Research Article
PDF Mendeley EndNote BibTex Cite

Vitamin D’nin Hepatoselüler Karsinom Üzerindeki Etkisi

Year 2020, Volume 42, Issue 3, 301 - 310, 27.05.2020
https://doi.org/10.20515/otd.584749

Abstract

Hepatoselüler karsinoma (HCC) dünya çapında görülme sıklığı açısından en çok görülen dördüncü kanser türüdür. Bu kanser türünün görülme nedenlerinin başında Tip II diyabet, obezite ve alkol kullanımı gelmektedir. Çalışmamızda, karaciğer hastalıklarında etkili olan, ancak hücresel mekanizmalar açısından etkileşimi henüz tam olarak belirlenemeyen vitamin D’nin hem ilaç formu hem de aktif formu olan 1,25-dihidroksivitaminin [1,25(OH)2D3] HepG2 hepatoselüler karsinom hücrelerinin karakteristik özelliklerinde oluşturduğu değişimlerin belirlenmesi amaçlanmıştır. HepG2 hücrelerine vitamin D’nin hem ilaç formu hem de 1,25(OH)2D3 formu ayrı ayrı uygulanarak en etkili konsantrasyonları ve saatleri belirlendi. Bu aşamadan sonra uygun konsantrasyon ve saatte uygulanan her iki maddenin HepG2 hücrelerinin proliferasyonu, adezyonu ve immunohistokimyasal olarak p53 miktarındaki etkileri belirlendi. Elde edilen verilere göre, 250 nM vitamin D’nin ilaç formu HepG2 hücrelerine uygulandıktan 96 saat; 250 nM 1,25(OH)2D3 uygulandıktan sonra 48 saat sonra kontrol grubuna göre istatistiksel olarak proliferasyonun en çok görüldüğü konsantrasyon ve saat olarak belirlendi. Hem vitamin D’nin ilaç hem de 1,25(OH)2D3 formu HepG2 hücrelerinin adezyonunu kontrol grubuna göre istatistiksel olarak anlamlı bir şekilde azaldığı belirlendi (p<0.001). Optimal konsantrasyon ve saatte uygulanan her iki vitamin D formunun p53 miktarındaki değişimleri immunohistokimyasal olarak incelendiğinde, kontrol ve sham gruplarına göre azaldığı gözlendi. Hepatoselüler kanser hastalarında uygulanacağı zaman, vitamin D dozuna dikkat edilmesi ve sürekli kontrol altında olunması yönünde ön veri sağlamaktadır. Her ne kadar bazı karaciğer hastalıklarından korunmak için önemli bir vitamin olmasına rağmen; kanser hücrelerinde proliferasyonu arttırması, adezyonu azaltması ve bir tümör baskılayıcı olan p53 miktarını azaltması konu üzerinde soru işaretleri yaratmaktadır. Vitamin D’nin hepatoselüler hastalar üzerinde uygulanması konusunda farklı bir bakış açısı yaratan sonuçlarımız, ilerleyen dönemlerde konu ile alakalı yapılacak olan çalışmalar önemli bir ön veri niteliği taşımaktadır.

