The mu-opioid receptor is a molecular marker for poor prognosis in hepatocellular carcinoma and represents a potential therapeutic target

Abstract

Background: Opioid receptors are implicated in cancer progression and long-term patient outcomes. However, the prognostic significance, underlying mechanisms, and therapeutic value of mu-opioid receptor (MOP) in hepatocellular carcinoma (HCC) remain unclear. Methods: MOP expression in human biopsy HCC samples was evaluated using RNA microarrays, quantitative real-time polymerase chain reaction (qRT-PCR), and immunochemical analyses. Molecular and cellular techniques, including siRNA-mediated depletion and lentiviral vector-mediated overexpression, were used to elucidate the functions and mechanisms of MOP. The effect of the MOP agonist morphine in HCC was evaluated both in vitro and in vivo. The therapeutic value of MOP inhibitors in HCC progression and metastasis was investigated with in vitro experiments and subcutaneous and orthotopic HCC mouse models in vivo. Results: Through microarray analysis and qRT-PCR, we identified that MOP is highly expressed in human HCC tumours. High MOP expression in HCC tumours was confirmed by immunocytochemistry and correlated with aggressive clinicopathological features and a worse prognosis. Depletion of MOP suppressed cell proliferation, migration, and invasion, whereas overexpression of MOP promoted cell growth and metastasis in human HCC cell lines. Both clinical and biological evidence revealed that MOP-mediated epithelial-mesenchymal transition promotes HCC metastasis and poor prognosis. Morphine promotes cell proliferation, migration, and invasion in vitro and in vivo in mouse models. More importantly, MOP inhibitors suppressed cell growth, invasion, and metastasis in vitro and in the subcutaneous and orthotopic xenograft models.

Mu Opioid Receptor 1 (MOR-1) Expression in Colorectal Cancer and Oncological Long-Term Outcomes: A Five-Year Retrospective Longitudinal Cohort Study

“…Increased MOR-1 expression in cancer tissue have been consistently reported in the literature [5,[18][19][20]. Moreover, previous in vitro results showed a higher expression of MOR-1 in colorectal cancer tissue than in normal mucosa tissue [21].…”

“…On the other hand, the association of MOR-1 over-expression with clinical outcomes is not clearly established with some trials reporting benefits [5,18,19] while others do not [20]. It is difficult to compare our results with preceding studies due to tissue specific considerations and methodological issues as previous data come from other organs cancers [5,[18][19][20]. Moreover, our study included patients with non-advanced cancer stages, while previous studies frequently including advanced or metastatic cancer disease and MOR-1 over-expression could be a reflection of this advanced stage without any causal relationship.…”

“…After primary treatment of non-metastatic CRCs, 20%-40% of the patients develop recurrences, associated with poor long-term prognosis [2]. Surgical resection is the cornerstone treatment in CRC, however it leads to inflammation, activation of sympathetic nervous system, hypercoagulability, ischemia/reperfusion injury, and suppression of the immune system [3][4][5]. This stress response decreases the host capability to deal with minimal residual disease, increasing the potential risk of local recurrences or metastasis [6][7][8][9].…”

“…The current evidence on the impact of MOR-1 over-expression on disease free survival (DFS) or overall survival (OS) is heterogeneous. MOR-1 over-expression is associated to poor DFS in advanced prostate cancer [18], gastric cancer [19], and hepatocellular carcinoma [5] while no association has been found in esophageal squamous cell carcinoma [20]. In CRC, MOR-1 expression has been demonstrated in vitro [21] but the association between tumor and non-tumor tissue differences in MOR-1 expression and long-term outcomes in humans has never been assessed.…”

Evaluation of Receptor Affinity, Analgesic Activity and Cytotoxicity of a Hybrid Peptide, AWL3020

“…conclusions (Chen et al 2017). The matter is subject of ongoing research summarized in several recent reviews (Zhang et al 2018;Brinkman et al 2018;Chen et al 2019a;Tuerxun and Cui 2019).…”