RETRACTED ARTICLE: Down-regulation of kappa opioid receptor promotes ESCC proliferation, invasion and metastasis via the PDK1-AKT signaling pathway
Tóm tắt
As a class of the opioid receptors, the kappa opioid receptor (KOR) has been verified to be a potential biomarker and therapeutic target for human malignant tumors. However, a thorough understanding of whether KOR affects progression of esophageal squamous cell carcinoma (ESCC) is still lacking. This study focused on exploring the effect of knocking down KOR in ESCC and its underlying mechanism. Bioinformatics analysis was used to compare the different expression level of OPRK1 (KOR gene) in tumor and adjacent normal tissues, and predict the relationship between KOR expression and overall survival. RNA-sequence analysis was performed to detect the altered functions and mechanisms after down regulating KOR. The in vitro and in vivo assays were used to detect the effects of down-regulated KOR on cell proliferation, migration and invasion. Substrate gel zymography and 3D cell culture assays were used to find the effect of KOR knockdown on the degradation of extracellular matrix (ECM), and immunefluorescence was performed to detect the altered cytoskeleton. Western blotting and immunohistochemistry were used to explore the underlying mechanism pathway. Bioinformatics analysis revealed that the expression of OPRK1 was lower in tumor tissue than that in adjacent normal tissues, and lowered expression of KOR was associated with poorer overall survival. The in vitro assays demonstrated that down-regulation of KOR enhanced ESCC proliferation, metastasis and invasion. Western blotting revealed that down-regulation of KOR could activate PDK1-AKT signaling pathway, which actively regulated the cancer progression. Down-regulation of KOR enhanced the formation of invadopodia, secretion of matrix metalloproteinase-2 (MMP2) and rearrangement of cytoskeleton, which were positively related with the invasion of ESCC. KOR knockdown enhanced the tumor invasion and elevated the AKT phosphorylation in nude mice. The AKT kinase inhibition could reverse the effect of down-regulation of KOR. KOR might act as a tumor suppressor in ESCC and down-regulation of KOR could enhance the ESCC tumor phenotype.
Tài liệu tham khảo
Huang FL, Yu SJ. Esophageal cancer: risk factors, genetic association, and treatment. Asian J Surg. 2018;41(3):210–5.
Torre LA, Siegel RL, Ward EM, et al. Global cancer incidence and mortality rates and trends–an update. Cancer Epidemiol Biomarkers Prev. 2016;25(1):16–27.
Codipilly DC, Qin Y, Dawsey SM, et al. Screening for esophageal squamous cell carcinoma: recent advances. Gastrointest Endosc. 2018;88(3):413–26.
Talukdar FR, di Pietro M, Secrier M, et al. Molecular landscape of esophageal cancer: implications for early detection and personalized therapy. Ann N Y Acad Sci. 2018;1434(1):342–59.
Minami M, Satoh M. Molecular biology of the opioid receptors: structures, functions and distributions. Neurosci Res. 1995;23:121–45.
Bodnar RJ. Endogenous Opiates and Behavior: 2018. Peptides. 2020; 132:170348.
Guo W, Imai S, Yang JL, et al. NF-KappaB pathway is involved in bone marrow stromal cell-produced pain relief. Front Integr Neurosci. 2018;12:49.
See Hoe L, Patel HH, Peart JN. Delta opioid receptors and cardioprotection. Handb Exp Pharmacol. 2018;247:301–34.
He C, Li H, Zhang J, et al. In vitro and in vivo characterization of the bifunctional μ- and δ- opioid receptors ligand MCRT on mouse gastrointestinal motility. Neuropeptides. 2019;74:82–7.
Ryu JH, Do SH, Han SH, et al. Morphine reduces mouse microglial engulfment induced by lipopolysaccharide and interferon-γ via δ opioid receptor and p38 mitogen-activated protein kinase. Neurol Res. 2018;40(7):600–6.
Fichna J, Janecka A. Opioid peptides in cancer. Cancer Metastasis Rev. 2004;23:351–66.
Wu Q, Chen X, Wang J, et al. Nalmefene attenuates malignant potential in colorectal cancer cell via inhibition of opioid receptor. Acta Biochim Biophys Sin (Shanghai). 2018;50(2):156–63.
Zhang Y, Wei Y, Li X, et al. microRNA-874 suppresses tumor proliferation and metastasis in hepatocellular carcinoma by targeting the DOR/EGFR/ERK pathway. Cell Death Dis. 2018;9(2):130.
