Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 3/2015

01-12-2015 | Translational Research and Biomarkers

Nuclear PROX1 is Associated with Hypoxia-Inducible Factor 1α Expression and Cancer Progression in Esophageal Squamous Cell Carcinoma

Authors: Takehiko Yokobori, MD, PhD, Pinjie Bao, MSc, Minoru Fukuchi, MD, PhD, Bolag Altan, MD, PhD, Daigo Ozawa, MD, PhD, Susumu Rokudai, PhD, Tuya Bai, MSc, Yuji Kumakura, MD, Hiroaki Honjo, MD, Keigo Hara, MD, Makoto Sakai, MD, PhD, Makoto Sohda, MD, PhD, Tatsuya Miyazaki, MD, PhD, Munenori Ide, MD, PhD, Masahiko Nishiyama, MD, PhD, Tetsunari Oyama, MD, PhD, Hiroyuki Kuwano, MD, PhD, FACS

Published in: Annals of Surgical Oncology | Special Issue 3/2015

Login to get access

Abstract

Background

Transcription factor prospero homeobox 1 (PROX1) has been identified as a master regulator of lymphangiogenesis associated with metastasis. Although PROX1 expression has been investigated in several cancers, its clinical significance remains controversial and needs further validation. In this study, we investigated the clinical and functional significance of PROX1 and PROX1 regulator hypoxia-inducible factor 1α (HIF1α) in esophageal squamous cell carcinoma (ESCC).

Methods

A total of 117 samples from ESCC patients were analyzed for PROX1, HIF1α, and E-cadherin expression by immunohistochemistry; correlation with clinicopathological characteristics was determined. PROX1 function was evaluated in PROX1 small interfering RNA (siRNA)-transfected human ESCC cells in vitro by assessing cell proliferation and migration.

Results

PROX1 expression was higher in ESCC than in normal tissues. Patients with higher PROX1 expression (n = 26) had increased nuclear accumulation of HIF1α (p = 0.004) and more advanced metastasis, both lymph node (N factor; p = 0.09) and hematogenous (M factor; p = 0.04), than those with lower PROX1 expression (n = 91). In addition, high PROX1 and HIF1α expression correlated with low levels of E-cadherin, an epithelial cell marker. Analysis of overall and cancer-specific survival indicated that elevated PROX1 expression was significantly correlated with poor prognosis (p = 0.0064). PROX1 downregulation in ESCC cells inhibited cellular proliferation and migration (p < 0.05). Hypoxia restored PROX1 levels that were reduced by PROX1-specific siRNA.

