Abstract
BackgroundOpioid receptors have become increasingly implicated in cancer progression and long-term patient outcomes. However, the expression and significance of the κ-opioid receptor (KOR) in hepatocellular carcinoma (HCC) remain unclear.MethodsIn this study, KOR mRNA expression was analysed by real-time quantitative PCR in 64 pairs of HCC tumour tissues and adjacent non-tumour tissues, and KOR protein expression was analysed by immunohistochemistry in 174 HCC patients. We investigated the correlation between KOR expression and clinicopathological parameters to illustrate the potential prognostic significance of KOR expression in HCC.ResultsKOR mRNA expression was significantly down-regulated in 79.69% (51 of 64) of the HCC tumour samples, and KOR expression in tumour tissue was significantly lower than that in adjacent non-tumour tissues (P < 0.001). ROC curve analysis showed that KOR mRNA expression yielded AUC of 0.745, for the detection of HCC patients. Low KOR mRNA expression in HCC was correlated with aggressive clinicopathological parameters, such as tumour size (P = 0.015), differentiation grade (P = 0.011), and TNM stage (P = 0.021). Moreover, down-regulation of KOR protein expression in HCC tissues was detected in 174 HCC patients. Similarly, negative KOR protein expression was significantly correlated with aggressive clinicopathological features, such as tumour size (P = 0.002), vascular invasion (P = 0.003), differentiation grade (P = 0.026), and TNM stage (P = 0.030). Furthermore, Kaplan-Meier survival analysis demonstrated that down-regulation of KOR in HCC indicated poor prognosis. KOR deficiency (KORT < N) was correlated to a shorter survival rate and an increased recurrence (both P < 0.001). In univariate and multivariate survival analyses, KOR was identified as a promising independent risk factor for both overall survival (OS, both P < 0.001) and recurrence-free survival (RFS, both P < 0.001).ConclusionsDown-regulation of KOR in HCC tumour tissues has a strong association with poor prognosis and KOR might be a potential tumour suppressor.
Highlights
Opioid receptors have become increasingly implicated in cancer progression and long-term patient outcomes
We detected a downregulation of κ-opioid receptor (KOR) in 79.69% (51 of 64) of the hepatocellular carcinoma (HCC) samples (Fig. 1a); KOR expression was significantly lower than in adjacent non-neoplastic tissues (P < 0.001; Fig. 1b)
A receiver operating characteristic (ROC) curve was constructed and the result showed that KOR mRNA expression yielded area under curve (AUC) of 0.745, for the detection of HCC patients (Fig. 1c)
Summary
Opioid receptors have become increasingly implicated in cancer progression and long-term patient outcomes. The expression and significance of the κ-opioid receptor (KOR) in hepatocellular carcinoma (HCC) remain unclear. There are more than 50% of the cases in China alone, according to the epidemiologic report [2]. This cancer has a very poor survival rate even with advanced diagnostic strategies and improved therapies. The expression profile of opioid receptors in different cancer cells has been reported [13] and experimental studies in investing the effects of opioid receptor agonists and antagonists on the proliferation and metastasis of cancer both in vivo and in vitro study have received lots of attention. Other reports described tumor-promoting effects of morphine by immunosuppression [14] or inducing angiogenesis [15]
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