, J., Silva, T. C., Gull, N., Yang, Q., Plummer, J., Chen, S., Daigo, K., Hamakubo, T., Gery, S., Ding, L., et al. (2020) · Cancer Research · doi:10.1158/0008-5472.can-20-0390 · Cited by 55 · see citing works
Tseng, C. (2021) · Biomolecules · doi:10.3390/biom11071022 · Cited by 55 · see citing works
Gastric intestinal metaplasia: progress and remaining challenges
Tong, Q.-Y., Pang, M.-J., Hu, X.-H., Huang, X., Sun, J., Wang, X., Burclaff, J., Mills, J. C., Wang, Z.-N., & Miao, Z. (2024) · Journal of Gastroenterology · doi:10.1007/s00535-023-02073-9 · Cited by 45 · see citing works
Role of AMP-activated protein kinase α1 in 17α-ethinylestradiol-induced cholestasis in rats
Li, X., Liu, R., Luo, L., Yu, L., Chen, X., Sun, L., Wang, T., Hylemon, P. B., Zhou, H., Jiang, Z., et al. (2016) · Archives of Toxicology · doi:10.1007/s00204-016-1697-8 · Cited by 44 · see citing works
Yuan, F., Cheng, C., Xiao, F., Liu, H., Cao, S., & Zhou, G. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.117276 · Cited by 43 · see citing works
miR-222/VGLL4/YAP-TEAD1 regulatory loop promotes proliferation and invasion of gastric cancer cells.
Li, N., Yu, N., Wang, J., Xi, H., Lu, W., Xu, H., Deng, M., Zheng, G., & Liu, H. (2015) · PubMed Central · Cited by 43 · see citing works
Phytochemicals: Potential Therapeutic Modulators of Radiation Induced Signaling Pathways
Jit, B. P., Pradhan, B., Dash, R., Bhuyan, P. P., Behera, C., Behera, R. K., Sharma, A. K., Alcaraz, M., & Jena, M. (2021) · Antioxidants · doi:10.3390/antiox11010049 · Cited by 42 · see citing works
Multiple roles and regulatory mechanisms of the transcription factor HNF4 in the intestine
Vemuri, K., Radi, S. H., Sladek, F. M., & Verzi, M. P. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1232569 · Cited by 39 · see citing works
Wang, W., Guo, C., Li, R., Xu, Z., Yu, J., Yan, Y., Zhao, J., Wang, J., Wang, W., Zhang, A., et al. (2019) · Aging · doi:10.18632/aging.102190 · Cited by 41 · see citing works
HNF4α pathway mapping identifies wild-type IDH1 as a targetable metabolic node in gastric cancer
Xu, C., Ooi, W. F., Qamra, A., Tan, J. Y., Chua, B. Y.-J., Ho, S. W. T., Das, K., Isa, Z. F. A., Li, Z., Yao, X., et al. (2019) · Gut · doi:10.1136/gutjnl-2018-318025 · Cited by 39 · see citing works
Ghadami, E., Nikbakhsh, N., Fattahi, S., Kosari‐Monfared, M., Ranaee, M., Taheri, H., Amjadi‐Moheb, F., Godazandeh, G., Shafaei, S., Nosrati, A., et al. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.27220 · Cited by 37 · see citing works
TGR5-HNF4α axis contributes to bile acid-induced gastric intestinal metaplasia markers expression
Ni, Z., Min, Y., Han, C., Yuan, T., Lu, W., Ashktorab, H., Smoot, D. T., Wu, Q., Wu, J., Zeng, W., et al. (2020) · Cell Death Discovery · doi:10.1038/s41420-020-0290-3 · Cited by 37 · see citing works
Huang, Y. C., Xian, L., Liu, Z., Wei, L., Qin, L., Xiong, Y., Hu, L., Zhou, S., Fu, Q., Li, B., et al. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.115198 · Cited by 35 · see citing works
Park, S., Lee, J., Kim, Y. H., Park, J., Shin, J., & Nam, S. (2016) · Scientific Reports · doi:10.1038/srep34822 · Cited by 34 · see citing works
