Original ArticlesThe μ-opioid receptor (MOR) promotes tumor initiation in hepatocellular carcinoma
Introduction
Hepatocellular carcinoma (HCC) is the fifth common malignant tumor and the third leading cause of death among all cancer victims [1]. Owing to recent progress in early diagnosis methods and surgical techniques, the incidence and death rates associated with HCC have declined slightly, but issues related to postoperative recurrence and metastasis continue to be problematic.
Opioids are typically used in cancer pain management, including pain associated with tumor resection and preoperative analgesia. Opioids work on receptors, blocking pain conduction in the nervous system. Generally, opioid receptors are categorized into 3 subtypes; μ, κ, and δ (MOR, KOR, DOR), which can modulate pain relief, cognition, and emotion, respectively [2]. Many studies have indicated that opioid receptors also exist in cancer cells of humans and other animals [[3], [4], [5], [6]]. The Μu opioid receptor, MOR, a G protein-coupled receptor found in squamous cells of lung, breast, colon, and prostate cancer cells, is among the most widely used opioid receptors [[7], [8], [9]]. A previous study of ours has demonstrated that MOR is specifically expressed in HCC tissues, whereas it shows no or very low expression in paracancerous tissues. We tested the hypothesis that MOR is associated with HCC, with a view to elucidating the mechanism underlying MOR-facilitated cancer development.
Recent studies have demonstrated the critical role played by cancer stem cells (CSCs) or cancer-initiating cells in tumorigenesis of many cancers [10,11], including hepatocellular carcinoma [12,13]. CSCs display the capacity to self-renew, differentiate, and give rise to new tumors [14]. In HCC, EpCAM, CD133, CD13, CD90 and CD44 have been defined as CSC surface markers [[15], [16], [17], [18]]. However, molecular therapeutic targets for CSC of HCC remain unestablished. The complicated nature of HCC treatment requires an interdisciplinary approach to ensure optimal outcomes. In a previous study, we sorted CD133+ and CD133- populations in Huh7 and HepG2 cells and evaluated MOR expression using flow cytometry, revealing that CD133+ subsets expressed higher levels of MOR than the CD133- subsets in both HCC cell lines, which predicates that MOR is associated with CSC.
We reported for the first time that MOR + cells have CSC properties in HCC and investigated whether MOR + cells offered a new therapeutic target. Furthermore, we explored possible signaling pathways of MOR in HCC. We found that downregulation of MOR inhibits the proliferation of hepatocarcinoma cells and can significantly retard tumor growth. Therapy targeting MOR can provide a new and promising approach to HCC treatment.
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Animal models
Nude mice used in this study were purchased from the Animal Center of the Chinese Academy of Medical Science (Beijing, China). Six-week-old female nude mice, weighing approximately 15 g, were used in the current study. The mice were fed under specific-pathogen-free (SPF) conditions. Xenografts of tumor cells were generated via subcutaneous injection of tumor cells (1 × 106 cells suspended in 200 μl PBS) into the dorsal skin of nude mice. Tumor sizes were monitored twice a week. Animal studies
MOR is generally expressed in the hepatocellular carcinoma cell lines, human tumor tissues and MOR + hepatocellular carcinoma cancer cells resembled cancer stem cells
MOR transcription was measured via qPCR in a normal liver cell line (L02) and several HCC cell lines (PLC, HLE, Huh7 and HepG2). MOR expression was the lowest in L02, higher in HCC cell lines at different levels. But the highest expression of MOR was observed in Huh7 and HepG2 (Fig. 1A).
CD133 is a surface marker of CSC. In order to analyze whether MOR is a potential marker for HCC CSCs, we sorted both CD133+ and CD133- populations in Huh7 and HepG2 cells, and determined their MOR expression
Discussion
All opioid receptor family members are G protein-coupled receptors. The μ-opioid receptor (MOR) is the main member of the opioid receptor super family, which plays an important role in relieving acute postoperative pain and chronic pain. MOR agonists are commonly used not only as analgesics during cancer surgery but also to relieve cancer pain in patients with late malignant tumors. Besides, opioid receptors have been reported to affect cardiovascular and immune systems significantly [20]. MOR
Conflicts of interest
No potential conflicts of interest were disclosed.
Acknowledgments
This work was supported by the National Natural Science Foundation of China (81472413, 81672956, 81602644), Beijing Science and Technology Project (Z181100003818003) and Fund for Fostering Young Scholars of Peking University Health Science Center (BMU2018PY020).
References (32)
- et al.
Down-regulation of the tumour suppressor kappa-opioid receptor predicts poor prognosis in hepatocellular carcinoma patients
BMC Canc.
(2017) - et al.
Significance of CD90+ cancer stem cells in human liver cancer
Cancer Cell
(2008) - et al.
Cancer stem cells: current status and evolving complexities
Cell Stem Cell
(2012) - et al.
Expression of a AC133, a novel stem cell marker, on human leukemic blasts lacking CD34-antigen and on a human CD34+ leukemic line:MUTZ-2
Blood
(1998) - et al.
The delta opioid receptor 1 is expressed by proliferating bile ductules in rats with cholestasis: implications for the study of liver regeneration and malignant transformation of biliary epithelium
Med. Hypotheses
(2005) - et al.
Cancer statistics, 2015
Ca - Cancer J. Clin.
(2015) - et al.
Opioid receptors and endogenous opioids in diverse human and animal cancers
J. Natl. Cancer Inst.
(1987) - et al.
Overexpression of the mu-opioid receptor in human non-small cell lung cancer promotes Akt and mTOR activation, tumor growth, and metastasis
Anesthesiology
(2012) - et al.
mu-Opioid receptor gene A118G polymorphism predicts survival in patients with breast cancer
Anesthesiology
(2012) - et al.
Regulation of STAT3 by mu-opioid receptors in human neuroblastoma SH-SY5Y cells
Neuroreport
(2004)
Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth
Cancer Res.
Functional expression of mu-opioid receptors in the human colon cancer cell line, HT-29, and their localization in human colon
Dig. Dis. Sci.
Opioid requirement, opioid receptor expression, and clinical outcomes in patients with advanced prostate cancer
Cancer
Stem cells, cancer, and cancer stem cells
Nature
Bladder cancer stem cells: clonal origin and therapeutic perspectives
Oncotarget
Regulatory MiR-148a-ACVR1/BMP circuit defines a cancer stem cell-like aggressive subtype of hepatocellular carcinoma
Hepatology
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These authors contributed equally and are joint first authors for this work.