Araştırma Makalesi
BibTex RIS Kaynak Göster

Epigenetic Changes in The Genome of The Cellular Model of Colon Cancer Metastasis

Yıl 2026, Cilt: 19 Sayı: 1 , 15 - 25 , 30.03.2026
https://izlik.org/JA52HM68YX

Öz

In this study, identified variants of the colon cancer cell line were analyzed to reveal the cellular phenotypic pattern. The cell line at hand was analyzed phenotypically as epithelial-mesenchymal and mesenchymal-epithelial transitions (EMT/MET), respectively. In the study, the tumor stroma structure, which was heavily exposed to IL6, was first induced by EMT.
DLD1 colon cancer cell line was used in the study. After RNA and miRNA isolation, real-time PCR was applied to the cells and metastasis structure was examined. During the examination process, the induction process of the structures exposed to IL6 was observed. qPCR analysis of miRNA indicated in CHD1 cell types was performed and it was observed that SA and SPH cells showed significantly higher expression.
In the study, fragments suitable for gene editing have been isolated from metastases with very low methylation in the cell structure. High expression was observed in mesenchymal-like cells associated with microRNAs (miR-17, miR-18a, miR-19). Demethylation of LncRNAs was observed in cells isolated as promoters in these metastatic processes.
As a result, an increase in miRNA expression was observed in cells isolated from metastases due to the part of the DNA that did not undergo chemical change in the promoter region, and this result was found to be associated with the survival of colon cancer patients.

Etik Beyan

This study does not require ethics committee approval.

Destekleyen Kurum

Università degli Studi di Napoli Federico II

Teşekkür

I thank my supervisor Claudia Ciniglia for her contributions to the study.