Self-citationLiu, Z., Hu, Y., Xie, H., Chen, K., Wen, L., Fu, W., Zhou, X., & Tang, F. (2024) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-1445 · Cited by 32 · see citing works
The emerging role of AMP-activated protein kinase in cholestatic liver diseases
Li, X., Liu, R., Zhang, L., & Jiang, Z. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.09.002 · Cited by 34 · see citing works
Xie, G., Dong, P., Chen, H., Xu, L., Liu, Y., Ma, Y., Zheng, Y., Yang, J., Zhou, Y., Chen, L., et al. (2021) · Experimental & Molecular Medicine · doi:10.1038/s12276-021-00694-9 · Cited by 33 · see citing works
Decreased LIPF expression is correlated with DGKA and predicts poor outcome of gastric cancer
Kong, Y., Zheng, Y., Jia, Y., Li, P., & Wang, Y. (2016) · Oncology Reports · doi:10.3892/or.2016.4989 · Cited by 33 · see citing works
Xie, W., Han, Z., Zuo, Z., Xin, D., Chen, H., Huang, J., Zhu, S., Lou, H., Yu, Z., Chen, C., et al. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-05648-9 · Cited by 30 · see citing works
Liu, Q., Yu, M., Lin, Z., Wu, L., Xia, P., Zhu, M., Huang, B., Wu, W., Zhang, R., Li, K., et al. (2025) · Cancer Letters · doi:10.1016/j.canlet.2025.217731 · Cited by 30 · see citing works
Babeu, J., Jones, C. M., Geha, S., Carrier, J. C., & Boudreau, F. (2018) · Journal of Cell Science · doi:10.1242/jcs.214734 · Cited by 30 · see citing works
Jin, L., Pan, Y., Zhang, J., & Cao, P.-G. (2021) · Translational Oncology · doi:10.1016/j.tranon.2021.101036 · Cited by 30 · see citing works
Chen, X., Zhao, Y., Wang, D., Lin, Y., Hou, J., Xu, X., Wu, J., Zhong, L., Zhou, Y., Shen, J., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-21-0980 · Cited by 30 · see citing works
The therapeutic potential of metformin in gastric cancer
Courtois, S., Lehours, P., & Bessède, E. (2019) · Gastric Cancer · doi:10.1007/s10120-019-00952-w · Cited by 27 · see citing works
Structural insights into the HNF4 biology
Beinsteiner, B., Billas, I. M. L., & Moras, D. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1197063 · Cited by 26 · see citing works
Jucá, P., Corrêa, S., Vignal, G. M., Accioly, M. T. D. S., Lustosa, S. A. S., Abdelhay, E. S. F. W., & Matos, D. (2017) · Diagnostic Pathology · doi:10.1186/s13000-017-0635-2 · Cited by 25 · see citing works
Zhang, Y., Yao, H., Li, C., Sun, W., Chen, X., Cao, Y. W., Liu, Y., Liu, Y., Chen, J., Qi, J., et al. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/6275505 · Cited by 24 · see citing works
Self-citationGastric cancer biomarkers; A systems biology approach
Anvar, M. S., Minuchehr, Z., Shahlaei, M., & Kheitan, S. (2018) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2018.01.001 · Cited by 24 · see citing works
Ma, H.-M., Zhang, Q., Yang, X., Hu, Y., Zhang, J., Chen, L., Zhao, B., Yang, W., & Xu, R. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/8168988 · Cited by 22 · see citing works
Chang, H. R., Nam, S., Lee, J., Kim, J.-H., Jung, H. R., Park, H. S., Park, S., Ahn, Y. Z., Huh, I., Balch, C., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.12963 · Cited by 22 · see citing works
Self-citationMechanism Underlying Metformin Action and Its Potential to Reduce Gastric Cancer Risk