Conclusion

Our data suggest that high expression of PROX1 in ESCC could be used as an indicator of poor prognosis, and that PROX1 is a promising candidate molecular target for ESCC treatment.
Appendix
Available only for authorised users
Literature
1.
Napier KJ, Scheerer M, Misra S. Esophageal cancer: a review of epidemiology, pathogenesis, staging workup and treatment modalities. World J Gastrointest Oncol. 2014;6(5):112–20.PubMedPubMedCentralCrossRef
2.
Kato H, Fukuchi M, Miyazaki T, et al. Surgical treatment for esophageal cancer. Current issues. Dig Surg. 2007;24(2):88–95.PubMedCrossRef
3.
4.
Karatzanis AD, Koudounarakis E, Papadakis I, Velegrakis G. Molecular pathways of lymphangiogenesis and lymph node metastasis in head and neck cancer. Eur Arch Otorhinolaryngol. 2012;269(3):731–7.PubMedCrossRef
5.
Nishida N, Mimori K, Yokobori T, et al. FOXC2 is a novel prognostic factor in human esophageal squamous cell carcinoma. Ann Surg Oncol. 2011;18(2):535–42.PubMedCrossRef
6.
He Y, Karpanen T, Alitalo K. Role of lymphangiogenic factors in tumor metastasis. Biochim Biophys Acta. 2004;1654(1):3–12.PubMed
7.
Harada K, Yamazaki T, Iwata C, et al. Identification of targets of Prox1 during in vitro vascular differentiation from embryonic stem cells: functional roles of HoxD8 in lymphangiogenesis. J Cell Sci. 2009;122(Pt 21):3923–30.PubMedCrossRef
8.
Hong YK, Harvey N, Noh YH, et al. Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate. Dev Dyn. 2002;225(3):351–7.PubMedCrossRef
9.
Liu Y, Zhang JB, Qin Y, et al. PROX1 promotes hepatocellular carcinoma metastasis by way of up-regulating hypoxia-inducible factor 1alpha expression and protein stability. Hepatology. 2013;58(2):692–705.PubMedCrossRef
10.
Petrova TV, Nykanen A, Norrmen C, et al. Transcription factor PROX1 induces colon cancer progression by promoting the transition from benign to highly dysplastic phenotype. Cancer Cell. 2008;13(5):407–19.PubMedCrossRef
11.
Lu MH, Huang CC, Pan MR, Chen HH, Hung WC. Prospero homeobox 1 promotes epithelial-mesenchymal transition in colon cancer cells by inhibiting E-cadherin via miR-9. Clin Cancer Res. 2012;18(23):6416–25.PubMedCrossRef
12.
Elsir T, Eriksson A, Orrego A, Lindstrom MS, Nister M. Expression of PROX1 Is a common feature of high-grade malignant astrocytic gliomas. J Neuropathol Exp Neurol. 2010;69(2):129–38.PubMedCrossRef
13.
Shimoda M, Takahashi M, Yoshimoto T, Kono T, Ikai I, Kubo H. A homeobox protein, prox1, is involved in the differentiation, proliferation, and prognosis in hepatocellular carcinoma. Clin Cancer Res. 2006;12(20 Pt 1):6005–11.PubMedCrossRef
14.
Foskolou IP, Stellas D, Rozani I, Lavigne MD, Politis PK. Prox1 suppresses the proliferation of neuroblastoma cells via a dual action in p27-Kip1 and Cdc25A. Oncogene. 2013;32(8):947–60.PubMedCrossRef
15.
Versmold B, Felsberg J, Mikeska T, et al. Epigenetic silencing of the candidate tumor suppressor gene PROX1 in sporadic breast cancer. Int J Cancer. 2007;121(3):547–54.PubMedCrossRef
16.
Schneider M, Buchler P, Giese N, et al. Role of lymphangiogenesis and lymphangiogenic factors during pancreatic cancer progression and lymphatic spread. Int J Oncol. 2006;28(4):883–90.PubMed
17.
Yoshimoto T, Takahashi M, Nagayama S, et al. RNA mutations of prox1 detected in human esophageal cancer cells by the shifted termination assay. Biochem Biophys Res Commun. 2007;359(2):258–62.PubMedCrossRef
18.
Akagami M, Kawada K, Kubo H, et al. Transcriptional factor Prox1 plays an essential role in the antiproliferative action of interferon-gamma in esophageal cancer cells. Ann Surg Oncol. 2011;18(13):3868–77.PubMedCrossRef
19.
Zhou B, Si W, Su Z, Deng W, Tu X, Wang Q. Transcriptional activation of the Prox1 gene by HIF-1alpha and HIF-2alpha in response to hypoxia. FEBS Lett. 2013;587(6):724–31.PubMedCrossRef
20.
Keith B, Johnson RS, Simon MC. HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer. 2012;12(1):9–22.
21.
Shimada Y, Imamura M, Wagata T, Yamaguchi N, Tobe T. Characterization of 21 newly established esophageal cancer cell lines. Cancer. 1992;69(2):277–84.PubMedCrossRef
22.
Yokobori T, Yokoyama Y, Mogi A, et al. FBXW7 mediates chemotherapeutic sensitivity and prognosis in NSCLCs. Mol Cancer Res. 2014;12(1):32–37.PubMedCrossRef
23.
Aranguren XL, Beerens M, Coppiello G, et al. COUP-TFII orchestrates venous and lymphatic endothelial identity by homo- or hetero-dimerisation with PROX1. J Cell Sci. 2013;126(Pt 5):1164–75.PubMedCrossRef
24.
Flister MJ, Wilber A, Hall KL, et al. Inflammation induces lymphangiogenesis through up-regulation of VEGFR-3 mediated by NF-kappaB and Prox1. Blood. 2010;115(2):418–29.PubMedPubMedCentralCrossRef
25.
Francois M, Caprini A, Hosking B, et al. Sox18 induces development of the lymphatic vasculature in mice. Nature. 2008;456(7222):643–7.PubMedCrossRef
26.
Yoo J, Lee HN, Choi I, et al. Opposing regulation of PROX1 by interleukin-3 receptor and NOTCH directs differential host cell fate reprogramming by Kaposi sarcoma herpes virus. PLoS Pathog. 2012;8(6):e1002770.PubMedPubMedCentralCrossRef