Kaynakça

  • [1] Siegel R., Ward E., Brawley O., Jemal A. (2011). Cancer Statistics, The İmpact of Eliminating Socioeconomic and Racial Disparities on Premature Cancer Deaths. CA: A Cancer Journal for Clinicians, 212, 36, 61.
  • [2] Brabletz T., Hlubek F., Spaderna S., Schmalhofer O., Hiendlmeyer E., Jung A. (2005). Invasion and Metastasis in Colorectal Cancer: Epithelial-Mesenchymal Transition, Mesenchymal–Epithelial Transition, Stem Cells and Beta-Catenin, Cells Tissues Organs, 179 56–65.
  • [3] Tsai JH., Donaher JL., Murphy DA., Chau S., Yang J. (2012). Spatiotemporal Regulation of Epithelial-Mesenchymal Transition is Essential for Squamous Cell Carcinoma Metastasis. Cancer Cells, 36, 22, 725.
  • [4] Ocana OH., Corcoles R., Fabra A., Moreno-Bueno G., Acloque H., Vega S. (2012). Metastatic Colonization Requires the Repression of the Epithelial-Mesenchymal Transition İnducer Prrx1. Cancer Cell, 22, 6, 709–724.
  • [5] Kahlert C., Lahes S., Radhakrishnan P., Dutta S., Mogler C., Herpel E., Brand K., Steinert G., Schneider M., Mollenhauer M. (2011). Overexpression of ZEB2 at The İnvasion Front of Colorectal Cancer İs an İndependent Prognostic Marker and Regulates Tumor İnvasion in Vitro. Clinical Cancer Research, 63, 7654–7663.
  • [6] Paterson EL., Kazenwadel J., Bert AG., Khew-Goodall Y., Ruszkiewicz A., Goodall GJ. (2013). Down-Regulation Of The Mirna-200 Family At The İnvasive Front Of Colorectal Cancers With Degraded Basement Membrane İndicates EMT İs İnvolved İn Cancer Progression. Neoplasia, 15, 180–191.
  • [7] Kunita A., Baeriswyl V., Meda C., Cabuy E., Takeshita K., Giraudo E., Wicki A., Fukayama M., Christofori G. (2018). İnflammatory Cytokines Induce Podoplanin Expression at the Tumor Invasive Front. The American Journal of Pathology, 188, 1276–1288.
  • [8] Friedl WKP. (2003). Tumour-Cell İnvasion and Migration: Diversity and Escape Mechanisms. Nature Reviews Cancer, 3(5) no. 365, 74.
  • [9] Tam WR., A. W. L. (2013). The epigenetics of epithelial-mesenchymal plasticity in cancer. Nature Medicine, 19 no. 831, 1438–1449.
  • [10] Vizoso EMM. (2015). DNA Methylation Plasticity Contributes to The Natural History of Metastasis. Cell Cycle, 14(18) 4, 2863.
  • [11] Lee RC., Feinbaum RL., Ambros V. (1993). The C. Elegansheterochronic Gene Lin-4 Encodes Small Rnas with Antisense Complementarity to Lin-14. Cell, 75(5) 54, 843.
  • [12] Wightman B., Ha I., Ruvkun G. (1993). Posttranscriptional Regulation of The Heterochronic Gene Lin-14 by Lin-4 Mediates Temporal Pattern Formation in C. Elegans. Cell, 5 62, 855.
  • [13] Hannon GJ., He L. (2004). Micrornas: Small Rnas with a Big Role in Gene Regulation. Nature Reviews Genetics, 5 522–531.
  • [14] Dhir H., Choudhry M., Patil K., Cheung C., Bodlak A., Pardo D., Adams A., Travaglino S., Rojas JA., Pai B. (2021). Interception of Signaling Circuits of Esophageal Adenocarcinoma Cells by Resveratrol Reveals Molecular and Immunomodulatory Signatures. Cancers, 13, 22, 5811.
  • [16] Mitchel J., Bajaj P., Patil K., Gunnarson A., Pourchet E., Kim YN., Skolnick J., Pai SB. (2021). Computational Identification of Stearic Acid as a Potential PDK1 Inhibitor and In Vitro Validation of Stearic Acid as Colon Cancer Therapeutic in Combination with 5-Fluorouracil. Cancer Informatics, 20
  • [15] Shaheen S., Ahmed M., Lorenzi F., and Nateri AS. (2016). Spheroid-Formation (Colonosphere) Assay for in Vitro Assessment and Expansion of Stem Cells in Colon Cancer. Stem Cell Reviews and Reports, 12 no. 4, 492.
  • [16] Okugawa Y., Grady WM., and Goel A. (2015). Epigenetic Alterations in Colorectal Cancer: Emerging Biomarkers. Revıew Genetıcs And Genetıc Testıng, 149 no. 5, pp. 1204–1225.
  • [17] Thiery JP., Acloque H., Huang RY., and Nieto MA. (2009). Epithelial-Mesenchymal Transitions in Development and Disease. Cell, 5 no. 139, p. 871.
  • [18] Tiwari N., Gheldof A., Tatari M., and Christofori G. (2012). EMT As the Ultimate Survival Mechanism of Cancer Cells. Semin Cancer Biology, 22, 3, 194–207.
  • [19] Vasudevan S., Tong Y., and Steitz JA. (2007). Switching from Repression to Activation: MicroRNAs Can Upregulate Translation. Science, 318, 1931–1934
  • [20] Gama-Sosa MA., Slagel VA., Trewyn RW., Oxenhandler R., Kuo KC., and Gehrke CW. (1983). The 5-Methylcytosine Content of DNA From Human Tumors. Nucleic Acids Research, 11, 19, 6883-6894.
  • [21] Rokavec M., Oner MG., Li H., Jackstadt R., Jiang L., and Lodygin D. (2014). IL6R/ STAT3/Mir-34a Feedback Loop Promotes EMT-Mediated Colorectal Cancer İnvasion and Metastasis. Journal of Clinical Investigation, 124, 4, 67.
  • [22] Gupta RA., Shah N., Wang KC., Kim J., Horlings HM., and Wong DJ. (2010). Long Non-Coding RNA HOTAIR Reprograms Chromatin State to Promote Cancer Metastasis. Nature, 464, 1071, 6.
  • [23] Dhamija S., and Diederichs S. (2016). From Junk to Master Regulators of İnvasion: Lncrna Functions in Migration, EMT and Metastasis. International Journal of Cancer, 139, 269, 80.

Kolon Kanseri Metastazının Hücresel Modelinde Genomdaki Epigenetik Değişiklikler”

