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Effect of Angiotensin II on the Malignant Biological Behaviors of Colorectal Cancer Cells and Its Mechanism of Action

Received: 17 May 2023     Accepted: 2 June 2023     Published: 9 June 2023
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Abstract

Objective To explore the effects of angiotensin II (AngII) and the angiotensin II type I receptor (AT1R) antagonist Losartan on the malignant biological behaviors of colorectal cancer (CRC) cells including proliferation, invasion, migration and epithelial-mesenchymal transition (EMT), as well as the underlying mechanism of action. Methods The CRC cell line CT26 was cultured in vitro, and the expression of AT1R in CT26 cells was detected by immunofluorescence staining. Cells were divided into control group, AngII treatment group, and Losartan + AngII treatment group. We analyzed cell growth, proliferation, migration and invasion in the above three groups by adopting functional experiments. Meanwhile, ELISA was performed to detect the expression levels of AngII, TGF-β and TNF-α in cell supernatants, and the Western blotting (WB) assay was carried out to detect the expression of related proteins. In addition, the xenograft tumor nude mouse model was constructed to explore the impact of AT1R antagonist Losartan on the in vivo growth of CRC cells. Results Through experiments in vitro, immunofluorescence staining results verified that AT1R was significantly expressed in CT26 cells. Compared with control group, AngII treatment remarkably promoted the growth, proliferation, migration and invasion of CT26 cells. In the meantime, relative to AngII treatment group, Losartan + AngII treatment group dramatically suppressed the growth, proliferation, migration and invasion of CT26 cells (P < 0.05). Moreover, relative to control group, AngII treatment evidently up-regulated the expression levels of MMP-2, MMP-9, N-cadherin, Vimentin, Snail and p-Smad proteins in cells, and induced the down-regulated expression of E-cadherin protein. Compared with AngII treatment group, Losartan + AngII treatment group showed dramatically decreased expression levels of MMP-2, MMP-9, N-cadherin, Vimentin, Snail and p-Smad proteins in cells, whereas significantly elevated expression of E-cadherin protein (P < 0.05). After AngII treatment, the TGF-β level secreted in cells was higher than that in control group, while that in cells of Losartan + AngII treatment group markedly decreased relative to AngII treatment group (P < 0.05). As revealed by in vivo experimental results, the xenograft tumor growth was evidently suppressed in Losartan + AngII treatment group compared with control group and AngII treatment group, and the serum AngII, TGF-β and TNF-α levels in mice were markedly reduced (P < 0.05). Conclusions AngII promotes the proliferation, migration, invasion and EMT of CT26 cells, while Losartan can antagonize the effect of AngII on promoting malignant growth of CRC both in vivo and in vitro.

Published in Cancer Research Journal (Volume 11, Issue 2)
DOI 10.11648/j.crj.20231102.17
Page(s) 78-85
Creative Commons

This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.

