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

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 12/2014

01-11-2014 | Translational Research and Biomarkers

Epithelial to Mesenchymal Transition is Associated with Shorter Disease-Free Survival in Hepatocellular Carcinoma

Authors: Suguru Yamada, MD, PhD, FACS, Norio Okumura, MD, Lan Wei, PhD, Bryan C. Fuchs, PhD, Tsutomu Fujii, MD, PhD, FACS, Hiroyuki Sugimoto, MD, PhD, Shuji Nomoto, MD, PhD, Shin Takeda, MD, PhD, Kenneth K. Tanabe, MD, FACS, Yasuhiro Kodera, MD, PhD, FACS

Published in: Annals of Surgical Oncology | Issue 12/2014

Login to get access

Abstract

Background

Epithelial to mesenchymal transition (EMT) is involved in cancer cell invasion and metastasis as well as chemoresistance. Elucidation of EMT in hepatocellular carcinoma (HCC) might contribute to deeper understanding of its biology.

Methods

Overall, 100 patients with HCC, who underwent resection, were analyzed. The messenger RNA (mRNA) expression of the epithelial marker E-cadherin and the mesenchymal marker Vimentin were measured, and the EMT status of each patient was determined as follows: Vimentin/E-cadherin <2 = Epithelial (E), Vimentin/E-cadherin ≥2 = Mesenchymal (M). The correlation between these values and clinicopathological factors and prognosis were analyzed statistically. Moreover, the expression of transcription factors involved in EMT (Twist-1, Snail, Slug, Zeb-1, and Zeb-2) were measured and the role of interleukin (IL)-6 in inducing EMT and chemoresistance was examined.

Results

Patients with a mesenchymal tumor were more prone to have an earlier recurrence than those with an epithelial tumor. EMT-inducing transcription factors were more highly expressed in mesenchymal tumors than in epithelial tumors, and Twist-1 and Zeb-2 were significantly overexpressed. α-Fetoprotein (AFP) values were significantly higher in patients with epithelial tumors, and AFP-expressing HCC cell lines were more responsive to sorafenib. IL-6 expression was significantly higher in mesenchymal tumors, and knockdown of IL-6 in mesenchymal HCC cell lines increased E-cadherin expression and sensitivity to sorafenib.

