Presentation Type
Poster
Discipline Track
Biomedical Science
Abstract Type
Research/Clinical
Abstract
Cancer metastasis is one of the deadliest aspects of the disease, with about 90% of all cancer-related deaths due to its development at different sites within the body. Colorectal cancer (CRC) is the second leading cause of cancer mortality in the United States, with 40-50% of all patients developing metastasis at some point during their fight with the disease. With the approval of Regorafenib for treating metastatic colorectal cancer, steps have been taken to combat metastasis in colorectal cancer. A vital aspect of the development of metastasis is the development of resistance to first-line chemotherapy. Regorafenib is an oral small-molecule multiple kinase inhibitor. It is indicated worldwide for patients with metastatic colorectal cancer (mCRC), Regorafenib has already begun to show resistance in CRC. Understanding the mechanisms behind Regorafenib resistance in CRC is vital. Studies have demonstrated the expression of Long-non-coding RNA (LncRNA) to be linked to cancer metastasis and drug resistance. LncRNA UCA1 has been shown in other cancers to lead to resistance to different drugs like cisplatin, gemcitabine, 5-FU, tamoxifen, imatinib, and EGFR-TKIs. In our lab, we have found the LncRNA UCA1 to be overexpressed in CRC patient tissues, with increasing expression across stages I-III, compared to normal tissue. High UCA1 expression has decreased survival among colorectal cancer patients, per the TCGA patient cohort analysis. Furthermore, we found that high UCA1 expression in colorectal cancer cell lines leads to high IC50 values for Regorafenib. Lentiviral transduce stable overexpression (SW480), and knockdown (SW620) cell lines were developed and are being used for UCA1-regorafenib drug resistance mechanistic studies. Increased expression of UCA1 led to increased expression of crucial drug resistance genes (MDR1, ABCB1, and FOXM1) and increased IC50 compared to the control vector. A 3D spheroid model was utilized to assay regorafenib sensitivity to the UCA1 overexpressed cell lines. High UCA1 expression leads to the formation of a higher number of 3D spheroid bodies and size when compared to vector. We treated the spheroid with IC50 concentration, and data will be presented. We also plan to study the lncRNA UCA1 associated Regorafenib resistance in the SW620 knockdown cell lines. In future, we will also analyze the signaling pathways modulated by UCA1 in CRC cell lines, which may be involved in enhancing the regorafenib resistance. This supports the notion that UCA1 is critical in enhancing the resistance to regorafenib in CRC by activating drug resistance pathways. For the first time, this study demonstrates that UCA1 provides drug resistance to regorafenib in CRC, facilitating the progression of CRC metastasis.
Academic/Professional Position
Graduate Student
Mentor/PI Department
Immunology and Microbiology
Recommended Citation
Pequeno Bracho, Ricardo; Doxtater, Kyle; Kwabiah, Dennis; Abuchard Anaya, Yamile; Leslie, Sophia; Hussain, Mohammad Shabir; and Tripathi, Manish, "LncRNA Impact on Regorafenib Resistance in Colorectal Cancer" (2024). Research Symposium. 45.
https://scholarworks.utrgv.edu/somrs/2024/posters/45
Included in
Medical Cell Biology Commons, Medical Immunology Commons, Medical Microbiology Commons, Medical Molecular Biology Commons, Oncology Commons
LncRNA Impact on Regorafenib Resistance in Colorectal Cancer
Cancer metastasis is one of the deadliest aspects of the disease, with about 90% of all cancer-related deaths due to its development at different sites within the body. Colorectal cancer (CRC) is the second leading cause of cancer mortality in the United States, with 40-50% of all patients developing metastasis at some point during their fight with the disease. With the approval of Regorafenib for treating metastatic colorectal cancer, steps have been taken to combat metastasis in colorectal cancer. A vital aspect of the development of metastasis is the development of resistance to first-line chemotherapy. Regorafenib is an oral small-molecule multiple kinase inhibitor. It is indicated worldwide for patients with metastatic colorectal cancer (mCRC), Regorafenib has already begun to show resistance in CRC. Understanding the mechanisms behind Regorafenib resistance in CRC is vital. Studies have demonstrated the expression of Long-non-coding RNA (LncRNA) to be linked to cancer metastasis and drug resistance. LncRNA UCA1 has been shown in other cancers to lead to resistance to different drugs like cisplatin, gemcitabine, 5-FU, tamoxifen, imatinib, and EGFR-TKIs. In our lab, we have found the LncRNA UCA1 to be overexpressed in CRC patient tissues, with increasing expression across stages I-III, compared to normal tissue. High UCA1 expression has decreased survival among colorectal cancer patients, per the TCGA patient cohort analysis. Furthermore, we found that high UCA1 expression in colorectal cancer cell lines leads to high IC50 values for Regorafenib. Lentiviral transduce stable overexpression (SW480), and knockdown (SW620) cell lines were developed and are being used for UCA1-regorafenib drug resistance mechanistic studies. Increased expression of UCA1 led to increased expression of crucial drug resistance genes (MDR1, ABCB1, and FOXM1) and increased IC50 compared to the control vector. A 3D spheroid model was utilized to assay regorafenib sensitivity to the UCA1 overexpressed cell lines. High UCA1 expression leads to the formation of a higher number of 3D spheroid bodies and size when compared to vector. We treated the spheroid with IC50 concentration, and data will be presented. We also plan to study the lncRNA UCA1 associated Regorafenib resistance in the SW620 knockdown cell lines. In future, we will also analyze the signaling pathways modulated by UCA1 in CRC cell lines, which may be involved in enhancing the regorafenib resistance. This supports the notion that UCA1 is critical in enhancing the resistance to regorafenib in CRC by activating drug resistance pathways. For the first time, this study demonstrates that UCA1 provides drug resistance to regorafenib in CRC, facilitating the progression of CRC metastasis.