A Homeobox Protein, Prox1, Is Involved in the Differentiation, Proliferation, and Prognosis in Hepatocellular Carcinoma
Open accessAbstract
Purpose: It has been shown that a lymphatic differentiation master gene, prox1, also plays an essential role in fetal hepatocyte migration. Its expression is detected in embryonic hepatoblasts and in adult hepatocytes. Hepatoma cells are similar to embryonic hepatoblasts to a certain extent because they both proliferate and invade the surrounding tissue. To address the possibility that Prox1 may be involved in the tumorigenesis of hepatocellular carcinoma (HCC), human clinical samples were analyzed. Experimental Design: To screen prox1 as a potential tumor suppressor gene, its expression was analyzed in HCC cell lines and in human HCC tissues. Its growth-conferring abilities were assessed by transiently overexpressing Prox1 in HCC cell lines and by knocking down its expression by RNA interference. Results: We found that there was a significant correlation between Prox1 expression and the differentiation scores of the tumors. Subsequently, we also showed that low expression of Prox1 in tumors was closely associated with a poor prognosis. The specific knockdown of Prox1 by RNA interference strongly accelerated in vitro cell growth, whereas the overexpression of Prox1 greatly suppressed the growth. Conclusions: Our results suggest that Prox1 is involved in the differentiation and progression of HCC, and thus it may be a candidate for the development of novel diagnostic and therapeutic strategies for HCC.
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Both tumor-promoting and suppressor roles have been reported for PROX1 in liver cancer models.
“but both tumor-promoting and suppressor roles have been reported in liver cancer models22,23”
From Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis (2025) · cites this paper as [23]
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Ntikoudi, E., Pergaris, A., Kykalos, S., et al. (2022) · Diagnostics · doi:10.3390/diagnostics12071624 · Cited by 15 · see citing works
“The authors of that study stated that the mechanism that regulates the PROX1 gene remains unknown [49].”
BackgroundPCNA interacts with Prox1 and represses its transcriptional activity.
Chen, X., Patel, T. P., Simirskii, V. N., & Duncan, M. K. (2008) · Europe PMC (PubMed Central) · Cited by 15 · see citing works
Impact of prospero homeobox-1 on tumor cell behavior and prognosis in colorectal cancer.
Park, Y., Myung, E., Park, S.-Y., et al. (2015) · PubMed · Cited by 15 · see citing works
Gan, L., Li, Q., Nie, W., Zhang, Y., Jiang, H., Tan, C., Zhang, L., Zhang, J., Li, Q., Hou, P., et al. (2022) · International Journal of Biological Sciences · doi:10.7150/ijbs.73530 · Cited by 14 · see citing works
“Since PROX1 was first linked to cancer through its ability to regulate cell differentiation [30], evidence for the importance of aberrant PROX1 expression in human malignancy has accumulated.”
Ramani, P., Norton, A., Somerville, M. S., et al. (2012) · Journal of Neuro-Oncology · doi:10.1007/s11060-012-0838-z · Cited by 14 · see citing works
MiR-670-5p induces cell proliferation in hepatocellular carcinoma by targeting PROX1
Cailing, S., & Xu, X. (2015) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2015.07.030 · Cited by 14 · see citing works
HOXB9 Expression Correlates with Histological Grade and Prognosis in LSCC
Sun, C., Han, C., Wang, P., Jin, Y., Sun, Y., & Qu, L. (2017) · BioMed Research International · doi:10.1155/2017/3680305 · Cited by 14 · see citing works
“HOX genes have been found to be aberrantly expressed in many tumors such as breast [9, 10], leukemia [11, 12], lung [13, 14], liver [15], and gastric cancer [16].”