References

  • Elangovan H, Chahal S, Gunton JE. Vitamin D in liver disease: Current evidence and potential directions. Biochim Biophys Acta. 2017;1863(4):907-16.
  • Kragballe K. Vitamin-D Analogs in the Treatment of Psoriasis. Journal of Cellular Biochemistry. 1992;49(1):46-52.
  • Zannis VI, Breslow JL, SanGiacomo TR, Aden DP, Knowles BB. Characterization of the major apolipoproteins secreted by two human hepatoma cell lines. Biochemistry. 1981;20(25):7089-96.
  • Matsuda T, Saika K. Trends in liver cancer mortality rates in Japan, USA, UK, France and Korea based on the WHO mortality database. Jpn J Clin Oncol. 2012;42(4):360-1.
  • Sintra SN, Tome L, Cipriano MA, Bento C, Furtado E. Long-term outcome of the first 150 liver transplant recipients: a single-center experience. Transplant Proc. 2013;45(3):1119-21.
  • Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. Int J Cancer. 2001;94(2):153-6.
  • Knowles BB, Howe CC, Aden DP. Human hepatocellular carcinoma cell lines secrete the major plasma proteins and hepatitis B surface antigen. Science. 1980;209(4455):497-9.
  • Krithika R, Mohankumar R, Verma RJ, Shrivastav PS, Mohamad IL, Gunasekaran P, et al. Isolation, characterization and antioxidative effect of phyllanthin against CCl4-induced toxicity in HepG2 cell line. Chem Biol Interact. 2009;181(3):351-8.
  • Masuda S, Byford V, Kremer R, Makin HLJ, Kubodera N, Nishii Y, et al. In vitro metabolism of the vitamin D analog, 22-oxacalcitriol, using cultured osteosarcoma, hepatoma, and keratinocyte cell lines. Journal of Biological Chemistry. 1996;271(15):8700-8.
  • Akhter JYL, Finlay I, Pourgholami MH, Morris DL. 1,25(OH)2D3 and its analogues, EB1089 and CB1093, profoundly inhibit the in vitro proliferation of the human hepatoblastoma cell line HepG2. ANZ J Surg 2001;71:414-7.
  • Eisman JA, Koga M, Sutherland RL, Barkla DH, Tutton PJ. 1,25-Dihydroxyvitamin D3 and the regulation of human cancer cell replication. Proc Soc Exp Biol Med. 1989;191(3):221-6.
  • Binderup L, Bramm E. Effects of a novel vitamin D analogue MC 903 on cell proliferation and differentiation in vitro and on calcium metabolism in vivo. Biochem Pharmacol 1988;37:889-95.
  • Bikle DD. Vitamin D and skin cancer. J Nutr. 2004;134(12 Suppl):3472S-8S.
  • Farhan M, Rizvi A, Naseem I, Hadi SM, Ahmad A. Targeting increased copper levels in diethylnitrosamine induced hepatocellular carcinoma cells in rats by epigallocatechin-3-gallate. Tumour Biol. 2015;36(11):8861-7.
  • Rizvi A, Farhan M, Naseem I, Hadi SM. Calcitriol-copper interaction leads to non enzymatic, reactive oxygen species mediated DNA breakage and modulation of cellular redox scavengers in hepatocellular carcinoma. Apoptosis. 2016;21(9):997-1007.
  • Pourgholami MH, Akhter J, Lu Y, Morris DL. In vitro and in vivo inhibition of liver cancer cells by 1,25-dihydroxyvitamin D3. Cancer Lett. 2000;151(1):97-102.
  • Caputo A, Pourgholami MH, Akhter J, Morris DL. 1,25-Dihydroxyvitamin D(3) induced cell cycle arrest in the human primary liver cancer cell line HepG2. Hepatol Res. 2003;26(1):34-9.
  • Huang J, Yang G, Huang Y, Kong W, Zhang S. 1,25(OH)2D3 inhibits the progression of hepatocellular carcinoma via downregulating HDAC2 and upregulating P21(WAFI/CIP1). Mol Med Rep. 2016;13(2):1373-80.
  • Huang J, Yang G, Huang Y, Zhang S. 1,25(OH)2D3 induced apoptosis of human hepatocellular carcinoma cells in vitro and inhibited their growth in a nude mouse xenograft model by regulating histone deacetylase 2. Biochimie. 2018;146:28-34.
  • Ozerkan D, Ozsoy N, Yilmaz E. Vitamin D and melatonin protect the cell's viability and ameliorate the CCl4 induced cytotoxicity in HepG2 and Hep3B hepatoma cell lines. Cytotechnology. 2015;67(6):995-1002.
  • Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA. Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2011;155 827-38.
  • Manson JE, Mayne ST, Clinton SK. Vitamin D and prevention of cancer--ready for prime time? The New England journal of medicine. 2011;364(15):1385-7.
  • Jenkins K. Vitamin D does not prevent cancer: Study. Medscape Medical News. 2018.
  • Scragg R, Khaw KT, Toop L, Sluyter J, Lawes CMM, Waayer D, et al. Monthly High-Dose Vitamin D Supplementation and Cancer Risk: A Post Hoc Analysis of the Vitamin D Assessment Randomized Clinical Trial. JAMA Oncol. 2018;4(11):e182178.
  • Lappe J, Watson P, Travers-Gustafson D. Effect of vitamin D and calcium supplementation on cancer incidence in older women: a randomized clinical trial. JAMA. 2017;317:1234-43.
  • Pivonello C, Provvisiero DP, Negri M, Di GG, De AC, Galdiero G. Potential role of vitamin D in restoring sensitivity to mTOR inhibitors in hepatocellular carcinoma (HCC): 1,25(OH)vitamin D (VITD) reverts everolimus (EVE) resistance in a HCC cell line. Endocrine Abstracts. 2016;41.
  • Mahmoud AM, El-Shemy HA. Cytotoxic Profiling of Some Compounds of Natural Origin against HepG2 Liver Cancer Cell Line in-vitro. Journal of Arid Land Studies. 2012;22(1):191 -4.
  • Posa F, Di Benedetto A, Cavalcanti-Adam EA, Colaianni G, Porro C, Trotta T, et al. Vitamin D Promotes MSC Osteogenic Differentiation Stimulating Cell Adhesion and alphaVbeta3 Expression. Stem cells international. 2018;2018:6958713.