Lan, W.-H., Lin, T., Yeh, J.-A., Feng, C., Hsu, J., Lin, H., Kuo, C., & Lai, C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232214163 · Cited by 20 · see citing works
Transcriptome sequencing identifies key pathways and genes involved in gastric adenocarcinoma
Zhang, W., Liu, S., Zhan, H., Yan, Z., & Zhang, G. (2018) · Molecular Medicine Reports · doi:10.3892/mmr.2018.9370 · Cited by 19 · see citing works
LINC00483 Has a Potential Tumor-Suppressor Role in Colorectal Cancer Through Multiple Molecular Axes
Brex, D., Barbagallo, C., Mirabella, F., Caponnetto, A., Battaglia, R., Barbagallo, D., Caltabiano, R., Broggi, G., Memeo, L., Pietro, C. D., et al. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2020.614455 · Cited by 19 · see citing works
Hepatocyte nuclear factor 4 a (HNF4α): A perspective in cancer
Qu, N., Luan, T., Liu, N., Kong, C., Xu, L., Yu, H., Kang, Y., & Han, Y. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115923 · Cited by 18 · see citing works
Integrated epigenomic analyses of enhancer as well as promoter regions in gastric cancer
Baek, S., Kim, M., Bae, D.-H., Kim, J., Kim, H., Han, M., Oh, S., Kim, S., & Kim, S. (2016) · Oncotarget · doi:10.18632/oncotarget.8239 · Cited by 18 · see citing works
Yamashita, A., Tamaki, M., Kasai, H., Tanaka, T., Otoguro, T., Ryo, A., Maekawa, S., Enomoto, N., de Voogd, N. J., Tanaka, J., et al. (2017) · Antiviral Research · doi:10.1016/j.antiviral.2017.08.001 · Cited by 18 · see citing works
Zhang, J., Wen, L., Zhou, Q., He, K., & Teng, L. (2020) · Cancer Management and Research · doi:10.2147/cmar.s264032 · Cited by 18 · see citing works
Wu, Z., Xu, C., Zheng, T., Li, Q., Yang, S., Shao, J., Guan, W., & Zhang, S. (2022) · Journal of Cellular Physiology · doi:10.1002/jcp.30841 · Cited by 17 · see citing works
Disruption of Tumor Suppressors HNF4α/HNF1α Causes Tumorigenesis in Liver
Teeli, A. S., Łuczyńska, K., Haque, E., Gayas, M. A., Winiarczyk, D., & Taniguchi, H. (2021) · Cancers · doi:10.3390/cancers13215357 · Cited by 16 · see citing works
Ma, L., Zeng, J., Guo, Q., Liang, X., Shen, L., Li, S., Sun, Y., Li, W., Liu, S., Han, Y. K., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.7239 · Cited by 16 · see citing works
Rational design of small molecule RHOA inhibitors for gastric cancer
Kim, J., Park, S., Lim, S. M., Eom, H. J., Balch, C., Lee, J., Kim, G. J., Jeong, J., Nam, S., & Kim, Y. H. (2020) · The Pharmacogenomics Journal · doi:10.1038/s41397-020-0153-6 · Cited by 15 · see citing works
Self-citationLi, L., Peng, Z., Hu, Q., Xu, L., Zou, X. G., Huang, D., & Yi, P. (2022) · World Journal of Gastrointestinal Oncology · doi:10.4251/wjgo.v14.i4.842 · Cited by 15 · see citing works
Differential effects, on oncogenic pathway signalling, by derivatives of the HNF4 α inhibitor BI6015
Kim, J.-H., Eom, H. J., Lim, G., Park, S., Lee, J., Nam, S., Kim, Y. H., & Jeong, J.-H. (2019) · British Journal of Cancer · doi:10.1038/s41416-018-0374-5 · Cited by 14 · see citing works
Self-citationImproving gastric cancer preclinical studies using diverse in vitro and in vivo model systems
Chang, H. R., Park, H. S., Ahn, Y. Z., Nam, S., Jung, H. R., Park, S., Lee, S. J., Balch, C., Powis, G., Ku, J., et al. (2016) · BMC Cancer · doi:10.1186/s12885-016-2232-2 · Cited by 13 · see citing works