The role of prospero homeobox 1 (PROX1) expression in follicular thyroid carcinoma cells
Rudzińska, M., Ledwon, J. K., Gaweł, D., Sikorska, J., & Czarnocka, B. (2017) · Oncotarget · doi:10.18632/oncotarget.23167 · Cited by 14 · see citing works
“It is well established that down-regulation of PROX1 reduces the proliferation of colorectal, cervical cancer, oral, esophageal cancer cells and lung squamouscell carcinoma cells whereas it significantly promotes the growth of hepatocellular carcinoma cells in vitro and does not significantly influence the proliferati…”
BackgroundInfluentialSotiropoulou, N., Bravou, V., Kounelis, S., et al. (2010) · Pathology · doi:10.3109/00313025.2010.522174 · Cited by 14 · see citing works
Jin, Y., Weng, Y., Wang, Y., et al. (2020) · OncoTargets and Therapy · doi:10.2147/ott.s249662 · Cited by 12 · see citing works
The emerging roles of long noncoding RNAs in lymphatic vascular development and disease
Ivanov, K. I., Samuilova, O. V., & Zamyatnin, A. A. (2023) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-04842-4 · Cited by 11 · see citing works
Molecular Signature of Prospero Homeobox 1 (PROX1) in Follicular Thyroid Carcinoma Cells
Rudzińska, M., Grzanka, M., Stachurska, A., Mikuła, M., Paczkowska, K., Stępień, T., Paziewska, A., Ostrowski, J., & Czarnocka, B. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20092212 · Cited by 8 · see citing works
PROX1 suppresses vitamin K-induced transcriptional activity of steroid and xenobiotic receptor
Azuma, K., Urano, T., Watabe, T., Ouchi, Y., & Inoue, S. (2011) · Genes to Cells · doi:10.1111/j.1365-2443.2011.01551.x · Cited by 10 · see citing works
“In HCC, SXR-independent action of PROX1 possibly exists, and level of SXR expression may affect the prognostic effect of PROX1.”
BackgroundRudzińska, M., & Czarnocka, B. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21093220 · Cited by 10 · see citing works
“Thus, PROX1 acts as a tumor suppressor in hepatocellular carcinoma [8], esophageal cancer [9], pancreatic cancer [10], oral cancer [11], hematologic malignancy [12], sporadic breast cancer [13], carcinoma of the biliary system [14], and papillary thyroid cancer (PTC) [15].”
BackgroundShpyleva, S., Dreval, K., de Conti, A., Kindrat, I., Melnyk, S., Yan, J., Chen, T., Beland, F. A., & Pogribny, I. P. (2016) · Toxicological Sciences · doi:10.1093/toxsci/kfw242 · Cited by 9 · see citing works
Lai, S., Cheng, Y., Kiu, K., et al. (2024) · Aging · doi:10.18632/aging.205447 · Cited by 9 · see citing works
Liu, Y., Huang, Y., He, Q., Shen, Y., & Wang, Y. (2025) · Frontiers in Oncology · doi:10.3389/fonc.2025.1598170 · Cited by 8 · see citing works
Saglietti, C., Rosa, S. L., Sykiotis, G. P., Letovanec, I., Bulliard, J., Piana, S., Mermod, M., Petrova, T. V., Uccella, S., Sessa, F., et al. (2019) · Endocrine Pathology · doi:10.1007/s12022-019-9576-5 · Cited by 5 · see citing works
Michail, A., Gkikas, D., Stellas, D., Kaltezioti, V., & Politis, P. K. (2023) · Cells · doi:10.3390/cells12141869 · Cited by 4 · see citing works
“Similarly, Prox1 exerted tumor-inhibiting actions in other tissues and organs, including the nervous system, pancreas, lung, and hematological cell lines [12,18,20,58].”
BackgroundHildebrandt, K., Klöppel, C., Gogel, J., Hartenstein, V., & Walldorf, U. (2022) · Developmental Biology · doi:10.1016/j.ydbio.2022.09.006 · Cited by 3 · see citing works
“…in hypothalamic neurons is also regulated by prox1 , a vertebrate homolog of the Drosophila gene prospero (Dyer et al., 2003; Choski et al., 2006; Shimoda et al., 2006) and zinc-fi nger containing protein Fez1 (Levkowitz et al., 2003), a vertebrate homolog of the Drosophila gene earmuff ( erm )…”
Gao, T., Ma, C., Li, Y., et al. (2018) · Journal of Oral and Maxillofacial Surgery · doi:10.1016/j.joms.2017.12.032 · Cited by 4 · see citing works
PROX1 is a regulator of neuroendocrine-related gene expression in lung carcinoid
Sakurai, K., Ando, T., Sakai, Y., Mori, Y., Nakamura, S., Kato, T., & Ito, H. (2024) · Human Cell · doi:10.1007/s13577-024-01109-3 · Cited by 3 · see citing works
“For example, PROX1 inhibits hepato-cellular carcinoma proliferation, and low PROX1 expression is associated with a poor prognosis [39, 40].”
Different Biological Pathways Between Good and Poor Inhaled Corticosteroid Responses in Asthma
Kim, B., Lee, H. S., Lee, S., & Park, H. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.652824 · Cited by 3 · see citing works
“PROX1 induces cell cycle arrest in liver hepatocellular carcinoma cells (34), but paradoxically increases proliferation in fetal hepatoblasts (35).”