The Effect of Vitamin D on Hepatocellular Carcinoma

Year 2020, Volume 42, Issue 3, 301 - 310, 27.05.2020
https://doi.org/10.20515/otd.584749

Abstract

Hepatocellular carcinoma (HCC) is the fourth most common cancer in terms of its incidence worldwide. The main causes of this type of cancer are Type II diabetes, obesity and alcohol. In this study, we aimed to determine the changes of both drug form and 1,25-dihydroxyvitamin [1,25(OH)2D3] form of vitamin D which is effective in liver diseases, but the interaction of cellular mechanisms is still unknown, on characteristics of HePG2 hepatocellular carcinoma cells. Both drug and 1,25(OH)2D3 form of vitamin D were applied separately to HepG2 cells and optimal concentrations and hours were determined. Then the proliferation, adhesion and immunohistochemically p53 amount of HepG2 cells were determined by the effects of both substances applied at the optimal concentration and hour. According to our obtained data, the optimal concentration and hour of each vitamin D substances was determined as 96th hour at 250 nM for drug form; 48th hour at 250 nM for 1,25(OH)2D3 form by observing the proliferation rates. It was determined that both drug and 1.25(OH)2D3 forms of vitamin D decreased adhesion of HepG2 cells statistically compared to the control group (p <0.001). When the changes in p53 amount of both vitamin D forms applied at optimal concentration and hour were examined immunohistochemically, it was observed that it decreased compared to control and sham groups. Our results provide preliminary data to ensure that vitamin D dose is maintained and controlled continuously when administered in hepatocellular cancer patients. Although it is an important vitamin to protect from some liver diseases; increasing proliferation in cancer cells, reducing adhesion and decreasing the amount of p53, a tumor suppressor, raises some questions about this subject. Furthermore, our results create a different perspective on the application of vitamin D on hepatocellular patients, and support important preliminary data for the studies to be conducted in the future.