Self-citationGhrelin Affects Gastric Cancer Progression by Activating AMPK Signaling Pathway
Hu, X., Zhu, Y., Hu, C., You, L., Wu, J., He, X., Huang, W., & Wu, Z. (2021) · Biochemical Genetics · doi:10.1007/s10528-020-10022-x · Cited by 13 · see citing works
Controversial roles of hepatocyte nuclear receptor 4 α on tumorigenesis (Review)
Wang, Z., Zhang, Y., Zhang, J., Deng, Q., & Liang, H. (2021) · Oncology Letters · doi:10.3892/ol.2021.12617 · Cited by 12 · see citing works
Self-citationMetformin: A New Inhibitor of the Wnt Signaling Pathway in Cancer
Conza, D., Mirra, P., Fiory, F., Insabato, L., Nicolò, A., Bèguinot, F., & Ulianich, L. (2023) · Cells · doi:10.3390/cells12172182 · Cited by 12 · see citing works
Ni, Z., Lu, W., Li, Q., Han, C. C., Yuan, T., Sun, N., & Shi, Y. (2021) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2020.0131 · Cited by 11 · see citing works
Li, P., Wang, L., Li, P., Hu, F., Cao, Y., Tang, D., Ye, G., Li, H., & Wang, D. (2020) · Cancer Gene Therapy · doi:10.1038/s41417-020-00220-5 · Cited by 11 · see citing works
RetractedTentu, S., Kumarswamyreddy, N., Muthuraj, P., Kesavan, V., Venkatraman, G., & Rayala, S. K. (2017) · Journal of Cellular Physiology · doi:10.1002/jcp.26139 · Cited by 10 · see citing works
Besskaya, V., Zhang, H., Bian, Y., Liang, J., Bi, G., Shan, G., Zhan, C., & Lin, Z. (2023) · PeerJ · doi:10.7717/peerj.15377 · Cited by 10 · see citing works
Yang, J., Fu, H., Xue, F., Li, M., Wu, Y., Yu, Z., Luo, H., Gong, J., Niu, X., & Zhang, W. (2024) · Briefings in Bioinformatics · doi:10.1093/bib/bbae418 · Cited by 10 · see citing works
PATHOME-Drug: a subpathway-based polypharmacology drug-repositioning method
Nam, S., Lee, S., Park, S., Lee, J., Park, A., Kim, Y. H., & Park, T. (2021) · Bioinformatics · doi:10.1093/bioinformatics/btab566 · Cited by 10 · see citing works
Self-citationHu, Q., Li, L., Peng, Z., & Yi, P. (2022) · World Journal of Clinical Cases · doi:10.12998/wjcc.v10.i21.7242 · Cited by 9 · see citing works
Kawai, H., Miura, T., Kawamatsu, N., Nakagawa, T., Shiba‐Ishii, A., Yoshimoto, T., Amano, Y., Kihara, A., Sakuma, Y., Fujita, K., et al. (2024) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s00428-024-03816-6 · Cited by 9 · see citing works
Huang, Y., Huang, S.-W., Hsu, Y.-F., Ou, G., Huang, W., & Hsu, M. (2015) · Scientific Reports · doi:10.1038/srep15900 · Cited by 9 · see citing works
Sudo, G., Yamamoto, E., Niinuma, T., Saito, M., Kitajima, H., Ishiguro, K., Yorozu, A., Toyota, M., Aoki, H., Mitsuhashi, K., et al. (2025) · Gastric Cancer · doi:10.1007/s10120-025-01646-2 · Cited by 8 · see citing works
Yang, J., Bai, X., Liu, G., & Li, X. (2022) · Drug Metabolism Reviews · doi:10.1080/03602532.2022.2103146 · Cited by 8 · see citing works
Li, Y., Bai, W. L., & Zhang, X. (2017) · Molecular Medicine Reports · doi:10.3892/mmr.2017.8329 · Cited by 8 · see citing works
Wang, X., Song, B., Zang, M., Ji, H., He, Y., Jiang, S., & Yang, X. (2021) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.16657 · Cited by 8 · see citing works
Lou, S., Zhang, J., Zhai, Z., Yin, X., Wang, Y., Fang, T., & Xue, Y. (2021) · Aging · doi:10.18632/aging.202393 · Cited by 8 · see citing works