Yıl 2026, Cilt: 19 Sayı: 1 , 15 - 25 , 30.03.2026
https://izlik.org/JA52HM68YX

Öz

Öz
Bu çalışmada, kolon kanseri hücre hattında tanımlanan varyantlar ayrıntılı biçimde incelenerek metastatik süreci yansıtan hücresel fenotipik örüntüler ortaya çıkarılmıştır. İncelenen hücre hattı, epitel-mezenkimal geçiş (EMT) ve mezenkimal-epitel geçiş (MET) süreçleri açısından kapsamlı bir fenotipik değerlendirmeye tabi tutulmuş; özellikle IL-6’ya yoğun şekilde maruz bırakılan tümör stromasında çalışmanın erken evrelerinde belirgin bir EMT indüksiyonu gözlenmiştir.
Bu amaçla model olarak DLD1 kolon kanseri hücre hattı kullanılmıştır. RNA ve miRNA izolasyonlarının ardından hücrelere gerçek zamanlı PCR uygulanmış, böylece metastaza ilişkin moleküler ve yapısal değişiklikler ayrıntılı şekilde analiz edilmiştir. Değerlendirme sürecinde IL-6’ya maruz kalan hücresel yapılardaki indüksiyon dinamikleri takip edilmiş; CHD1 ile ilişkili hücre tiplerinde gerçekleştirilen qPCR analizleri, özellikle SA ve SPH hücre gruplarında çeşitli metastaz ilişkili miRNA’ların anlamlı düzeyde arttığını ortaya koymuştur.
Ek olarak, metilasyon seviyesi oldukça düşük olan metastatik bölgelerden gen düzenlemesine uygun DNA fragmanları izole edilmiş ve mezenkimal fenotipe benzer hücrelerde miR-17, miR-18a ve miR-19 gibi mikroRNA’ların yüksek düzeyde eksprese edildiği belirlenmiştir. Metastatik süreçlerde promotör bölgesi olarak tanımlanan hücrelerde uzun kodlamayan RNA’ların (lncRNA) demetilasyona uğradığı saptanmıştır. Sonuç olarak, promotör bölgesinde kimyasal modifikasyona uğramayan DNA dizilerinin varlığına bağlı olarak metastazdan izole edilen hücrelerde artmış miRNA ekspresyonunun kolon kanseri hastalarının sağkalımı ile ilişkili olabileceği gösterilmiştir.

Etik Beyan

Bu çalışmada etik kurul onayına ihtiyaç yoktur.

Destekleyen Kurum

Università degli Studi di Napoli Federico II

Teşekkür

Çalışmaya katkılarından dolayı danışmanım Claudia Ciniglia'ya teşekkür ederim.

