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
BMC Cancer
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

High expression of forkhead box protein C2 is associated with aggressive phenotypes and poor prognosis in clinical hepatocellular carcinoma

Authors: Yuki Shimoda, Yasunari Ubukata, Tadashi Handa, Takehiko Yokobori, Takayoshi Watanabe, Dolgormaa Gantumur, Kei Hagiwara, Takahiro Yamanaka, Mariko Tsukagoshi, Takamichi Igarashi, Akira Watanabe, Norio Kubo, Kenichiro Araki, Norifumi Harimoto, Ayaka Katayama, Toshiaki Hikino, Takaaki Sano, Kyoichi Ogata, Hiroyuki Kuwano, Ken Shirabe, Tetsunari Oyama

Published in: BMC Cancer | Issue 1/2018

Login to get access

Abstract

Background

Hepatocellular carcinoma (HCC) is one of the major causes of tumor death; thus, the identification of markers related to its diagnosis and prognosis is critical. Previous studies have revealed that epithelial-to-mesenchymal transition (EMT) is involved in tumor invasion and metastasis, and the forkhead box protein C2 (FOXC2) has been shown to promote tumor cell proliferation, invasion, and EMT. In the present study, we examined the clinicopathological significance of FOXC2 and EMT-related markers in clinical HCC specimens and identified factors related to the diagnosis and prognosis of HCC.

Methods

The expression of FOXC2 and EMT-related markers was evaluated by immunohistochemistry in 84 cases of hepatocellular carcinoma.

Results

A high expression of FOXC2 was observed in 26 of 84 cases, and expression was significantly correlated with background liver cirrhosis, poor tumor differentiation, high serum AFP, and elevated cell proliferation markers. In addition, this high expression was related to the induction of the Cadherin switch and vimentin expression and was an independent predictor for poor prognosis.