Chen, H., Lü, S., Guan, J., Zhu, X., Sun, F., Huang, J., Zhu, J., Wang, J., Zhen, Z., Que, Y., et al. (2021) · Aging · doi:10.18632/aging.202475 · Cited by 8 · see citing works
Shi, B., Lin, H., Zhang, M., Lu, W., Qu, Y., & Zhang, H. (2018) · Journal of Visualized Experiments · doi:10.3791/56526 · Cited by 7 · see citing works
Qin, Z., Li, Y., Shao, X., Li, K., Bai, Y., Wang, B., Ma, F., Shi, W., Song, L., Zhuang, A., et al. (2025) · Cancer Letters · doi:10.1016/j.canlet.2025.217732 · Cited by 6 · see citing works
Hepatocyte nuclear factor 4-Alpha: a key regulator in liver carcinogenesis
Hamdy, H., Shen, C., Xu, J., Fan, D., Zhang, Y., Li, H., Wei, Y., & Sun, J. (2025) · Cellular Oncology · doi:10.1007/s13402-025-01064-7 · Cited by 6 · see citing works
Santos, M. M., Costa, T. C., da Silva, W., Pistillo, L. Z., Júnior, D. T. V., Verardo, L. L., Paulino, P. V. R., Sampaio, C. B., Gionbelli, M. P., Du, ., et al. (2023) · Meat Science · doi:10.1016/j.meatsci.2023.109286 · Cited by 7 · see citing works
Nam, S. (2017) · OMICS A Journal of Integrative Biology · doi:10.1089/omi.2016.0169 · Cited by 6 · see citing works
Self-citationHypoxia reduces SLC27A5 to promote hepatocellular carcinoma proliferation by repressing HNF4A
Tao, J., Liu, Y., Tang, X., Nie, D., Wu, K., Wang, K., & Tang, N. (2025) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2025.119916 · Cited by 5 · see citing works
HNF4A-Bridging the Gap Between Intestinal Metaplasia and Gastric Cancer
Zhao, Y., Tang, H., Xu, J., Sun, F., Zhao, Y., & Yang, L. (2024) · Evolutionary Bioinformatics · doi:10.1177/11769343241249017 · Cited by 5 · see citing works
Regulatory feedback loops bridge the human gene regulatory network and regulate carcinogenesis
Chen, Y.-R., Huang, H., & Lin, C.-C. (2017) · Briefings in Bioinformatics · doi:10.1093/bib/bbx166 · Cited by 5 · see citing works
The transcription factor HNF4a: A Key player in haematological disorders
Belali, T. M., Abomughaid, M. M., & Alhujaily, M. M. (2021) · Archives of Medical Science · doi:10.5114/aoms/141219 · Cited by 4 · see citing works
Gu, R., & Syed, N. (2023) · Undergraduate Research in Natural and Clinical Science and Technology (URNCST) Journal · doi:10.26685/urncst.417 · Cited by 3 · see citing works
HNF4A Negatively Regulated Posterior Capsular Opacification via Transcriptional Inhibition of MMP2
Hu, C., Jing, R., Wen, C., Qi, T., Bai, X., Wang, Y., Shao, Y., & Pei, C. (2023) · Current Eye Research · doi:10.1080/02713683.2023.2195138 · Cited by 4 · see citing works
Sun, J., Li, X., Wang, W., Li, W., Gao, S., & Yan, J. (2017) · PubMed Central · Cited by 4 · see citing works
Ectopic expression of HNF4α in Het1A cells induces an invasive phenotype
Rodriguez, C. G., Rimmer, E. F., Colleypriest, B. J., Tosh, D., Slack, J. M. W., & Jungwirth, U. (2023) · Differentiation · doi:10.1016/j.diff.2023.08.003 · Cited by 3 · see citing works
Comparative transcriptome analysis in the caput segment of yak and cattleyak epididymis
Adjei, M., Yan, Y., Li, C., Pan, C. J., Pan, M., Wang, P., Li, K., Shahzad, K., Chen, X., & Zhao, W. (2022) · Theriogenology · doi:10.1016/j.theriogenology.2022.10.039 · Cited by 3 · see citing works