Qu N, Wang X, Meng Y, Shan F. Prospective oncotarget for gynecological cancer: Opioid growth factor (OGF)—opioid growth factor receptor (OGFr) axis. Int Immunopharmacol. 2019;75:105723.
Chen D, Chen Y, Yan Y, et al. Down-regulation of the tumour suppressor κ-opioid receptor predicts poor prognosis in hepatocellular carcinoma patients. BMC Cancer. 2017;17(1):553.
Kharmate G, Rajput PS, Lin YC, et al. Inhibition of tumor promoting signals by activation of SSTR2 and opioid receptors in human breast cancer cells. Cancer Cell Int. 2013;13(1):93.
Kuzumaki N, Suzuki A, Narita M, et al. Effect of κ-opioid receptor agonist on the growth of non-small cell lung cancer (NSCLC) cells. Br J Cancer. 2012;106(6):1148–52.
Wang H, Wen C, Chen S, et al. Toosendanin-induced apoptosis in colorectal cancer cells is associated with the κ-opioid receptor/β-catenin signaling axis. Biochem Pharmacol. 2020;177:114014.
Yamamizu K, Hamada Y, Narita M. κ Opioid receptor ligands regulate angiogenesis in development and in tumours. Br J Pharmacol. 2015;172(2):268–76.
Yamamizu K, Furuta S, Hamada Y, et al. к Opioids inhibit tumor angiogenesis by suppressing VEGF signaling. Sci Rep. 2013;3:3213.
Yamamizu K, Furuta S, Katayama S, et al. The κ opioid system regulates endothelial cell differentiation and pathfinding in vascular development. Blood. 2011;118(3):775–85.
Shimada Y, Imamura M, Wagata T, Yamaguchi N, Tobe T. Characterization of twenty-one newly established esophageal cancer cell lines. Cancer. 1991;69:277–84.
Yuferov V, Fussell D, LaForge KS, et al. Redefinition of the human kappa opioid receptor gene (OPRK1) structure and association of haplotypes with opiate addiction. Pharmacogenetics. 2004;14(12):793–804.
Gerra G, Leonardi C, Cortese E, et al. Human kappa opioid receptor gene (OPRK1) polymorphism is associated with opiate addiction. Am J Med Genet B Neuropsychiatr Genet. 2007;144B(6):771–5.
Peng JM, Bera R, Chiou CY, et al. Actin cytoskeleton remodeling drives epithelial-mesenchymal transition for hepatoma invasion and metastasis in mice. Hepatology. 2018;67(6):2226–43.
Kumar S, Das A, Barai A, et al. MMP secretion rate and inter-invadopodia spacing collectively govern cancer invasiveness. Biophys J. 2018;114(3):650–62.
Li X, Wang J. Mechanical tumor microenvironment and transduction: cytoskeleton mediates cancer cell invasion and metastasis. Int J Biol Sci. 2020;16(12):2014–28.
Gagliardi PA, Puliafito A, Primo L. PDK1: at the crossroad of cancer signaling pathways. Semin Cancer Biol. 2018;48:27–35.
Emmanouilidi A, Falasca M. Targeting PDK1 for chemosensitization of cancer cells. Cancers (Basel). 2017;9(10):140.
Revathidevi S, Munirajan AK. Akt in cancer: mediator and more. Semin Cancer Biol. 2019;59:80–91.
Pan W, Li W, Zhao J, et al. lncRNA-PDPK2P promotes hepatocellular carcinoma progression through the PDK1/AKT/Caspase 3 pathway. Mol Oncol. 2019;13(10):2246–58.
Bamodu OA, Chang HL, Ong JR, et al. Elevated PDK1 expression drives PI3K/AKT/MTOR signaling promotes radiation-resistant and dedifferentiated phenotype of hepatocellular carcinoma. Cells. 2020;9(3):746.
Zhu Y, Yan L, Zhu W, et al. MMP2/3 promote the growth and migration of laryngeal squamous cell carcinoma via PI3K/Akt-NF-κB-mediated epithelial-mesenchymal transformation. J Cell Physiol. 2019.
Cenni V, Sirri A, Riccio M, et al. Targeting of the Akt/PKB kinase to the actin skeleton. Cell Mol Life Sci. 2003;60(12):2710–20.
Montagna G, Gupta HV, Hannum M, et al. Intraoperative opioids are associated with improved recurrence-free survival in triple-negative breast cancer. Br J Anaesth. 2021;126(2):367–76.