Elsevier

Surgical Oncology

Volume 25, Issue 3, September 2016, Pages 171-177
Surgical Oncology

Low CDX1 expression predicts a poor prognosis for hepatocellular carcinoma patients after hepatectomy

https://doi.org/10.1016/j.suronc.2016.05.026Get rights and content

Abstract

The caudal-type homeobox 1 (CDX1) transcription factor is a member of the caudal-related homeobox transcription factor gene family and has been reported to be down-regulated in a variety of cancers. However, the expression status and significance of CDX1 in hepatocellular carcinoma (HCC) is still controversial, and little is known about the role of CDX1 in HCC·In our previous study, we investigated the expression and clinical significance of CDX1 in HCC samples from 313 HCC patients. We found CDX1 was strikingly down-regulated in HCC samples. CDX1 expression was associated with poor differentiation (P = 0.002), and patients with low CDX1 expression had a significantly poorer prognosis. A subgroup analysis revealed a difference in prognosis between groups with low and high CDX1 expression among patients who had tumors <5 cm in size and who were alpha-fetoprotein (AFP) negative. Moreover, low expression was more frequently observed in the early recurrence group (within 2 years, P = 0.002). In addition, multivariate Cox regression analysis indicated that the CDX1 expression level, tumor size, presence of hepatitis B e antigen (HBeAg), vascular invasion, and presence of hepatitis B surface antigen (HBsAg) were independent risk factors for HCC recurrence, and the CDX1 expression level, tumor size, tumor number, and presence of HBsAg were independent predictor of overall survival of HCC patients. In conclusion, the downregulation of CDX1 is associated with poor prognosis; and it may serve as a novel predictor of the prognosis of HCC patients after curative resection.

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common solid cancer and approximately 70% of HCC patients have an extremely poor prognosis due to advanced disease and lack of treatment modalities [23]. HCC is likely to spread via hematogenous dissemination at an early stage [28]. Due to the absence of simple and effective diagnostic indicators and recognizable early symptoms, most HCC patients are diagnosed at an advanced stage, when surgery is no longer feasible, which results in a poor prognosis [11]. Abnormal expression of genes has been reported to predict the prognosis of HCC patients [6], [19], [36], [37], [38], [42]. However, few genes have been effectively tested in clinical settings. Therefore, searching for effective early tumor markers for diagnosis and exploring the molecular mechanism of hepatocarcinogenesis are important methods to improve the diagnosis and treatment of HCC.

The caudal-type homeobox 1 (CDX1) transcription factor is a member of the caudal-related homeobox transcription factor gene family and is an intestine-specific transcription factor [3], [31], [34]. It is important for intestinal development and is specifically expressed in the small and large intestine of both mice and humans [3], [9], [17], [25]. CDX1 plays a role in intestinal epithelial cell differentiation [32]. The expression of CDX1 has been reported to be reduced ingastric cancer and colorectal cancer patients and may be clinically useful for improved prediction of the outcome of patients with advanced cancer [20], [21]. Several articles have reported that CDX1 acts as a tumor suppressor via aberrant Wnt signaling [12], [26], [13]) and acts via TGF-β signaling [16] to enhance tumor formation. However, there have been no reports to date regarding the expression and clinical significance of CDX1 in HCC patients.

In our previous study, we investigated the expression and clinical significance of CDX1 in HCC samples using high-throughput tissue microarray technology and the rich HCC clinical sample resources of Eastern Hepatobiliary Surgery Hospital (Shanghai, China). We found that CDX1 is notably down-regulated in HCC samples and can serve as a novel predictor for the prognosis of HCC patients after hepatectomy.