Conclusions

Analysis of surgically resected tumors suggests that EMT is involved in early disease recurrence in HCC. Twist-1 and Zeb-2 might be important for inducing EMT, and IL-6 might be a potential therapeutic target for alleviating the chemoresistance of mesenchymal HCC tumors.
Appendix
Available only for authorised users
Literature
1.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.PubMedCrossRef
2.
Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2(6):442–54.PubMedCrossRef
3.
4.
5.
Cheng GZ, Chan J, Wang Q, Zhang W, Sun CD, Wang LH. Twist transcriptionally up-regulates AKT2 in breast cancer cells leading to increased migration, invasion, and resistance to paclitaxel. Cancer Res. 2007;67(5):1979–87.PubMedCrossRef
6.
Fuchs BC, Fujii T, Dorfman JD, et al. Epithelial-to-mesenchymal transition and integrin-linked kinase mediate sensitivity to epidermal growth factor receptor inhibition in human hepatoma cells. Cancer Res. 2008;68(7):2391–9.PubMedCrossRef
7.
Arumugam T, Ramachandran V, Fournier KF, et al. Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res. 2009;69(14):5820–8.PubMedCrossRef
8.
Cano A, Perez-Moreno MA, Rodrigo I, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000;2(2):76–83.PubMedCrossRef
9.
Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008;14(6):818–29.PubMedCrossRef
10.
Yang J, Mani SA, Donaher JL, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004;117(7):927–39.PubMedCrossRef
11.
Lee KD, Kuo TK, Whang-Peng J, et al. In vitro hepatic differentiation of human mesenchymal stem cells. Hepatology. 2004;40(6):1275–84.PubMedCrossRef
12.
Boyault S, Rickman DS, de Reynies A, et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology. 2007;45(1):42–52.PubMedCrossRef
13.
Hoshida Y, Nijman SM, Kobayashi M, et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res. 2009;69(18):7385–92.PubMedCrossRefPubMedCentral
14.
Lee TK, Poon RT, Yuen AP, et al. Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition. Clin Cancer Res. 2006;12(18):5369–76.PubMedCrossRef
15.
Zhao H, Desai V, Wang J, Epstein DM, Miglarese M, Buck E. Epithelial-mesenchymal transition predicts sensitivity to the dual IGF-1R/IR inhibitor OSI-906 in hepatocellular carcinoma cell lines. Mol Cancer Ther. 2012;11(2):503–13.PubMedCrossRef
16.
Giannelli G, Bergamini C, Fransvea E, Sgarra C, Antonaci S. Laminin-5 with transforming growth factor-beta1 induces epithelial to mesenchymal transition in hepatocellular carcinoma. Gastroenterology. 2005;129(5):1375–83.PubMedCrossRef
17.
Lee TK, Man K, Poon RT, et al. Signal transducers and activators of transcription 5b activation enhances hepatocellular carcinoma aggressiveness through induction of epithelial-mesenchymal transition. Cancer Res. 2006;66(20):9948–56.PubMedCrossRef
18.
Yau T, Yao TJ, Chan P, et al. The significance of early alpha-fetoprotein level changes in predicting clinical and survival benefits in advanced hepatocellular carcinoma patients receiving sorafenib. Oncologist. 2011;16(9):1270–9.PubMedCrossRefPubMedCentral
19.
Shao YY, Lin ZZ, Hsu C, Shen YC, Hsu CH, Cheng AL. Early alpha-fetoprotein response predicts treatment efficacy of antiangiogenic systemic therapy in patients with advanced hepatocellular carcinoma. Cancer. 2010;116(19):4590–6.PubMedCrossRef
20.
21.
22.
Shen CH, Wu JD, Jou YC, et al. The correlation between TWIST, E-cadherin, and beta-catenin in human bladder cancer. J BUON. 2011;16(4):733–7.PubMed
23.
Sasaki K, Natsugoe S, Ishigami S, et al. Significance of Twist expression and its association with E-cadherin in esophageal squamous cell carcinoma. J Exp Clin Cancer Res. 2009;28:158.PubMedCrossRefPubMedCentral
24.
Liu AN, Zhu ZH, Chang SJ, Hang XS. Twist expression associated with the epithelial-mesenchymal transition in gastric cancer. Mol Cell Biochem. 2012;367(1–2):195–203.PubMedCrossRef
25.
26.
Yang MH, Chen CL, Chau GY, et al. Comprehensive analysis of the independent effect of twist and snail in promoting metastasis of hepatocellular carcinoma. Hepatology. 2009;50(5):1464–74.PubMedCrossRef
27.
ElMoneim HM, Zaghloul NM. Expression of E-cadherin, N-cadherin and snail and their correlation with clinicopathological variants: an immunohistochemical study of 132 invasive ductal breast carcinomas in Egypt. Clinics. 2011;66(10):1765–71.PubMedPubMedCentral
28.
29.
Kurrey NK, K A, Bapat SA. Snail and Slug are major determinants of ovarian cancer invasiveness at the transcription level. Gynecol Oncol. 2005;97(1):155–65.PubMedCrossRef
30.
Nishioka R, Itoh S, Gui T, et al. SNAIL induces epithelial-to-mesenchymal transition in a human pancreatic cancer cell line (BxPC3) and promotes distant metastasis and invasiveness in vivo. Exp Mol Pathol. 2010;89(2):149–57.PubMedCrossRef
31.
Porta C, De Amici M, Quaglini S, et al. Circulating interleukin-6 as a tumor marker for hepatocellular carcinoma. Ann Oncol. 2008;19(2):353–8.PubMedCrossRef
32.
Shackel NA, McCaughan GW, Warner FJ. Hepatocellular carcinoma development requires hepatic stem cells with altered transforming growth factor and interleukin-6 signaling. Hepatology. 2008;47(6):2134–6.PubMedCrossRef
33.
Wong VW, Yu J, Cheng AS, et al. High serum interleukin-6 level predicts future hepatocellular carcinoma development in patients with chronic hepatitis B. Int J Cancer. 2009;124(12):2766–70.PubMedCrossRef
34.
Sansone P, Storci G, Tavolari S, et al. IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest. 2007;117(12):3988–4002.PubMedCrossRefPubMedCentral
35.
Sasser AK, Sullivan NJ, Studebaker AW, Hendey LF, Axel AE, Hall BM. Interleukin-6 is a potent growth factor for ER-alpha-positive human breast cancer. FASEB J. 2007;21(13):3763–70.PubMedCrossRef
36.
Studebaker AW, Storci G, Werbeck JL, et al. Fibroblasts isolated from common sites of breast cancer metastasis enhance cancer cell growth rates and invasiveness in an interleukin-6-dependent manner. Cancer Res. 2008;68(21):9087–95.PubMedCrossRef
37.
Naugler WE, Sakurai T, Kim S, et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science. 2007;317(5834):121–4.PubMedCrossRef
38.
He G, Dhar D, Nakagawa H, et al. Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell. 2013;155(2):384–96.PubMedCrossRefPubMedCentral
39.
Sullivan NJ, Sasser AK, Axel AE, et al. Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene. 2009;28(33):2940–7.PubMedCrossRef
Metadata
Title
Epithelial to Mesenchymal Transition is Associated with Shorter Disease-Free Survival in Hepatocellular Carcinoma
Authors
Suguru Yamada, MD, PhD, FACS
Norio Okumura, MD
Lan Wei, PhD
Bryan C. Fuchs, PhD
Tsutomu Fujii, MD, PhD, FACS
Hiroyuki Sugimoto, MD, PhD
Shuji Nomoto, MD, PhD
Shin Takeda, MD, PhD
Kenneth K. Tanabe, MD, FACS
Yasuhiro Kodera, MD, PhD, FACS
Publication date
01-11-2014
Publisher
Springer US
Published in
Annals of Surgical Oncology / Issue 12/2014
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-014-3779-2

Other articles of this Issue 12/2014

Annals of Surgical Oncology 12/2014 Go to the issue

Head and Neck Oncology

What’s Old is New Again

Colorectal Cancer

Association Between Palliative Resection of the Primary Tumor and Overall Survival in a Population-Based Cohort of Metastatic Colorectal Cancer Patients

Colorectal Cancer

The Diagnostic Value of One-Step Nucleic acid Amplification (OSNA) for Sentinel Lymph Nodes in Colon Cancer Patients

Breast Oncology

Intraoperative Radiation Therapy: A Critical Analysis of the ELIOT and TARGIT Trials. Part 1—ELIOT

Endocrine Tumors

Predictors of Hemodynamic Instability During Surgery for Pheochromocytoma

Breast Oncology

Intraoperative Radiation Therapy: A Critical Analysis of the ELIOT and TARGIT Trials. Part 2—TARGIT