References

  • Elangovan H, Chahal S, Gunton JE. Vitamin D in liver disease: Current evidence and potential directions. Biochim Biophys Acta. 2017;1863(4):907-16.
  • Kragballe K. Vitamin-D Analogs in the Treatment of Psoriasis. Journal of Cellular Biochemistry. 1992;49(1):46-52.
  • Zannis VI, Breslow JL, SanGiacomo TR, Aden DP, Knowles BB. Characterization of the major apolipoproteins secreted by two human hepatoma cell lines. Biochemistry. 1981;20(25):7089-96.
  • Matsuda T, Saika K. Trends in liver cancer mortality rates in Japan, USA, UK, France and Korea based on the WHO mortality database. Jpn J Clin Oncol. 2012;42(4):360-1.
  • Sintra SN, Tome L, Cipriano MA, Bento C, Furtado E. Long-term outcome of the first 150 liver transplant recipients: a single-center experience. Transplant Proc. 2013;45(3):1119-21.
  • Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. Int J Cancer. 2001;94(2):153-6.
  • Knowles BB, Howe CC, Aden DP. Human hepatocellular carcinoma cell lines secrete the major plasma proteins and hepatitis B surface antigen. Science. 1980;209(4455):497-9.
  • Krithika R, Mohankumar R, Verma RJ, Shrivastav PS, Mohamad IL, Gunasekaran P, et al. Isolation, characterization and antioxidative effect of phyllanthin against CCl4-induced toxicity in HepG2 cell line. Chem Biol Interact. 2009;181(3):351-8.
  • Masuda S, Byford V, Kremer R, Makin HLJ, Kubodera N, Nishii Y, et al. In vitro metabolism of the vitamin D analog, 22-oxacalcitriol, using cultured osteosarcoma, hepatoma, and keratinocyte cell lines. Journal of Biological Chemistry. 1996;271(15):8700-8.
  • Akhter JYL, Finlay I, Pourgholami MH, Morris DL. 1,25(OH)2D3 and its analogues, EB1089 and CB1093, profoundly inhibit the in vitro proliferation of the human hepatoblastoma cell line HepG2. ANZ J Surg 2001;71:414-7.
  • Eisman JA, Koga M, Sutherland RL, Barkla DH, Tutton PJ. 1,25-Dihydroxyvitamin D3 and the regulation of human cancer cell replication. Proc Soc Exp Biol Med. 1989;191(3):221-6.
  • Binderup L, Bramm E. Effects of a novel vitamin D analogue MC 903 on cell proliferation and differentiation in vitro and on calcium metabolism in vivo. Biochem Pharmacol 1988;37:889-95.
  • Bikle DD. Vitamin D and skin cancer. J Nutr. 2004;134(12 Suppl):3472S-8S.
  • Farhan M, Rizvi A, Naseem I, Hadi SM, Ahmad A. Targeting increased copper levels in diethylnitrosamine induced hepatocellular carcinoma cells in rats by epigallocatechin-3-gallate. Tumour Biol. 2015;36(11):8861-7.
  • Rizvi A, Farhan M, Naseem I, Hadi SM. Calcitriol-copper interaction leads to non enzymatic, reactive oxygen species mediated DNA breakage and modulation of cellular redox scavengers in hepatocellular carcinoma. Apoptosis. 2016;21(9):997-1007.
  • Pourgholami MH, Akhter J, Lu Y, Morris DL. In vitro and in vivo inhibition of liver cancer cells by 1,25-dihydroxyvitamin D3. Cancer Lett. 2000;151(1):97-102.
  • Caputo A, Pourgholami MH, Akhter J, Morris DL. 1,25-Dihydroxyvitamin D(3) induced cell cycle arrest in the human primary liver cancer cell line HepG2. Hepatol Res. 2003;26(1):34-9.
  • Huang J, Yang G, Huang Y, Kong W, Zhang S. 1,25(OH)2D3 inhibits the progression of hepatocellular carcinoma via downregulating HDAC2 and upregulating P21(WAFI/CIP1). Mol Med Rep. 2016;13(2):1373-80.
  • Huang J, Yang G, Huang Y, Zhang S. 1,25(OH)2D3 induced apoptosis of human hepatocellular carcinoma cells in vitro and inhibited their growth in a nude mouse xenograft model by regulating histone deacetylase 2. Biochimie. 2018;146:28-34.
  • Ozerkan D, Ozsoy N, Yilmaz E. Vitamin D and melatonin protect the cell's viability and ameliorate the CCl4 induced cytotoxicity in HepG2 and Hep3B hepatoma cell lines. Cytotechnology. 2015;67(6):995-1002.
  • Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA. Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2011;155 827-38.
  • Manson JE, Mayne ST, Clinton SK. Vitamin D and prevention of cancer--ready for prime time? The New England journal of medicine. 2011;364(15):1385-7.
  • Jenkins K. Vitamin D does not prevent cancer: Study. Medscape Medical News. 2018.
  • Scragg R, Khaw KT, Toop L, Sluyter J, Lawes CMM, Waayer D, et al. Monthly High-Dose Vitamin D Supplementation and Cancer Risk: A Post Hoc Analysis of the Vitamin D Assessment Randomized Clinical Trial. JAMA Oncol. 2018;4(11):e182178.
  • Lappe J, Watson P, Travers-Gustafson D. Effect of vitamin D and calcium supplementation on cancer incidence in older women: a randomized clinical trial. JAMA. 2017;317:1234-43.
  • Pivonello C, Provvisiero DP, Negri M, Di GG, De AC, Galdiero G. Potential role of vitamin D in restoring sensitivity to mTOR inhibitors in hepatocellular carcinoma (HCC): 1,25(OH)vitamin D (VITD) reverts everolimus (EVE) resistance in a HCC cell line. Endocrine Abstracts. 2016;41.
  • Mahmoud AM, El-Shemy HA. Cytotoxic Profiling of Some Compounds of Natural Origin against HepG2 Liver Cancer Cell Line in-vitro. Journal of Arid Land Studies. 2012;22(1):191 -4.
  • Posa F, Di Benedetto A, Cavalcanti-Adam EA, Colaianni G, Porro C, Trotta T, et al. Vitamin D Promotes MSC Osteogenic Differentiation Stimulating Cell Adhesion and alphaVbeta3 Expression. Stem cells international. 2018;2018:6958713.