Conclusion

The high expression of FOXC2 in HCC is correlated with tumor malignancy and poor prognosis, suggesting that FOXC2 may be an important prognostic factor for HCC.
Literature
1.
Thun MJ, DeLancey JO, Center MM, Jemal A, Ward EM. The global burden of cancer: priorities for prevention. Carcinogenesis. 2010;31(1):100–10.CrossRefPubMed
2.
Torrecilla S, Llovet JM. New molecular therapies for hepatocellular carcinoma. Clin Res Hepatol Gastroenterol. 2015;39(Suppl 1):S80–5.CrossRefPubMed
3.
De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013;13(2):97–110.CrossRefPubMed
4.
Iwatsuki M, Mimori K, Yokobori T, Ishi H, Beppu T, Nakamori S, Baba H, Mori M. Epithelial-mesenchymal transition in cancer development and its clinical significance. Cancer Sci. 2010;101(2):293–9.CrossRefPubMed
5.
Kitisin K, Saha T, Blake T, Golestaneh N, Deng M, Kim C, Tang Y, Shetty K, Mishra B, Mishra L. Tgf-Beta signaling in development. Sci STKE. 2007;2007(399):cm1.CrossRefPubMed
6.
Schmierer B, Hill CS. TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol. 2007;8(12):970–82.CrossRefPubMed
7.
Mani SA, Yang J, Brooks M, Schwaninger G, Zhou A, Miura N, Kutok JL, Hartwell K, Richardson AL, Weinberg RA. Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proc Natl Acad Sci U S A. 2007;104(24):10069–74.CrossRefPubMedPubMedCentral
8.
9.
Kriederman BM, Myloyde TL, Witte MH, Dagenais SL, Witte CL, Rennels M, Bernas MJ, Lynch MT, Erickson RP, Caulder MS, et al. FOXC2 haploinsufficient mice are a model for human autosomal dominant lymphedema-distichiasis syndrome. Hum Mol Genet. 2003;12(10):1179–85.CrossRefPubMed
10.
Hader C, Marlier A, Cantley L. Mesenchymal-epithelial transition in epithelial response to injury: the role of Foxc2. Oncogene. 2010;29(7):1031–40.CrossRefPubMed
11.
Nishida N, Mimori K, Yokobori T, Sudo T, Tanaka F, Shibata K, Ishii H, Doki Y, Mori M. FOXC2 is a novel prognostic factor in human esophageal squamous cell carcinoma. Ann Surg Oncol. 2011;18(2):535–42.CrossRefPubMed
12.
Watanabe A, Suzuki H, Yokobori T, Altan B, Kubo N, Araki K, Wada S, Mochida Y, Sasaki S, Kashiwabara K, et al. Forkhead box protein C2 contributes to invasion and metastasis of extrahepatic cholangiocarcinoma, resulting in a poor prognosis. Cancer Sci. 2013;104(11):1427–32.CrossRefPubMed
13.
Hollier BG, Tinnirello AA, Werden SJ, Evans KW, Taube JH, Sarkar TR, Sphyris N, Shariati M, Kumar SV, Battula VL, et al. FOXC2 expression links epithelial-mesenchymal transition and stem cell properties in breast cancer. Cancer Res. 2013;73(6):1981–92.CrossRefPubMedPubMedCentral
14.
Cui YM, Jiao HL, Ye YP, Chen CM, Wang JX, Tang N, Li TT, Lin J, Qi L, Wu P, et al. FOXC2 promotes colorectal cancer metastasis by directly targeting MET. Oncogene. 2015;34(33):4379–90.CrossRefPubMed
15.
Song L, Tang H, Liao W, Luo X, Li Y, Chen T, Zhang X. FOXC2 positively regulates YAP signaling and promotes the glycolysis of nasopharyngeal carcinoma. Exp Cell Res. 2017;357(1):17–24.CrossRefPubMed
16.
Jiang W, Fan H, Qian C, Ding J, Wang Q, Pang X. Prognostic value of high FoxC2 expression in resectable non-small cell lung cancer, alone or in combination with E-cadherin expression. BMC Cancer. 2016;16:16.CrossRefPubMedPubMedCentral
17.
Liu B, Han SM, Tang XY, Han L, Li CZ. Overexpressed FOXC2 in ovarian cancer enhances the epithelial-to-mesenchymal transition and invasion of ovarian cancer cells. Oncol Rep. 2014;31(6):2545–54.CrossRefPubMed
18.
Yang F, Lv L, Zhang K, Cai Q, Liu J, Jiang Y. Elevated FOXC2 expression promotes invasion of HCC cell lines and is associated with poor prognosis in hepatocellular carcinoma. Cell Physiol Biochem. 2017;44(1):99–109.CrossRefPubMed
19.
Katayama A, Handa T, Komatsu K, Togo M, Horiguchi J, Nishiyama M, Oyama T. Expression patterns of claudins in patients with triple-negative breast cancer are associated with nodal metastasis and worse outcome. Pathol Int. 2017;67(8):404–13.CrossRefPubMed
20.
Katoh M, Katoh M. Integrative genomic analyses of CXCR4: transcriptional regulation of CXCR4 based on TGFbeta, nodal, Activin signaling and POU5F1, FOXA2, FOXC2, FOXH1, SOX17, and GFI1 transcription factors. Int J Oncol. 2010;36(2):415–20.PubMed
21.
Taube JH, Herschkowitz JI, Komurov K, Zhou AY, Gupta S, Yang J, Hartwell K, Onder TT, Gupta PB, Evans KW, et al. Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc Natl Acad Sci U S A. 2010;107(35):15449–54.CrossRefPubMedPubMedCentral
22.
Li Q, Wu J, Wei P, Xu Y, Zhuo C, Wang Y, Li D, Cai S. Overexpression of forkhead box C2 promotes tumor metastasis and indicates poor prognosis in colon cancer via regulating epithelial-mesenchymal transition. Am J Cancer Res. 2015;5(6):2022–34.PubMedPubMedCentral
23.
