In vivo and in vitro inhibition of human liver cancer progress by downregulation of the μ-opioid receptor and relevant mechanisms

Lu,Jin; Liu,Zefeng; Zhao,Lingling; Tian,Huimin; Liu,Xiuhua; Yuan,Changji

doi:10.3892/or.2013.2640

In vivo and in vitro inhibition of human liver cancer progress by downregulation of the μ-opioid receptor and relevant mechanisms

Authors:
- Jin Lu
- Zefeng Liu
- Lingling Zhao
- Huimin Tian
- Xiuhua Liu
- Changji Yuan
View Affiliations

Affiliations: Department of Hematology and Oncology, First Hospital, Jilin University, Changchun 130021, P.R. China, Department of General Surgery, First Hospital, Jilin University, Changchun 130021, P.R. China
Published online on: July 26, 2013 https://doi.org/10.3892/or.2013.2640
Pages: 1731-1738

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Opiates have long been used as analgesics to relieve pain associated with various medical conditions. μ-opioid receptor (MOR) is the main member of the opioid receptor super-family and the excitation or overexpression of MOR promotes the proliferation of many kinds of tumor cells. It was found in our previous studies that MOR was highly expressed in the tissue and cells of human liver cancer. However, the impact of MOR on the progress of human liver cancer remains unknown. The purpose of this study is to investigate the impact of MOR downregulation on the progress of human liver cancer and the mechanisms involved. RNA interfering or specific inhibitor was administered to downregulate the MOR in human hepatocellular carcinoma cells and it was found that the proliferation of hepatocellular carcinoma cells was significantly inhibited with the increase of the apoptotic rate, while the cell cycle was blocked in G0/G1 phase and the tumor growth in the mice was retarded. In addition, downregulation of MOR resulted in the increase of phosphorylation of the MKK7 expression and JNK activation. On the contrary, blockade of MKK7 pathway can reverse the antitumor role of MOR. In summary, downregulation of MOR is able to inhibit both in vivo and in vitro human liver cancer progress and it shows potential to be used in cancer therapy.

View Figures

View References

1	El-Serag HB and Rudolph KL: Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 132:2557–2576. 2007. View Article : Google Scholar : PubMed/NCBI
2	Rampone B, Schiavone B, Martino A, Viviano C and Confuorto G: Current management strategy of hepatocellular carcinoma. World J Gastroenterol. 15:3210–3216. 2009. View Article : Google Scholar : PubMed/NCBI
3	Rahbari NN, Mehrabi A, Mollberg NM, Müller SA, Koch M, Büchler MW and Weitz J: Hepatocellular carcinoma: current management and perspectives for the future. Ann Surg. 253:453–469. 2011. View Article : Google Scholar : PubMed/NCBI
4	Merle P and Mornex F: Medical therapies for hepatocellular carcinoma. Cancer Radiother. 15:28–31. 2011.(In French).
5	Kim E, Clark AL, Kiss A, Hahn JW, Wesselschmidt R, Coscia CJ and Belcheva MM: Mu- and kappa-opioids induce the differentiation of embryonic stem cells to neural progenitors. J Biol Chem. 281:33749–33760. 2006. View Article : Google Scholar : PubMed/NCBI
6	Brillet K, da Conceição MM, Pattus F and Pereira CA: Bioprocess parameters of cell growth and human mu opioid receptor expression in recombinant Drosophila S2 cell cultures in a bioreactor. Bioprocess Biosyst Eng. 28:291–293. 2006. View Article : Google Scholar : PubMed/NCBI
7	Gein SV, Simonenko TA and Chereshnev VA: Effect of beta-endorphin and DAGO, a selective agonist of mu-opioid receptors, on the proliferative activity of lymphocytes. Dokl Biol Sci. 391:289–291. 2003. View Article : Google Scholar : PubMed/NCBI
8	Harburg GC, Hall FS, Harrist AV, Sora I, Uhl GR and Eisch AJ: Knockout of the mu opioid receptor enhances the survival of adult-generated hippocampal granule cell neurons. Neuroscience. 144:77–87. 2007. View Article : Google Scholar : PubMed/NCBI
9	Lennon FE, Mirzapoiazova T, Mambetsariev B, Salgia R, Moss J and Singleton PA: Overexpression of the μ-opioid receptor in human non-small cell lung cancer promotes Akt and mTOR activation, tumor growth, and metastasis. Anesthesiology. 116:857–867. 2012.
10	Bortsov AV, Millikan RC, Belfer I, Boortz-Marx RL, Arora H and McLean SA: μ-Opioid receptor gene A118G polymorphism predicts survival in patients with breast cancer. Anesthesiology. 116:896–902. 2012.
11	Yuen JW, So IY, Kam AY and Wong YH: Regulation of STAT3 by mu-opioid receptors in human neuroblastoma SH-SY5Y cells. Neuroreport. 15:1431–1435. 2004. View Article : Google Scholar : PubMed/NCBI
12	Nylund G, Pettersson A, Bengtsson C, Khorram-Manesh A, Nordgren S and Delbro DS: Functional expression of mu-opioid receptors in the human colon cancer cell line, HT-29, and their localization in human colon. Dig Dis Sci. 53:461–466. 2008. View Article : Google Scholar : PubMed/NCBI
13	Chang L and Karin M: Mammalian MAP kinase signalling cascades. Nature. 410:37–40. 2001. View Article : Google Scholar : PubMed/NCBI
14	Molton SA, Todd DE and Cook SJ: Selective activation of the c-Jun N-terminal kinase (JNK) pathway fails to elicit Bax activation or apoptosis unless the phosphoinositide 3′-kinase (PI3K) pathway is inhibited. Oncogene. 22:4690–4701. 2003.
15	Dérijard B, Raingeaud J, Barrett T, Wu IH, Han J, Ulevitch RJ and Davis RJ: Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science. 267:682–685. 1995.
16	Kishimoto H, Nakagawa K, Watanabe T, Kitagawa D, Momose H, Seo J, Nishitai G, Shimizu N, Ohata S, Tanemura S, Asaka S, Goto T, Fukushi H, Yoshida H, Suzuki A, Sasaki T, Wada T, Penninger JM, Nishina H and Katada T: Different properties of SEK1 and MKK7 in dual phosphorylation of stress-induced activated protein kinase SAPK/JNK in embryonic stem cells. J Biol Chem. 278:16595–16601. 2003. View Article : Google Scholar : PubMed/NCBI
17	Tournier C, Dong C, Turner TK, Jones SN, Flavell RA and Davis RJ: MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines. Genes Dev. 15:1419–1426. 2001. View Article : Google Scholar : PubMed/NCBI
18	Wang X, Destrument A and Tournier C: Physiological roles of MKK4 and MKK7: insights from animal models. Biochim Biophys Acta. 1773:1349–1357. 2007. View Article : Google Scholar : PubMed/NCBI
19	Iglesias M, Segura MF, Comella JX and Olmos G: Mu-opioid receptor activation prevents apoptosis following serum withdrawal in differentiated SH-SY5Y cells and cortical neurons via phosphatidylinositol 3-kinase. Neuropharmacology. 44:482–492. 2003. View Article : Google Scholar
20	Maslov LN, Lasukova TV, Solenkova NV, Lishmanov AIu, Bogomaz SA, Tam SV and Gross GJ: Participation of K(ATP)-channels in cardioprotective effect of mu-opioid receptor agonists in acute ischemia and reperfusion of the isolated heart. Eksp Klin Farmakol. 64:23–27. 2001.(In Russian).
21	Gross GJ, Hsu A, Nithipatikom K, Bobrova I and Bissessar E: Eribis peptide 94 reduces infarct size in rat hearts via activation of centrally located μ opioid receptors. J Cardiovasc Pharmacol. 59:194–197. 2012.PubMed/NCBI
22	Goldsmith JR, Uronis JM and Jobin C: Mu opioid signaling protects against acute murine intestinal injury in a manner involving Stat3 signaling. Am J Pathol. 179:673–683. 2011. View Article : Google Scholar : PubMed/NCBI
23	Mathew B, Lennon FE, Siegler J, Mirzapoiazova T, Mambetsariev N, Sammani S, Gerhold LM, LaRiviere PJ, Chen CT, Garcia JG, Salgia R, Moss J and Singleton PA: The novel role of the mu opioid receptor in lung cancer progression: a laboratory investigation. Anesth Analg. 112:558–567. 2011. View Article : Google Scholar : PubMed/NCBI
24	Galeotti N and Ghelardini C: Regionally selective activation and differential regulation of ERK, JNK and p38 MAP kinase signalling pathway by protein kinase C in mood modulation. Int J Neuropsychopharmacol. 20:1–13. 2011.PubMed/NCBI
25	Raman M, Chen W and Cobb MH: Differential regulation and properties of MAPKs. Oncogene. 26:3100–3112. 2007. View Article : Google Scholar : PubMed/NCBI
26	Kim EK and Choi EJ: Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta. 1802:396–405. 2010. View Article : Google Scholar : PubMed/NCBI
27	Bermudez O, Pagès G and Gimond C: The dual-specificity MAP kinase phosphatases: critical roles in development and cancer. Am J Physiol Cell Physiol. 299:C189–C202. 2010. View Article : Google Scholar : PubMed/NCBI
28	Huang P, Han J and Hui L: MAPK signaling in inflammation-associated cancer development. Protein Cell. 1:218–226. 2010. View Article : Google Scholar : PubMed/NCBI
29	Haeusgen W, Herdegen T and Waetzig V: The bottleneck of JNK signaling: molecular and functional characteristics of MKK4 and MKK7. Eur J Cell Biol. 90:536–544. 2011. View Article : Google Scholar : PubMed/NCBI
30	Tang B, Du J, Wang J, Tan G, Gao Z, Wang Z and Wang L: Alpinetin suppresses proliferation of human hepatoma cells by the activation of MKK7 and elevates sensitization to cis-diammined dichloridoplatium. Oncol Rep. 27:1090–1096. 2012.
31	Giaroni C, Zanetti E, Vanti A, Canciani L, Lecchini S and Frigo G: Sympathetic denervation-induced changes in G protein expression in enteric neurons of the guinea pig colon. Life Sci. 71:1961–1973. 2002. View Article : Google Scholar : PubMed/NCBI
32	Chen ZC, Shieh JP, Chung HH, Hung CH, Lin HJ and Cheng JT: Activation of peripheral opioid μ-receptors in blood vessel may lower blood pressure in spontaneously hypertensive rats. Pharmacology. 87:257–264. 2011.
33	Wang Q and Traynor JR: Modulation of μ-opioid receptor signaling by RGS19 in SH-SY5Y cells. Mol Pharmacol. 83:512–520. 2013.