Details

Primary Language Turkish
Subjects Health Care Sciences and Services
Journal Section ORİJİNAL MAKALE
Authors

Çağrı ÖNER (Primary Author)
MALTEPE ÜNİVERSİTESİ, TIP FAKÜLTESİ, TEMEL TIP BİLİMLERİ BÖLÜMÜ, TIBBİ BİYOLOJİ VE GENETİK ANABİLİM DALI
0000-0003-3771-3277
Türkiye


Hatice İSAN This is me
MALTEPE ÜNİVERSİTESİ, KANSER VE KÖK HÜCREUYGULAMA VE ARAŞTIRMA MERKEZİ
0000-0000-0000-0000
Türkiye


Ranan Gülhan AKTAŞ This is me
MALTEPE ÜNİVERSİTESİ, TIP FAKÜLTESİ, TEMEL TIP BİLİMLERİ BÖLÜMÜ, HİSTOLOJİ VE EMBRİYOLOJİ ANABİLİM DALI
0000-0002-4474-7371
Türkiye


Ertuğrul ÇOLAK
ESKİŞEHİR OSMANGAZİ ÜNİVERSİTESİ, TIP FAKÜLTESİ, TEMEL TIP BİLİMLERİ BÖLÜMÜ, BİYOİSTATİSTİK ANABİLİM DALI
0000-0003-3251-1043
Türkiye

Supporting Institution MALTEPE ÜNİVERSİTESİ BİLİMSEL ARAŞTIRMA PROJE KOMİSYONU
Thanks Bu çalışma Maltepe Üniversitesi Bilimsel Araştırma Proje komisyonu tarafından desteklenmektedir.
Publication Date May 27, 2020
Published in Issue Year 2020, Volume 42, Issue 3