Copyright

Copyright © The Author(s), 2023. Published by Science Publishing Group

Keywords

Colorectal Cancer, Angiotensin II, Epithelial-mesenchymal Transition

References
[1] Siegel RL, Miller KD, Goding Sauer A, Fedewa SA, Butterly LF, Anderson JC, Cercek A, Smith RA, Jemal A. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020 May; 70 (3): 145-164. doi: 10.3322/caac.21601. Epub 2020 Mar 5. PMID: 32133645.
[2] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov; 68 (6): 394-424. doi: 10.3322/caac.21492. Epub 2018 Sep 12. Erratum in: CA Cancer J Clin. 2020 Jul; 70 (4): 313. PMID: 30207593.
[3] Biller LH, Schrag D. Diagnosis and Treatment of Metastatic Colorectal Cancer: A Review. JAMA. 2021 Feb 16; 325 (7): 669-685. doi: 10.1001/jama.2021.0106. PMID: 33591350.
[4] Ahmadian E, Khosroushahi AY, Eftekhari A, Farajnia S, Babaei H, Eghbal MA. Novel angiotensin receptor blocker, azilsartan induces oxidative stress and NFkB-mediated apoptosis in hepatocellular carcinoma cell line HepG2. Biomed Pharmacother. 2018 Mar; 99: 939-946. doi: 10.1016/j.biopha.2018.01.117. Epub 2018 Feb 20. PMID: 29710494.
[5] Y Segin S, Berlin M, Richter C, Flockerzi RMV, Worley P, Freichel M, Londoño JEC. Cardiomyocyte-Specific Deletion of Orai1 Reveals Its Protective Role in Angiotensin-II-Induced Pathological Cardiac Remodeling. Cells. 2020 Apr 28; 9 (5): 1092. doi: 10.3390/cells9051092. PMID: 32354146; PMCID: PMC7290784.
[6] Oh E, Kim JY, Cho Y, An H, Lee N, Jo H, Ban C, Seo JH. Overexpression of angiotensin II type 1 receptor in breast cancer cells induces epithelial-mesenchymal transition and promotes tumor growth and angiogenesis. Biochim Biophys Acta. 2016 Jun; 1863 (6 Pt A): 1071-81. doi: 10.1016/j.bbamcr.2016.03.010. Epub 2016 Mar 11. PMID: 26975580.
[7] Fujihara S, Morishita A, Ogawa K, Tadokoro T, Chiyo T, Kato K, Kobara H, Mori H, Iwama H, Masaki T. The angiotensin II type 1 receptor antagonist telmisartan inhibits cell proliferation and tumor growth of esophageal adenocarcinoma via the AMPKα/mTOR pathway in vitro and in vivo. Oncotarget. 2017 Jan 31; 8 (5): 8536-8549. doi: 10.18632/oncotarget.14345. PMID: 28052030; PMCID: PMC5352420.
[8] Saber S, Mahmoud AAA, Goda R, Helal NS, El-Ahwany E, Abdelghany RH. Perindopril, fosinopril and losartan inhibited the progression of diethylnitrosamine-induced hepatocellular carcinoma in mice via the inactivation of nuclear transcription factor kappa-B. Toxicol Lett. 2018 Oct 1; 295: 32-40. doi: 10.1016/j.toxlet.2018.05.036. Epub 2018 May 31. PMID: 29859236.
[9] Ager EI, Neo J, Christophi C. The renin-angiotensin system and malignancy. Carcinogenesis. 2008 Sep; 29 (9): 1675-84. doi: 10.1093/carcin/bgn171. Epub 2008 Jul 16. PMID: 18632755.
[10] Lever AF, Hole DJ, Gillis CR, McCallum IR, McInnes GT, MacKinnon PL, Meredith PA, Murray LS, Reid JL, Robertson JW. Do inhibitors of angiotensin-I-converting enzyme protect against risk of cancer? Lancet. 1998 Jul 18; 352 (9123): 179-84. doi: 10.1016/S0140-6736(98)03228-0. PMID: 9683206.
[11] Li SH, Lu HI, Chang AY, Huang WT, Lin WC, Lee CC, Tien WY, Lan YC, Tsai HT, Chen CH. Angiotensin II type I receptor (AT1R) is an independent prognosticator of esophageal squamous cell carcinoma and promotes cells proliferation via mTOR activation. Oncotarget. 2016 Oct 11; 7 (41): 67150-67165. doi: 10.18632/oncotarget.11567. PMID: 27564102; PMCID: PMC5341864.
[12] Domińska K, Lachowicz-Ochedalska A. Zaangazowanie układu renina-angiotensyna (RAS) w proces kancerogenezy [The involvement of the renin-angiotensin system (RAS) in cancerogenesis]. Postepy Biochem. 2008; 54 (3): 294-300. Polish. PMID: 19112828.
[13] Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000 Jan 7; 100 (1): 57-70. doi: 10.1016/s0092-8674(00)81683-9. PMID: 10647931.
[14] Greenburg G, Hay ED. Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells. J Cell Biol. 1982 Oct; 95 (1): 333-9. doi: 10.1083/jcb.95.1.333. PMID: 7142291; PMCID: PMC2112361.
[15] Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009 Jun; 119 (6): 1420-8. doi: 10.1172/JCI39104. Erratum in: J Clin Invest. 2010 May 3; 120 (5): 1786. PMID: 19487818; PMCID: PMC2689101.
[16] De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013 Feb; 13 (2): 97-110. doi: 10.1038/nrc3447. PMID: 23344542.
[17] Skeen VR, Paterson I, Paraskeva C, Williams AC. TGF-β1 signalling, connecting aberrant inflammation and colorectal tumorigenesis. Curr Pharm Des. 2012; 18 (26): 3874-88. doi: 10.2174/138161212802083734. PMID: 22632753.
[18] Secker GA, Shortt AJ, Sampson E, Schwarz QP, Schultz GS, Daniels JT. TGFbeta stimulated re-epithelialisation is regulated by CTGF and Ras/MEK/ERK signalling. Exp Cell Res. 2008 Jan 1; 314 (1): 131-42. doi: 10.1016/j.yexcr.2007.09.001. Epub 2007 Sep 7. PMID: 17915216.
[19] Xu J, Lamouille S, Derynck R. TGF-beta-induced epithelial to mesenchymal transition. Cell Res. 2009 Feb; 19 (2): 156-72. doi: 10.1038/cr.2009.5. PMID: 19153598; PMCID: PMC4720263.
[20] Zhu M, Jiang B, Yan D, Wang X, Ge H, Sun Y. Knockdown of TMEM45A overcomes multidrug resistance and epithelial-mesenchymal transition in human colorectal cancer cells through inhibition of TGF-β signalling pathway. Clin Exp Pharmacol Physiol. 2020 Mar; 47 (3): 503-516. doi: 10.1111/1440-1681.13220. Epub 2019 Dec 29. PMID: 31788833.
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  • APA Style

