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Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis
Published on: March 30, 2019
Deregulated expression of microRNA-200b/c and SUZ12, a Polycomb repressive complex 2 subunit, in chemoresistant
KayKay San1, Megan Horita1, Aravinda Ganapathy1
1Department of Clinical Health Sciences, Doisy College of Health Sciences, Saint Louis University, St. Louis, MO, USA.
Abstract:
In colorectal cancer, chemotherapy and/or radiotherapy can lead to the formation of resistant cells that become metastatic through Epithelial-Mesenchymal Transition (EMT). Invasive and metastatic characteristics of carcinoma cells in primary tumors are mediated by EMT. During EMT, the primary tumor cells lose cell-cell adhesion, have increased intercellular separation, and gain an elongated shape with pseudopodia. There is also dysregulation of Polycomb group proteins (such as BMI1, SUZ12, and EZH2), and changes in the expression of microRNA-200 (miR-200) family. In this study, we developed a chemoresistant colorectal cancer cell line (DLD-1-OxR) by exposing DLD-1 colorectal cancer cells to increasing concentrations of oxaliplatin (a chemotherapy drug used for colorectal cancer), and tested for EMT characteristics. We found that DLD-1-OxR exhibited EMT characteristics by morphologic, biochemical and molecular markers. SUZ12, a Polycomb repressive complex 2 subunit, was upregulated in DLD-1-OxR. The miRNA-200 family members that target SUZ12 were downregulated. Drug resistance is an impediment to chemotherapy and understanding the molecular mechanisms of chemoresistance can lead to its reversal and improvement of chemotherapy outcomes.
Insights
Chemotherapy resistance in colorectal cancer cells can lead to metastasis via Epithelial-Mesenchymal Transition (EMT). This study found that chemoresistant cells showed EMT markers, with increased SUZ12 and decreased miR-200, offering insights into reversing drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Chemotherapy resistance and metastasis are significant challenges in colorectal cancer treatment.
- Epithelial-Mesenchymal Transition (EMT) is a key process driving cancer cell invasion and metastasis.
- Dysregulation of Polycomb group proteins and microRNAs are implicated in EMT and cancer progression.
Purpose of the Study:
- To develop and characterize a chemoresistant colorectal cancer cell line exhibiting EMT.
- To investigate the role of Polycomb group proteins and microRNAs in chemoresistance-induced EMT.
- To identify potential molecular targets for overcoming drug resistance in colorectal cancer.
Main Methods:
- Development of an oxaliplatin-resistant colorectal cancer cell line (DLD-1-OxR) from DLD-1 cells.
- Assessment of EMT characteristics using morphologic, biochemical, and molecular markers.
- Analysis of the expression levels of SUZ12 and the miR-200 family in DLD-1-OxR cells.
Main Results:
- The DLD-1-OxR cell line demonstrated clear characteristics of EMT.
- SUZ12, a component of Polycomb repressive complex 2, was found to be upregulated in DLD-1-OxR cells.
- Members of the miR-200 family, which target SUZ12, were downregulated in the chemoresistant cells.
Conclusions:
- Chemoresistant colorectal cancer cells acquire metastatic properties through EMT.
- The observed upregulation of SUZ12 and downregulation of miR-200 in chemoresistant cells are key molecular events.
- Understanding these molecular mechanisms is crucial for developing strategies to reverse drug resistance and improve colorectal cancer therapy.
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