Section snippets

Patients and clinical samples

TMA slides were constructed as described previously [39], [45] (in collaboration with Shanghai Biochip Company, Shanghai, China). The detailed clinicopathological characteristics of the patients are listed in Table 1. All patients were followed until August 2012, according to a uniform guideline reported previously, with a median observation time of 60 months. The time of the surgery was used to calculate the time to a given event. Overall survival (OS) was defined as the interval between

Expression of CDX1 is down-regulated in HCC samples

First, we examined the mRNA levels of CDX1 in the tumor tissues and adjacent noncancerous tissues of 50 HCC patients using real-time PCR. As shown in Fig. 1a, the CDX1 mRNA level in tumor tissues was significantly lower than that in adjacent noncancerous tissues. We further examined the protein levels of CDX1 using immunohistochemical techniques on a tissue microarray that included tumor tissues and adjacent noncancerous tissues from 313 valid HCC patients. We found that the tumors exhibited

Discussion

Over the past few decades, mounting evidence has demonstrated that some genes are of great clinical value for early detection, curative observation, and prognostic evaluation of human cancers. Some genes are up-regulated in HCC patients and play oncogenicroles, whereas other genes are down-regulated in HCC patients and act as tumor suppressors. All of these interactions are positively correlated with the carcinogenesis, progression, and poor prognosis of HCC, indicating great potential as

Funding

This work was supported by the National Key Basic Research Program of China (2014CB542102), the Science Fund for Creative Research Groups, NSFC, China(81221061), the State Key Infectious Disease Project of China (2012ZX10002010), and the Shanghai New Excellent Youth Plan (XYQ2013074).

Conflict of interest

All authors declared no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Acknowledgements

We thank American Journal Experts for editing the grammar, spelling and other common errors.

References (45)

  • N. Rich et al.

    Hepatocellular carcinoma tumour markers: current role and expectations

    Best. Pract. Res. Clingastroenterol

    (2014)
  • K. Shiraki et al.

    A clinical study of lectin-reactive alpha-fetoprotein as an early indicator of hepatocellular carcinoma in the follow-up of cirrhotic patients

    Hepatology

    (1995)
  • D.G. Silberg et al.

    Cdx1 and cdx2 expression during intestinal development

    Gastroenterol

    (2000)
  • P. Soubeyran et al.

    Cdx1 promotes differentiation in a rat intestinal epithelial cell line

    Gastroenterol

    (1999)
  • L.J. Staloch et al.

    C/EBP and Cdx family factors regulate liver fatty acid binding protein transgene expression in the small intestinal epithelium

    Biochim . Biophys. Acta

    (2005)
  • E.R. Suh et al.

    DNA methylation down-regulates CDX1 gene expression in colorectal cancer cell lines

    J. Biol. Chem.

    (2002)
  • C.C. Wong et al.

    The microRNA miR-139 suppresses metastasis and progression of hepatocellular carcinoma by down-regulating Rho-kinase 2

    Gastroenterology

    (2011)
  • J.H. Yuan et al.

    A long noncoding RNA activated by TGF-beta promotes the invasion-metastasis cascade in hepatocellular carcinoma

    Cancer Cell

    (2014)
  • N. Ashley et al.

    Stem cell differentiation and lumen formation in colorectal cancer cell lines and primary tumors

    Cancer Res.

    (2013)
  • C.W. Chan et al.

    Gastrointestinal differentiation marker Cytokeratin 20 is regulated by homeobox gene CDX1

    Proc. Natl. Acad. Sci. U. S. A.

    (2009)
  • J. Chen et al.

    GIT1 is a novel prognostic biomarker and facilitates tumor progression via activating ERK/MMP9 signaling in hepatocellular carcinoma

    Onco Targets Ther.

    (2015)
  • A.S. Cheng et al.

    Helicobacter pylori causes epigenetic dysregulation of FOXD3 to promote gastric carcinogenesis

    Gastroenterology

    (2013)
  • Cited by (11)

    • MiRNA-155 promotes proliferation by targeting caudal-type homeobox 1 (CDX1) in glioma cells

      2017, Biomedicine and Pharmacotherapy
      Citation Excerpt :

      Recent studies showed that CDX1 was involved in diverse cancers, and was a potential therapeutic target for anticancer treatment. For example, Zheng et al. showed that low CDX1 expression predicted a poor prognosis for hepatocellular carcinoma patients after hepatectomy [22]. Jones et al. showed that the CDX1-microRNA-215 axis regulated colorectal cancer stem cell differentiation [23].

    View all citing articles on Scopus
    1

    Hao Zheng, Yuan Yang and Meng-chao Wang have contributed equally to this study.

    View full text