Kaynakça

  • [1] Siegel R., Ward E., Brawley O., Jemal A. (2011). Cancer Statistics, The İmpact of Eliminating Socioeconomic and Racial Disparities on Premature Cancer Deaths. CA: A Cancer Journal for Clinicians, 212, 36, 61.
  • [2] Brabletz T., Hlubek F., Spaderna S., Schmalhofer O., Hiendlmeyer E., Jung A. (2005). Invasion and Metastasis in Colorectal Cancer: Epithelial-Mesenchymal Transition, Mesenchymal–Epithelial Transition, Stem Cells and Beta-Catenin, Cells Tissues Organs, 179 56–65.
  • [3] Tsai JH., Donaher JL., Murphy DA., Chau S., Yang J. (2012). Spatiotemporal Regulation of Epithelial-Mesenchymal Transition is Essential for Squamous Cell Carcinoma Metastasis. Cancer Cells, 36, 22, 725.
  • [4] Ocana OH., Corcoles R., Fabra A., Moreno-Bueno G., Acloque H., Vega S. (2012). Metastatic Colonization Requires the Repression of the Epithelial-Mesenchymal Transition İnducer Prrx1. Cancer Cell, 22, 6, 709–724.
  • [5] Kahlert C., Lahes S., Radhakrishnan P., Dutta S., Mogler C., Herpel E., Brand K., Steinert G., Schneider M., Mollenhauer M. (2011). Overexpression of ZEB2 at The İnvasion Front of Colorectal Cancer İs an İndependent Prognostic Marker and Regulates Tumor İnvasion in Vitro. Clinical Cancer Research, 63, 7654–7663.
  • [6] Paterson EL., Kazenwadel J., Bert AG., Khew-Goodall Y., Ruszkiewicz A., Goodall GJ. (2013). Down-Regulation Of The Mirna-200 Family At The İnvasive Front Of Colorectal Cancers With Degraded Basement Membrane İndicates EMT İs İnvolved İn Cancer Progression. Neoplasia, 15, 180–191.
  • [7] Kunita A., Baeriswyl V., Meda C., Cabuy E., Takeshita K., Giraudo E., Wicki A., Fukayama M., Christofori G. (2018). İnflammatory Cytokines Induce Podoplanin Expression at the Tumor Invasive Front. The American Journal of Pathology, 188, 1276–1288.
  • [8] Friedl WKP. (2003). Tumour-Cell İnvasion and Migration: Diversity and Escape Mechanisms. Nature Reviews Cancer, 3(5) no. 365, 74.
  • [9] Tam WR., A. W. L. (2013). The epigenetics of epithelial-mesenchymal plasticity in cancer. Nature Medicine, 19 no. 831, 1438–1449.
  • [10] Vizoso EMM. (2015). DNA Methylation Plasticity Contributes to The Natural History of Metastasis. Cell Cycle, 14(18) 4, 2863.
  • [11] Lee RC., Feinbaum RL., Ambros V. (1993). The C. Elegansheterochronic Gene Lin-4 Encodes Small Rnas with Antisense Complementarity to Lin-14. Cell, 75(5) 54, 843.
  • [12] Wightman B., Ha I., Ruvkun G. (1993). Posttranscriptional Regulation of The Heterochronic Gene Lin-14 by Lin-4 Mediates Temporal Pattern Formation in C. Elegans. Cell, 5 62, 855.
  • [13] Hannon GJ., He L. (2004). Micrornas: Small Rnas with a Big Role in Gene Regulation. Nature Reviews Genetics, 5 522–531.
  • [14] Dhir H., Choudhry M., Patil K., Cheung C., Bodlak A., Pardo D., Adams A., Travaglino S., Rojas JA., Pai B. (2021). Interception of Signaling Circuits of Esophageal Adenocarcinoma Cells by Resveratrol Reveals Molecular and Immunomodulatory Signatures. Cancers, 13, 22, 5811.
  • [16] Mitchel J., Bajaj P., Patil K., Gunnarson A., Pourchet E., Kim YN., Skolnick J., Pai SB. (2021). Computational Identification of Stearic Acid as a Potential PDK1 Inhibitor and In Vitro Validation of Stearic Acid as Colon Cancer Therapeutic in Combination with 5-Fluorouracil. Cancer Informatics, 20
  • [15] Shaheen S., Ahmed M., Lorenzi F., and Nateri AS. (2016). Spheroid-Formation (Colonosphere) Assay for in Vitro Assessment and Expansion of Stem Cells in Colon Cancer. Stem Cell Reviews and Reports, 12 no. 4, 492.
  • [16] Okugawa Y., Grady WM., and Goel A. (2015). Epigenetic Alterations in Colorectal Cancer: Emerging Biomarkers. Revıew Genetıcs And Genetıc Testıng, 149 no. 5, pp. 1204–1225.
  • [17] Thiery JP., Acloque H., Huang RY., and Nieto MA. (2009). Epithelial-Mesenchymal Transitions in Development and Disease. Cell, 5 no. 139, p. 871.
  • [18] Tiwari N., Gheldof A., Tatari M., and Christofori G. (2012). EMT As the Ultimate Survival Mechanism of Cancer Cells. Semin Cancer Biology, 22, 3, 194–207.
  • [19] Vasudevan S., Tong Y., and Steitz JA. (2007). Switching from Repression to Activation: MicroRNAs Can Upregulate Translation. Science, 318, 1931–1934
  • [20] Gama-Sosa MA., Slagel VA., Trewyn RW., Oxenhandler R., Kuo KC., and Gehrke CW. (1983). The 5-Methylcytosine Content of DNA From Human Tumors. Nucleic Acids Research, 11, 19, 6883-6894.
  • [21] Rokavec M., Oner MG., Li H., Jackstadt R., Jiang L., and Lodygin D. (2014). IL6R/ STAT3/Mir-34a Feedback Loop Promotes EMT-Mediated Colorectal Cancer İnvasion and Metastasis. Journal of Clinical Investigation, 124, 4, 67.
  • [22] Gupta RA., Shah N., Wang KC., Kim J., Horlings HM., and Wong DJ. (2010). Long Non-Coding RNA HOTAIR Reprograms Chromatin State to Promote Cancer Metastasis. Nature, 464, 1071, 6.
  • [23] Dhamija S., and Diederichs S. (2016). From Junk to Master Regulators of İnvasion: Lncrna Functions in Migration, EMT and Metastasis. International Journal of Cancer, 139, 269, 80.
Toplam 24 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Eczacılık ve İlaç Bilimleri (Diğer)
Bölüm Araştırma Makalesi
Yazarlar

Ayla Eren Özdemir 0000-0002-0555-7049

Gönderilme Tarihi 9 Aralık 2025
Kabul Tarihi 16 Mart 2026
Yayımlanma Tarihi 30 Mart 2026
IZ https://izlik.org/JA52HM68YX
Yayımlandığı Sayı Yıl 2026 Cilt: 19 Sayı: 1

Kaynak Göster

APA Eren Özdemir, A. (2026). Epigenetic Changes in The Genome of The Cellular Model of Colon Cancer Metastasis. Erzincan University Journal of Science and Technology, 19(1), 15-25. https://izlik.org/JA52HM68YX