Association of mu-opioid receptor expression with lymph node metastasis in esophageal squamous cell carcinoma

Abstract

The mu-opioid receptor (MOR), a membrane-bound G protein-coupled receptor, is the main target for opioids in the nervous system. MOR1 has been found in several types of cancer cells and reported to be involved in tumor progression and metastasis. However, the expression and clinical significance of MOR1 in esophageal squamous cell carcinoma (ESCC) remain unclear. In our study, the expression of MOR1 was confirmed in ESCC cell lines (KYSE180, KYSE150, and EC109) by Western blot. MOR1 was also detected on tissue microarrays of ESCC samples in 239 cases using immunohistochemical staining. We found that MOR1 was mainly located in the cytoplasm and occasionally occurred in the membrane or nucleus of ESCC cells. Moreover, results indicated that MOR1 expression in the cytoplasm was associated with lymph node metastasis (R = 0.164, P = 0.008, Kendall's tau-b-test). No more associations were found between MOR1 expression status and other clinical parameters. However, no statistical significant differences were found between MOR1 expression in the cytoplasm, nucleus/membrane, and the overall survival of ESCC patients (P = 0.848; P = 0.167; P = 0.428, respectively, log-rank test). Our results suggest that the cytoplasmic MOR1 may be a high-risk factor for lymph node metastasis of ESCC patients. We also hypothesize that MOR1 agonists used in ESCC patients should be prudent, and opioid receptor antagonists may be novel therapeutic drugs for ESCC patients.

MOR1 Expression in Gastric Cancer: A Biomarker Associated With Poor Outcome

“…In the previous study, Mathew et al once described MOR is a novel regulator in lung cancer progression . In another study carried out by Zhang et al., cytoplasmic MOR1 expression was shown to be a high‐risk factor for lymph node metastasis of the patients. These hypotheses were further provided by our results, common to emphasize the specific involvement of MOR1 in the GC tumor progressive and metastatic procession.…”

“…14 Previous studies showed that the cytoplasmic MOR1 expression may be a high-risk factor for lymph node metastasis of esophageal squamous cell carcinoma patients. 13 More recently, a study performed by Singleton et al suggested an increased mu-opioid receptor expression in the progression of metastatic lung cancer. 15 Moreover, stimulation of MOR1 in some tumor cells by opioids has been reported to influence tumor cell growth, migration and metastatic spread, indicating that opioids may have direct effects on cancer cell through activation of MOR1.…”

“…Among opioids system subtypes, the mu‐opioid receptor (MOR), is the main target for opioids such as morphine, fentanyl, and heroin, with nearly two orders of magnitude greater binding affinity compared with the other two opioid receptors (delta and kappa opioid receptors) . MOR1 (the most abundant MOR transcript that consists of exons 1, 2, 3, and 4) has been found in several types of cancer (including breast, colon, lung cancer, and esophageal squamous cell carcinoma) and involved in the cancer progression and metastasis . Previous studies showed that the cytoplasmic MOR1 expression may be a high‐risk factor for lymph node metastasis of esophageal squamous cell carcinoma patients .…”

“…MOR1 (the most abundant MOR transcript that consists of exons 1, 2, 3, and 4) has been found in several types of cancer (including breast, colon, lung cancer, and esophageal squamous cell carcinoma) and involved in the cancer progression and metastasis . Previous studies showed that the cytoplasmic MOR1 expression may be a high‐risk factor for lymph node metastasis of esophageal squamous cell carcinoma patients . More recently, a study performed by Singleton et al suggested an increased mu‐opioid receptor expression in the progression of metastatic lung cancer .…”

Influence of opioids on immune function in patients with cancer pain: from bench to bedside

“…Overexpression of the μ receptor on cancer cells in murine models has been shown to increase the growth of lung cancer (Lennon et al, ), and decreasing μ receptor activity (using μ receptor small hairpin RNA mice or the opioid receptor antagonist methylnaltrexone) has been shown to reduce the growth of lung cancer (Mathew et al, ). Furthermore, μ receptor overexpression has been associated with the development of metastasis in patients with prostate, oesophageal and lung cancer (Zylla et al, ; Singleton et al, ; Zhang et al, ). Morphine influences the proliferation and survival of cancer cells via direct effects on tumour cell DNA cleavage, MAPK, Src, GRB2‐associated binding protein 1 (Gab‐1), PI3K, Akt and STAT3 signalling pathways (Mathew et al, ; Lennon et al, ; ).…”