Databases and tools for constructing signal transduction networks in cancer
Nam, S. (2017) · BMB Reports · doi:10.5483/bmbrep.2017.50.1.135 · Cited by 3 · see citing works
Self-citationWan, C., Xu, Y., Zhu, Y., Cao, X., Wang, P., & Gu, Y. (2025) · Molecular Medicine Reports · doi:10.3892/mmr.2025.13550 · Cited by 2 · see citing works
Zhang, X., Shi, L., Gao, Y., Zhou, C., Wang, X., & Shi, X. (2025) · Cell Death and Disease · doi:10.1038/s41419-025-08247-y · Cited by 2 · see citing works
A mutational co-occurrence network of a stomach adenocarcinoma using an association index
Park, S., & Nam, S. (2017) · IEEE International Conference on Bioinformatics and Biomedicine (BIBM) · doi:10.1109/bibm.2017.8217931 · Cited by 2 · see citing works
Self-citation
- Authors
- Chang, H. R., Nam, S., Kook, M.-C., Kim, K.-T., Liu, X., Yao, H., Jung, H. R., Lemos, R., Seo, H. H., Park, H. S., Gim, Y., Hong, D., Huh, I., Kim, Y.-W., Tan, D., Liu, C.-G., Powis, G., Park, T., Liang, H., & Kim, Y. H.
- Affiliations
- National Cancer Center (KR)
- The University of Texas MD Anderson Cancer Center (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Seoul National University (KR)
- Corresponding author
- Kim, Yon Hui
- ORCID
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2014-11-19
- Volume
- 65
- Issue
- 1
- Pages
- 19-32
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- PMC
- PMC4717359
- OpenAlex
- W1974918249
- Cited by
- 119
- References
- 39
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 11 · 2023: 10 · 2022: 9 · 2021: 20 · 2020: 11 · 2019: 6 · 2018: 7 · 2017: 13 · 2016: 12 · 2015: 3
- FWCI
- 7.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Gut (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- National Research Foundation (2013M3A9C4078158, 2008–0062618, 2012R1A3A2026438)
- Ministry of Science, ICT and Future Planning (2013M3A9C4078158, 2012R1A3A2026438, 2008-0062618)
- National Research Foundation of Korea (2013M3A9C4078158, 2012R1A3A2026438, 20080062618)
- National Institutes of Health (CA- 016672, CA143883, CA95060)
- National Cancer Institute (CA 016672, P01CA017094, CA143883, R01CA098920, CA9506, CA-170-94, U24CA143883, CA98920, R01CA129616, CA129616, P50CA095060, P30CA016672)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Gastric Cancer Management and Outcomes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- HNF4α, gastric cancer, AMPK signaling, Wnt signaling, Wnt5a, metformin, therapeutic target, oncogenic mechanisms, cell cycle arrest, metabolic switch, prognostic factors, diffuse-type gastric cancer, gene expression profiling, xenograft models
- MeSH terms
- Wnt-5a Protein, Adenocarcinoma, Animals, Female, Humans, Immunohistochemistry, Mice, Inbred BALB C, Neoplasm Transplantation, Proto-Oncogene Proteins, Random Allocation, Retrospective Studies, Stomach Neoplasms, Biomarkers, Tumor, Blotting, Western, Down-Regulation, Up-Regulation, Gene Expression Regulation, Neoplastic, Case-Control Studies, Reverse Transcriptase Polymerase Chain Reaction, White People, Asian People, Cell Line, Tumor, Wnt Proteins, Mice, Hepatocyte Nuclear Factor 4, AMP-Activated Protein Kinases, Wnt Signaling Pathway
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