    Yingxue Yang, Xiaotian Yang, Qinghua Wang. (2023). Effect of Angiotensin II on the Malignant Biological Behaviors of Colorectal Cancer Cells and Its Mechanism of Action. Cancer Research Journal, 11(2), 78-85. https://doi.org/10.11648/j.crj.20231102.17

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    ACS Style

    Yingxue Yang; Xiaotian Yang; Qinghua Wang. Effect of Angiotensin II on the Malignant Biological Behaviors of Colorectal Cancer Cells and Its Mechanism of Action. Cancer Res. J. 2023, 11(2), 78-85. doi: 10.11648/j.crj.20231102.17

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    AMA Style

    Yingxue Yang, Xiaotian Yang, Qinghua Wang. Effect of Angiotensin II on the Malignant Biological Behaviors of Colorectal Cancer Cells and Its Mechanism of Action. Cancer Res J. 2023;11(2):78-85. doi: 10.11648/j.crj.20231102.17

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  • @article{10.11648/j.crj.20231102.17,
      author = {Yingxue Yang and Xiaotian Yang and Qinghua Wang},
      title = {Effect of Angiotensin II on the Malignant Biological Behaviors of Colorectal Cancer Cells and Its Mechanism of Action},
      journal = {Cancer Research Journal},
      volume = {11},
      number = {2},
      pages = {78-85},
      doi = {10.11648/j.crj.20231102.17},
      url = {https://doi.org/10.11648/j.crj.20231102.17},
      eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.crj.20231102.17},
      abstract = {Objective To explore the effects of angiotensin II (AngII) and the angiotensin II type I receptor (AT1R) antagonist Losartan on the malignant biological behaviors of colorectal cancer (CRC) cells including proliferation, invasion, migration and epithelial-mesenchymal transition (EMT), as well as the underlying mechanism of action. Methods The CRC cell line CT26 was cultured in vitro, and the expression of AT1R in CT26 cells was detected by immunofluorescence staining. Cells were divided into control group, AngII treatment group, and Losartan + AngII treatment group. We analyzed cell growth, proliferation, migration and invasion in the above three groups by adopting functional experiments. Meanwhile, ELISA was performed to detect the expression levels of AngII, TGF-β and TNF-α in cell supernatants, and the Western blotting (WB) assay was carried out to detect the expression of related proteins. In addition, the xenograft tumor nude mouse model was constructed to explore the impact of AT1R antagonist Losartan on the in vivo growth of CRC cells. Results Through experiments in vitro, immunofluorescence staining results verified that AT1R was significantly expressed in CT26 cells. Compared with control group, AngII treatment remarkably promoted the growth, proliferation, migration and invasion of CT26 cells. In the meantime, relative to AngII treatment group, Losartan + AngII treatment group dramatically suppressed the growth, proliferation, migration and invasion of CT26 cells (P in vivo experimental results, the xenograft tumor growth was evidently suppressed in Losartan + AngII treatment group compared with control group and AngII treatment group, and the serum AngII, TGF-β and TNF-α levels in mice were markedly reduced (P Conclusions AngII promotes the proliferation, migration, invasion and EMT of CT26 cells, while Losartan can antagonize the effect of AngII on promoting malignant growth of CRC both in vivo and in vitro.},
     year = {2023}
    }
    