BackgroundHafez, A. M., Harb, O. A., Alattar, A. Z., Hefzi, N., Ahmed, R. Z., Shaker, S. E., Ibrahim, A. E. S. T., & El-Taher, A. K. (2020) · Współczesna Onkologia · doi:10.5114/wo.2020.102671 · Cited by 3 · see citing works
“In carcinoma of the liver [37], pancreatic cancer [38] and gall bladder carcinomas [39], increased PROX1 expression is associated with better prognosis.”
BackgroundImpact of Prospero Homeobox-1 (PROX-1) οn the Oncogenic Phenotypes of Hepatocellular Carcinoma Cells
Hong, J.-Y., Park, S.-Y., Park, Y., et al. (2024) · Cancer Genomics & Proteomics · doi:10.21873/cgp.20448 · Cited by 2 · see citing works
“A high PROX-1 expression is involved in the inhibition of tumor cell proliferation and associated with well-differentiated tumors and favorable prognosis in HCC, suggesting its tumor suppressive role (22-26).”
BackgroundRole of anti-tumorigenic cytokines in gastrointestinal cancers
Hooks, O., Childers, L. T., Childers, J. T., Machado, C., Mowers, C. C., & Ahmad, S. (2025) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2025.12.004 · Cited by 2 · see citing works
Blei, F. (2006) · Lymphatic Research and Biology · doi:10.1089/lrb.2006.4407 · Cited by 1 · see citing works
Eurola, A., Ristimäki, A., Mustonen, H. K., et al. (2022) · Tumor Biology · doi:10.3233/tub-211581 · Cited by 1 · see citing works
Benitha, G., Ramani, P., Jayakumar, S., et al. (2024) · Journal of Oral and Maxillofacial Pathology · doi:10.4103/jomfp.jomfp_394_23 · Cited by 1 · see citing works
“[20,43] Prospero homeobox has been shown to function as both a tumour‑suppressor gene and oncogene in various cancers.”
BackgroundTranscription factors PROX1 and p53 in cancer development
Elsir, T. (2010) · Figshare · Cited by 1 · see citing works
The Role of Protein-Protein Interactions in Controlling Prox1 Function
Isaacs, L. H. (2009) · Library, Museums and Press - UDSpace (University of Delaware)
Wangsa, D. (2009) · Figshare
Towards Novel Biomarkers for Low-grade Glioma
Berntsson, S. G. (2012) · KTH Publication Database DiVA (KTH Royal Institute of Technology)
Ratajska, A., Jankowska-Steifer, E. A., Flaht‐Zabost, A., & Radomska-Leśniewska, D. M. (2012)
Coordinating Cell Cycle Exit and Differentiation in the Mammalian Retina and its Dependence on Rb
Pacal, M. (2012) · TSpace (University of Toronto)
- Authors
- Shimoda, M., Takahashi, M., Yoshimoto, T., Kono, T., Ikai, I., & Kubo, H.
- Affiliations
- Kyoto University (JP)
- 1Molecular and Cancer Research Unit, HMRO, and
- Venue
- Clinical Cancer Research
- Published
- 2006-10-15
- Volume
- 12
- Issue
- 20
- Pages
- 6005-6011
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2133384911
- Semantic Scholar
- 36f5c5b98748041985bc89acca6189a59ec35025
- Cited by
- 106
- References
- 15
- Citations by year
- 2025: 5 · 2024: 5 · 2023: 2 · 2022: 5 · 2021: 1 · 2020: 3 · 2019: 6 · 2018: 4 · 2017: 3 · 2016: 4 · 2015: 7 · 2014: 5 · 2013: 5 · 2012: 12
- FWCI
- 5.45
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Clinical Cancer Research (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Kyoto University Research Information Repository (Kyoto University) (submittedVersion)
- Funders
- Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care
- Princess Takamatsu Cancer Research Fund
- Topics
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- Prox1, homeodomain transcription factor, hepatocellular carcinoma, tumor suppressor, hepatocyte differentiation, tumor cell proliferation, prognosis, hepatoblasts, RNAi knockdown, gene overexpression
- MeSH terms
- Prospero-Related Homeobox 1 Protein, Cell Differentiation, Cell Division, Female, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Lymphatic Metastasis, Male, Neoplasm Metastasis, Prognosis, RNA, Neoplasm, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, DNA Primers, Homeodomain Proteins, Reverse Transcriptase Polymerase Chain Reaction, Tumor Suppressor Proteins, RNA Interference
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