Low CDX1 expression predicts a poor prognosis for hepatocellular carcinoma patients after hepatectomy
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.
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Hao Zheng, Yuan Yang and Meng-chao Wang have contributed equally to this study.