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  • TY  - JOUR
    T1  - Effect of Angiotensin II on the Malignant Biological Behaviors of Colorectal Cancer Cells and Its Mechanism of Action
    AU  - Yingxue Yang
    AU  - Xiaotian Yang
    AU  - Qinghua Wang
    Y1  - 2023/06/09
    PY  - 2023
    N1  - https://doi.org/10.11648/j.crj.20231102.17
    DO  - 10.11648/j.crj.20231102.17
    T2  - Cancer Research Journal
    JF  - Cancer Research Journal
    JO  - Cancer Research Journal
    SP  - 78
    EP  - 85
    PB  - Science Publishing Group
    SN  - 2330-8214
    UR  - https://doi.org/10.11648/j.crj.20231102.17
    AB  - Objective To explore the effects of angiotensin II (AngII) and the angiotensin II type I receptor (AT1R) antagonist Losartan on the malignant biological behaviors of colorectal cancer (CRC) cells including proliferation, invasion, migration and epithelial-mesenchymal transition (EMT), as well as the underlying mechanism of action. Methods The CRC cell line CT26 was cultured in vitro, and the expression of AT1R in CT26 cells was detected by immunofluorescence staining. Cells were divided into control group, AngII treatment group, and Losartan + AngII treatment group. We analyzed cell growth, proliferation, migration and invasion in the above three groups by adopting functional experiments. Meanwhile, ELISA was performed to detect the expression levels of AngII, TGF-β and TNF-α in cell supernatants, and the Western blotting (WB) assay was carried out to detect the expression of related proteins. In addition, the xenograft tumor nude mouse model was constructed to explore the impact of AT1R antagonist Losartan on the in vivo growth of CRC cells. Results Through experiments in vitro, immunofluorescence staining results verified that AT1R was significantly expressed in CT26 cells. Compared with control group, AngII treatment remarkably promoted the growth, proliferation, migration and invasion of CT26 cells. In the meantime, relative to AngII treatment group, Losartan + AngII treatment group dramatically suppressed the growth, proliferation, migration and invasion of CT26 cells (P in vivo experimental results, the xenograft tumor growth was evidently suppressed in Losartan + AngII treatment group compared with control group and AngII treatment group, and the serum AngII, TGF-β and TNF-α levels in mice were markedly reduced (P Conclusions AngII promotes the proliferation, migration, invasion and EMT of CT26 cells, while Losartan can antagonize the effect of AngII on promoting malignant growth of CRC both in vivo and in vitro.
    VL  - 11
    IS  - 2
    ER  - 

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Author Information
  • Department of Gastroenterology, Affiliated Kunshan Hospital of Jiangsu University, Suzhou, China

  • Department of Hematology, Affiliated Huaian Hospital of Xuzhou Medical University, Huaian, China

  • Department of Gastroenterology, Affiliated Kunshan Hospital of Jiangsu University, Suzhou, China

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