Down-regulation of the tumour suppressor κ-opioid receptor predicts poor prognosis in hepatocellular carcinoma patients

Pan

British Journal of Anaesthesia

et al. 2019

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.

mentioning

confidence: 99%

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

Pan

British Journal of Anaesthesia

et al. 2019

“…We found that 1020 TSGs were expressing in different stages of cardiac differentiation from human iPSCs, of which, 227 TSGs had expression levels of UMI/cell ≥1.00 at one or more stages. Then, we focused on those TSGs that continuously decreased their expression level during the cardiac differentiation because the downregulation or dysfunction of TSGs has been associated with cancer development ( Chen et al, 2017 ; Klacz et al, 2016 ; Okugawa et al, 2013 ). In total, we found seven TSGs with continuously decreasing their expression levels by single-cell sequencing, such as SFRP2 was expressed at high level in the early stage and at very low level in the late stage of differentiation ( P <0.001), and it was confirmed by bulk RNA sequencing ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Single-cell sequencing reveals the potential oncogenic expression atlas of human iPSC-derived cardiomyocytes

Zhao

et al. 2021

Biology Open

Human induced pluripotent stem cells (iPSCs) are important source for regenerative medicine. However, the links between pluripotency and oncogenic transformation raise safety issues. To understand the characteristics of iPSC-derived cells at single-cell resolution, we directly reprogrammed two human iPSC lines into cardiomyocytes and collected cells from four time points during cardiac differentiation for single-cell sequencing. We captured 32,365 cells and identified five molecularly distinct clusters that aligned well with our reconstructed differentiation trajectory. We discovered a set of dynamic expression events related to the upregulation of oncogenes and the decreasing expression of tumor suppressor genes during cardiac differentiation, which were similar to the gain-of-function and loss-of-function patterns during oncogenesis. In practice, we characterized the dynamic expression of the TP53 and Yamanaka factor genes (OCT4, SOX2, KLF4 and MYC), which were widely used for human iPSCs lines generation; and revealed the co-occurrence of MYC overexpression and TP53 silencing in some of human iPSC-derived TNNT2+ cardiomyocytes. In summary, our oncogenic expression atlas is valuable for human iPSCs application and the single-cell resolution highlights the clues potentially associated with the carcinogenic risk of human iPSC-derived cells.

“…As shown by the schematic in Fig. 7 , inflammatory mediators activate G proteins that upregulate cyclic adenosine monophosphate (cAMP) generation, which in turn activates the protein kinase A pathway for VEGF production, whereas KOR activation suppresses VEGF production by promoting Gαi/o inhibition of adenylyl cyclase, which decreases cAMP levels and attenuates protein kinase A activation 29 , 30 It has been reported that the downregulation of KOR expression in hepatocellular carcinoma had a strong association with poor prognosis 31 . We showed here that topically administered nalfurafine, which activates KOR, inhibited the expression of genes encoding VEGF-A, VEGF-C, as well as VEGFR-1–3 (Figs.…”

Section: Discussionmentioning

confidence: 99%

Topical administration of the kappa opioid receptor agonist nalfurafine suppresses corneal neovascularization and inflammation

Shokirova

Inomata

Saitoh

et al. 2021

Sci Rep

Corneal neovascularization (CNV) causes higher-order aberrations, corneal edema, ocular inflammation, and corneal transplant rejection, thereby decreasing visual acuity. In this study, we investigated the effects of topical administration of the kappa opioid receptor agonist nalfurafine (TRK-820) on CNV. To induce CNV, intrastromal corneal sutures were placed on the corneal stroma of BALB/c mice for 2 weeks. Nalfurafine (0.1 µg/2 μL/eye) was topically administered to the cornea once or twice daily after CNV induction. The CNV score, immune cell infiltration, and mRNA levels of angiogenic and pro-inflammatory factors in neovascularized corneas were evaluated using slit-lamp microscopy, immunohistochemistry, flow cytometry, and polymerase chain reaction. The mRNA expression of the kappa opioid receptor gene Oprk1 was significantly upregulated following CNV induction. Topical administration of nalfurafine twice daily significantly suppressed CNV and lymphangiogenesis, as well as reduced the mRNA levels of angiogenic and pro-inflammatory factors in the neovascularized corneas. Moreover, nalfurafine administration twice daily reduced the numbers of infiltrating leukocytes, neutrophils, macrophages, and interferon-γ-producing CD4+ T cells in the neovascularized corneas. In this study, we demonstrated that topical administration of nalfurafine suppressed local CNV in a mouse model along with the activation of KOR, suggesting that nalfurafine may prevent and control CNV in humans.