D'Amico G, Morabito A, D'Amico M, Pasta L, Malizia G, Rebora P, Valsecchi MG. Clinical states of cirrhosis and competing risks. J Hepatol 2018;68(3):563–76.
24.
Xiao G, Zhu S, Xiao X, Yan L, Yang J, Wu G. Comparison of laboratory tests, ultrasound, or magnetic resonance elastography to detect fibrosis in patients with nonalcoholic fatty liver disease: a meta-analysis. Hepatology. 2017;66(5):1486–501.CrossRefPubMed
25.
26.
Cui L, Dang S, Qu J, Mao Z, Wang X, Zhang J, Chen J. FOXC2 is up-regulated in pancreatic ductal adenocarcinoma and promotes the growth and migration of cancer cells. Tumour Biol. 2016;37(7):8579–85.CrossRefPubMed
27.
Cui YM, Jiang D, Zhang SH, Wu P, Ye YP, Chen CM, Tang N, Liang L, Li TT, Qi L, et al. FOXC2 promotes colorectal cancer proliferation through inhibition of FOXO3a and activation of MAPK and AKT signaling pathways. Cancer Lett. 2014;353(1):87–94.CrossRefPubMed
28.
Li C, Ding H, Tian J, Wu L, Wang Y, Xing Y, Chen M. Forkhead box protein C2 (FOXC2) promotes the resistance of human ovarian Cancer cells to cisplatin in vitro and in vivo. Cell Physiol Biochem. 2016;39(1):242–52.CrossRefPubMed
29.
Yang C, Cui X, Dai X, Liao W. Downregulation of Foxc2 enhances apoptosis induced by 5-fluorouracil through activation of MAPK and AKT pathways in colorectal cancer. Oncol Lett. 2016;11(2):1549–54.CrossRefPubMedPubMedCentral
30.
Zhou Z, Zhang L, Xie B, Wang X, Yang X, Ding N, Zhang J, Liu Q, Tan G, Feng D, et al. FOXC2 promotes chemoresistance in nasopharyngeal carcinomas via induction of epithelial mesenchymal transition. Cancer Lett. 2015;363(2):137–45.CrossRefPubMed
31.
Paranjape AN, Soundararajan R, Werden SJ, Joseph R, Taube JH, Liu H, Rodriguez-Canales J, Sphyris N, Wistuba I, Miura N, et al. Inhibition of FOXC2 restores epithelial phenotype and drug sensitivity in prostate cancer cells with stem-cell properties. Oncogene. 2016;35(46):5963–76.CrossRefPubMedPubMedCentral
32.
Cai J, Tian AX, Wang QS, Kong PZ, Du X, Li XQ, Feng YM. FOXF2 suppresses the FOXC2-mediated epithelial-mesenchymal transition and multidrug resistance of basal-like breast cancer. Cancer Lett. 2015;367(2):129–37.CrossRefPubMed
33.
Zhang CL, Zhu KP, Ma XL. Antisense lncRNA FOXC2-AS1 promotes doxorubicin resistance in osteosarcoma by increasing the expression of FOXC2. Cancer Lett. 2017;396:66–75.CrossRefPubMed
34.
Yu YH, Chen HA, Chen PS, Cheng YJ, Hsu WH, Chang YW, Chen YH, Jan Y, Hsiao M, Chang TY, et al. MiR-520h-mediated FOXC2 regulation is critical for inhibition of lung cancer progression by resveratrol. Oncogene. 2013;32(4):431–43.CrossRefPubMed
35.
Chai R, Fu H, Zheng Z, Liu T, Ji S, Li G. Resveratrol inhibits proliferation and migration through SIRT1 mediated posttranslational modification of PI3K/AKT signaling in hepatocellular carcinoma cells. Mol Med Rep. 2017;16(6):8037–44.CrossRefPubMedPubMedCentral
36.
Gao F, Deng G, Liu W, Zhou K, Li M. Resveratrol suppresses human hepatocellular carcinoma via targeting HGF-c-met signaling pathway. Oncol Rep. 2017;37(2):1203–11.CrossRefPubMed
37.
Dai W, Wang F, Lu J, Xia Y, He L, Chen K, Li J, Li S, Liu T, Zheng Y, et al. By reducing hexokinase 2, resveratrol induces apoptosis in HCC cells addicted to aerobic glycolysis and inhibits tumor growth in mice. Oncotarget. 2015;6(15):13703–17.CrossRefPubMedPubMedCentral
Metadata
Title
High expression of forkhead box protein C2 is associated with aggressive phenotypes and poor prognosis in clinical hepatocellular carcinoma
Authors
Yuki Shimoda
Yasunari Ubukata
Tadashi Handa
Takehiko Yokobori
Takayoshi Watanabe
Dolgormaa Gantumur
Kei Hagiwara
Takahiro Yamanaka
Mariko Tsukagoshi
Takamichi Igarashi
Akira Watanabe
Norio Kubo
Kenichiro Araki
Norifumi Harimoto
Ayaka Katayama
Toshiaki Hikino
Takaaki Sano
Kyoichi Ogata
Hiroyuki Kuwano
Ken Shirabe
Tetsunari Oyama
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-4503-6

Other articles of this Issue 1/2018

BMC Cancer 1/2018 Go to the issue

Research article

Putative cancer stem cells may be the key target to inhibit cancer cell repopulation between the intervals of chemoradiation in murine mesothelioma

Research article

Identification of novel enriched recurrent chimeric COL7A1-UCN2 in human laryngeal cancer samples using deep sequencing

Research article

BRAF V600E mutation and 9p21: CDKN2A/B and MTAP co-deletions - Markers in the clinical stratification of pediatric gliomas

Research article

Dose escalation can maximize therapeutic potential of sunitinib in patients with metastatic renal cell carcinoma

Research article

Deficiency in hormone-sensitive lipase accelerates the development of pancreatic cancer in conditional KrasG12D mice

Research article

Development of the body image self-rating questionnaire for breast cancer (BISQ-BC) for Chinese mainland patients
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits