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Alpha7 nicotinic acetylcholine receptor expression in Sorafenib-resistant Hepatocellular carcinoma cells

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Abstract

Hepatocellular carcinoma (HCC), the most prevalent kind of liver cancer, remains one of the world’s main causes of death. The alpha7 nicotinic acetylcholine receptor (α7nAchR) has been recognized to be overexpressed in malignancies and chemoresistance. Since little is known about the role of α7nAchR expression in drug-resistant cells, this study was designed to investigate the effect of α7nAchR suppression in combination with Sorafenib (SOR) on SOR-resistant HCC cells. First, SOR-resistant HCC cells were generated. To suppress the expression of α7nAchR, cells were treated with SOR following siRNA transfection. qRT-PCR was used to examine the expression of α7nAchR and apoptotic genes by evaluating the IC50 of SOR and the combination of α7nAchR siRNA and SOR on the survival of resistant cells. Moreover, apoptosis, autophagy, and cell cycle analysis for resistant HCC cells were performed using flow cytometry. Cell migration and colony formation assays were also used for further confirmation. Our results suggest that inhibiting α7nAchR can lead resistant HCC cells to become sensitive. Furthermore, when siRNA and SOR were treated together, HCC-resistant cells showed a considerable reduction in α7nAchR mRNA gene expression. In addition, when α7nAchR was downregulated in combination with SOR, migration and colony formation were inhibited. Apoptosis was triggered by modulating the expression of apoptotic target genes, and cell cycle arrest was observed in the G2-M and subG1 phases. Overexpression of α7nAchR in SOR-resistant HCC cells suggests that it might be a therapeutic target for HCC cell resistance therapy.

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References

  1. Liu CY, Chen KF, Chen PJ. Treatment of liver cancer. Cold Spring Harb perspect med. 2015;5(9):a021535. https://doi.org/10.1101/cshperspect.a021535.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bruix J, Tak WY, Gasbarrini A, et al. Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: multicentre, open-label, phase II safety study. Eur J Cancer. 2013;49(16):3412–9. https://doi.org/10.1016/j.ejca.2013.05.028.

    Article  CAS  PubMed  Google Scholar 

  3. Zhu Y-J, Zheng B, Wang H-Y, Chen L. New knowledge of the mechanisms of sorafenib resistance in liver cancer. Acta Pharmacol Sin. 2017;38(5):614–22. https://doi.org/10.1038/aps.2017.5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wu SY, Lopez-Berestein G, Calin GA, Sood AK. RNAi Therapies: drugging the undruggable. Sci Transl Med. 2014;6(240):240ps7. https://doi.org/10.1126/scitranslmed.3008362.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Mansoori B, Sandoghchian Shotorbani S, Baradaran B. RNA interference and its role in cancer therapy. Adv Pharm Bull. 2014;4(4):313–21. https://doi.org/10.5681/apb.2014.046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hajiasgharzadeh K, Somi MH, Sadigh-Eteghad S, et al. The dual role of alpha7 nicotinic acetylcholine receptor in inflammation-associated gastrointestinal cancers. Heliyon. 2020;6(3):e03611–e03611. https://doi.org/10.1016/j.heliyon.2020.e03611.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Millar NS, Harkness PC. Assembly and trafficking of nicotinic acetylcholine receptors (Review). Mol Membr Biol. 2008;25(4):279–92. https://doi.org/10.1080/09687680802035675.

    Article  CAS  PubMed  Google Scholar 

  8. Hurst R, Rollema H, Bertrand D. Nicotinic acetylcholine receptors: from basic science to therapeutics. Pharmacol Ther. 2013;137(1):22–54. https://doi.org/10.1016/j.pharmthera.2012.08.012.

    Article  CAS  PubMed  Google Scholar 

  9. Hajiasgharzadeh K, Somi MH, Mansoori B, et al. Small interfering RNA targeting alpha7 nicotinic acetylcholine receptor sensitizes hepatocellular carcinoma cells to sorafenib. Life Sci. 2020;244:117332. https://doi.org/10.1016/j.lfs.2020.117332.

    Article  CAS  PubMed  Google Scholar 

  10. Ferlay J, Colombet M, Soerjomataram I, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019;144(8):1941–53. https://doi.org/10.1002/ijc.31937.

    Article  CAS  PubMed  Google Scholar 

  11. Daher S, Massarwa M, Benson AA, Khoury T. Current and future treatment of hepatocellular carcinoma: an updated comprehensive review. J Clin Transl Hepatol. 2018;6(1):69–78. https://doi.org/10.14218/JCTH.2017.00031.

    Article  PubMed  Google Scholar 

  12. Filipits M. Mechanisms of cancer: multidrug resistance. Drug Discov Today Dis Mech. 2004;1(2):229–34. https://doi.org/10.1016/j.ddmec.2004.10.001.

    Article  CAS  Google Scholar 

  13. Afrashteh Nour M, Hajiasgharzadeh K, Kheradmand F, et al. Nicotinic acetylcholine receptors in chemotherapeutic drugs resistance: an emerging targeting candidate. Life Sci. 2021;278:119557. https://doi.org/10.1016/j.lfs.2021.119557.

    Article  CAS  PubMed  Google Scholar 

  14. Le Grazie M, Biagini MR, Tarocchi M, Polvani S, Galli A. Chemotherapy for hepatocellular carcinoma: the present and the future. World J Hepatol. 2017;9(21):907–20. https://doi.org/10.4254/wjh.v9.i21.907.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Babu A, Munshi A, Ramesh R. Combinatorial therapeutic approaches with RNAi and anticancer drugs using nanodrug delivery systems. Drug Dev Ind Pharm. 2017;43(9):1391–401. https://doi.org/10.1080/03639045.2017.1313861.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wang S, Hu Y. α7 nicotinic acetylcholine receptors in lung cancer. Oncol Lett. 2018;16(2):1375–82. https://doi.org/10.3892/ol.2018.8841.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sun H-J, Jia Y-F, Ma X-L. Alpha5 nicotinic acetylcholine receptor contributes to nicotine-induced lung cancer development and progression. Front Pharmacol. 2017. https://doi.org/10.3389/fphar.2017.00573.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Huang L-C, Lin C-L, Qiu J-Z, et al. "Nicotinic acetylcholine receptor subtype alpha-9 mediates triple-negative breast cancers based on a spontaneous pulmonary metastasis mouse model. Front Cell Neurosci. 2017;11:336. https://doi.org/10.3389/fncel.2017.00336.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Nguyen HD, Liao Y-C, Ho Y-S, et al. The α9 nicotinic acetylcholine receptor mediates nicotine-induced PD-L1 expression and regulates melanoma cell proliferation and migration. Cancers (Basel). 2019;11(12):1991.

    Article  CAS  Google Scholar 

  20. Tu CC, Huang CY, Cheng WL, et al. Silencing A7-nAChR levels increases the sensitivity of gastric cancer cells to ixabepilone treatment. Tumour Biol. 2016;37(7):9493–501. https://doi.org/10.1007/s13277-015-4751-x.

    Article  CAS  PubMed  Google Scholar 

  21. Tu CC, Huang CY, Cheng WL, et al. The α7-nicotinic acetylcholine receptor mediates the sensitivity of gastric cancer cells to taxanes. Tumour Biol. 2016;37(4):4421–8. https://doi.org/10.1007/s13277-015-4260-y.

    Article  CAS  PubMed  Google Scholar 

  22. Clarke MR, Jones B, Squires CLM, et al. Cyclic imine pinnatoxin G is cytotoxic to cancer cell lines via nicotinic acetylcholine receptor-driven classical apoptosis. J Nat Prod. 2021;84(7):2035–42. https://doi.org/10.1021/acs.jnatprod.1c00418.

    Article  CAS  PubMed  Google Scholar 

  23. Witayateeraporn W, Arunrungvichian K, Pothongsrisit S, et al. α7-Nicotinic acetylcholine receptor antagonist QND7 suppresses non-small cell lung cancer cell proliferation and migration via inhibition of Akt/mTOR signaling. Biochem Biophys Res Commun. 2020;521(4):977–83. https://doi.org/10.1016/j.bbrc.2019.11.018.

    Article  CAS  PubMed  Google Scholar 

  24. Hsu CC, Tsai KY, Su YF, et al. α7-Nicotine acetylcholine receptor mediated nicotine induced cell survival and cisplatin resistance in oral cancer. Arch Oral Biol. 2020;111: 104653. https://doi.org/10.1016/j.archoralbio.2020.104653.

    Article  CAS  PubMed  Google Scholar 

  25. Cingir Koker S, Jahja E, Shehwana H, Keskus AG, Konu O. Cholinergic Receptor Nicotinic Alpha 5 (CHRNA5) RNAi is associated with cell cycle inhibition, apoptosis, DNA damage response and drug sensitivity in breast cancer. PLoS ONE. 2018;13(12): e0208982. https://doi.org/10.1371/journal.pone.0208982.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhang C, Ding XP, Zhao QN, et al. Role of α7-nicotinic acetylcholine receptor in nicotine-induced invasion and epithelial-to-mesenchymal transition in human non-small cell lung cancer cells. Oncotarget. 2016;7(37):59199–208. https://doi.org/10.18632/oncotarget.10498.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Bu X, Zhang A, Chen Z, et al. Migration of gastric cancer is suppressed by recombinant Newcastle disease virus rL-RVG via regulating α7-nicotinic acetylcholine receptors/ERK- EMT. BMC Cancer. 2019;19(1):976. https://doi.org/10.1186/s12885-019-6225-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nishioka T, Kim HS, Luo LY, et al. Sensitization of epithelial growth factor receptors by nicotine exposure to promote breast cancer cell growth. Breast Cancer Res. 2011;13(6):R113. https://doi.org/10.1186/bcr3055.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran

    Mina Afrashteh Nour, Fatemeh Kheradmand & Yousef Rasmi

  2. Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran

    Yousef Rasmi

  3. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Behzad Baradaran

  4. Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Behzad Baradaran

  5. Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz, 516615731, Iran

    Behzad Baradaran

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  1. Mina Afrashteh Nour
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  2. Fatemeh Kheradmand
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  3. Yousef Rasmi
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  4. Behzad Baradaran
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Correspondence to Fatemeh Kheradmand or Behzad Baradaran.

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The present study was supported by Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. R.UMSU.REC.1399.083

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Nour, M.A., Kheradmand, F., Rasmi, Y. et al. Alpha7 nicotinic acetylcholine receptor expression in Sorafenib-resistant Hepatocellular carcinoma cells. Med Oncol 39, 165 (2022). https://doi.org/10.1007/s12032-022-01745-5

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  • DOI: https://doi.org/10.1007/s12032-022-01745-5

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