Cite

Bibtex @research article { otd584749, journal = {Osmangazi Tıp Dergisi}, issn = {1305-4953}, eissn = {2587-1579}, address = {}, publisher = {Eskişehir Osmangazi University}, year = {2020}, volume = {42}, number = {3}, pages = {301 - 310}, doi = {10.20515/otd.584749}, title = {Vitamin D’nin Hepatoselüler Karsinom Üzerindeki Etkisi}, key = {cite}, author = {Öner, Çağrı and İsan, Hatice and Aktaş, Ranan Gülhan and Çolak, Ertuğrul} }
APA Öner, Ç. , İsan, H. , Aktaş, R. G. & Çolak, E. (2020). Vitamin D’nin Hepatoselüler Karsinom Üzerindeki Etkisi . Osmangazi Tıp Dergisi , 42 (3) , 301-310 . DOI: 10.20515/otd.584749
MLA Öner, Ç. , İsan, H. , Aktaş, R. G. , Çolak, E. "Vitamin D’nin Hepatoselüler Karsinom Üzerindeki Etkisi" . Osmangazi Tıp Dergisi 42 (2020 ): 301-310 <https://dergipark.org.tr/en/pub/otd/issue/54015/584749>
Chicago Öner, Ç. , İsan, H. , Aktaş, R. G. , Çolak, E. "Vitamin D’nin Hepatoselüler Karsinom Üzerindeki Etkisi". Osmangazi Tıp Dergisi 42 (2020 ): 301-310
RIS TY - JOUR T1 - Vitamin D’nin Hepatoselüler Karsinom Üzerindeki Etkisi AU - Çağrı Öner , Hatice İsan , Ranan Gülhan Aktaş , Ertuğrul Çolak Y1 - 2020 PY - 2020 N1 - doi: 10.20515/otd.584749 DO - 10.20515/otd.584749 T2 - Osmangazi Tıp Dergisi JF - Journal JO - JOR SP - 301 EP - 310 VL - 42 IS - 3 SN - 1305-4953-2587-1579 M3 - doi: 10.20515/otd.584749 UR - https://doi.org/10.20515/otd.584749 Y2 - 2019 ER -
EndNote %0 Osmangazi Journal of Medicine Vitamin D’nin Hepatoselüler Karsinom Üzerindeki Etkisi %A Çağrı Öner , Hatice İsan , Ranan Gülhan Aktaş , Ertuğrul Çolak %T Vitamin D’nin Hepatoselüler Karsinom Üzerindeki Etkisi %D 2020 %J Osmangazi Tıp Dergisi %P 1305-4953-2587-1579 %V 42 %N 3 %R doi: 10.20515/otd.584749 %U 10.20515/otd.584749
ISNAD Öner, Çağrı , İsan, Hatice , Aktaş, Ranan Gülhan , Çolak, Ertuğrul . "Vitamin D’nin Hepatoselüler Karsinom Üzerindeki Etkisi". Osmangazi Tıp Dergisi 42 / 3 (May 2020): 301-310 . https://doi.org/10.20515/otd.584749
AMA Öner Ç. , İsan H. , Aktaş R. G. , Çolak E. Vitamin D’nin Hepatoselüler Karsinom Üzerindeki Etkisi. Osmangazi Tıp Dergisi. 2020; 42(3): 301-310.
Vancouver Öner Ç. , İsan H. , Aktaş R. G. , Çolak E. Vitamin D’nin Hepatoselüler Karsinom Üzerindeki Etkisi. Osmangazi Tıp Dergisi. 2020; 42(3): 301-310.
IEEE Ç. Öner , H. İsan , R. G. Aktaş and E. Çolak , "Vitamin D’nin Hepatoselüler Karsinom Üzerindeki Etkisi", Osmangazi Tıp Dergisi, vol. 42, no. 3, pp. 301-310, May. 2020, doi:10.20515/otd.584749

13299         13287  13308       13306       13305    13307  13301