27.
Kurokawa T, Miyamoto M, Kato K, et al. Overexpression of hypoxia-inducible-factor 1alpha(HIF-1alpha) in oesophageal squamous cell carcinoma correlates with lymph node metastasis and pathologic stage. Br J Cancer. 2003;89(6):1042–7.PubMedPubMedCentralCrossRef
28.
Izzo JG, Malhotra U, Wu TT, et al. Association of activated transcription factor nuclear factor kappab with chemoradiation resistance and poor outcome in esophageal carcinoma. J Clin Oncol. 2006;24(5):748–54.PubMedCrossRef
29.
Wigle JT, Harvey N, Detmar M, et al. An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. EMBO J. 2002;21(7):1505–13.PubMedPubMedCentralCrossRef
30.
Pan MR, Chang TM, Chang HC, Su JL, Wang HW, Hung WC. Sumoylation of Prox1 controls its ability to induce VEGFR3 expression and lymphatic phenotypes in endothelial cells. J Cell Sci. 2009;122(Pt 18):3358–64.PubMedCrossRef
31.
Lv T, Liu Y, Zhang J, et al. Impact of an altered PROX1 expression on clinicopathology, prognosis and progression in renal cell carcinoma. PloS One. 2014;9(5):e95996.PubMedPubMedCentralCrossRef
32.
Taban O, Cimpean AM, Raica M, Olariu S. PROX1 expression in gastric cancer: from hypothesis to evidence. Anticancer Res. 2014;34(7):3439–46.PubMed
33.
Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9(4):265–73.PubMedCrossRef
34.
Bellovin DI, Bates RC, Muzikansky A, Rimm DL, Mercurio AM. Altered localization of p120 catenin during epithelial to mesenchymal transition of colon carcinoma is prognostic for aggressive disease. Cancer Res. 2005;65(23):10938–45.PubMedCrossRef
35.
Bellovin DI, Simpson KJ, Danilov T, et al. Reciprocal regulation of RhoA and RhoC characterizes the EMT and identifies RhoC as a prognostic marker of colon carcinoma. Oncogene. 2006;25(52):6959–67.PubMedCrossRef
36.
Hollier BG, Tinnirello AA, Werden SJ, et al. FOXC2 expression links epithelial-mesenchymal transition and stem cell properties in breast cancer. Cancer Res. 2013;73(6):1981–92.PubMedPubMedCentralCrossRef
37.
Sun S, Ning X, Zhang Y, et al. Hypoxia-inducible factor-1alpha induces Twist expression in tubular epithelial cells subjected to hypoxia, leading to epithelial-to-mesenchymal transition. Kidney Int. 2009;75(12):1278–87.PubMedCrossRef
38.
Sun X, Fa P, Cui Z, et al. The EDA-containing cellular fibronectin induces epithelial-mesenchymal transition in lung cancer cells through integrin alpha9beta1-mediated activation of PI3-K/AKT and Erk1/2. Carcinogenesis. 2014;35(1):184–91.PubMedCrossRef
39.
Mishima K, Watabe T, Saito A, et al. Prox1 induces lymphatic endothelial differentiation via integrin alpha9 and other signaling cascades. Mol Biol Cell. 2007;18(4):1421–9.PubMedPubMedCentralCrossRef
40.
Chang TM, Hung WC. The homeobox transcription factor Prox1 inhibits proliferation of hepatocellular carcinoma cells by inducing p53-dependent senescence-like phenotype. Cancer Biol Ther. 2013;14(3):222–9.PubMedPubMedCentralCrossRef
41.
Agrawal N, Jiao Y, Bettegowda C, et al. Comparative genomic analysis of esophageal adenocarcinoma and squamous cell carcinoma. Cancer Discov. 2012;2(10):899–905.PubMedPubMedCentralCrossRef
42.
Guichard C, Amaddeo G, Imbeaud S, et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet. 2012;44(6):694–8.PubMedPubMedCentralCrossRef
43.
Metadata
Title
Nuclear PROX1 is Associated with Hypoxia-Inducible Factor 1α Expression and Cancer Progression in Esophageal Squamous Cell Carcinoma
Authors
Takehiko Yokobori, MD, PhD
Pinjie Bao, MSc
Minoru Fukuchi, MD, PhD
Bolag Altan, MD, PhD
Daigo Ozawa, MD, PhD
Susumu Rokudai, PhD
Tuya Bai, MSc
Yuji Kumakura, MD
Hiroaki Honjo, MD
Keigo Hara, MD
Makoto Sakai, MD, PhD
Makoto Sohda, MD, PhD
Tatsuya Miyazaki, MD, PhD
Munenori Ide, MD, PhD
Masahiko Nishiyama, MD, PhD
Tetsunari Oyama, MD, PhD
Hiroyuki Kuwano, MD, PhD, FACS
Publication date
01-12-2015
Publisher
Springer US
Published in
Annals of Surgical Oncology / Issue Special Issue 3/2015
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-015-4831-6

Other articles of this Special Issue 3/2015

Annals of Surgical Oncology 3/2015 Go to the issue

Reconstructive Oncology

Liposuction for Advanced Lymphedema: A Multidisciplinary Approach for Complete Reduction of Arm and Leg Swelling

Gastrointestinal Oncology

Pattern of Lymphatic Spread of Esophageal Cancer at the Cervicothoracic Junction Based on the Tumor Location

Gastrointestinal Oncology

Both GLUT-1 and GLUT-14 are Independent Prognostic Factors in Gastric Adenocarcinoma

Gastrointestinal Oncology

Value of Peritoneal Drain Placement After Total Gastrectomy for Gastric Adenocarcinoma: A Multi-institutional Analysis from the US Gastric Cancer Collaborative

Urologic Oncology

Renal Function is Associated with Nephrometry Score After Partial Nephrectomy: A Study Using Diethylene Triamine Penta-Acetic Acid (DTPA) Renal Scanning

Breast Oncology

Variation in Additional Breast Imaging Orders and Impact on Surgical Wait Times at a Comprehensive Cancer Center