Genetic variants in the Folic acid Metabolic Pathway Genes predict outcomes of metastatic Colorectal Cancer patients receiving first-line Chemotherapy

Abstract

Background: Paclitaxel plays a pivotal role in the chemotherapy of breast cancer, but resistance to this drug is an important obstacle in the treatment. It is reported that microRNA-152-3p (miR-152-3p) is involved in tamoxifen resistance in breast cancer, but whether it is involved in paclitaxel resistance in breast cancer remains unknown. Materials and methods: We examined the expression of miR-152-3p in breast cancer tissues and cells by qRT-PCR. After transfecting paclitaxel-resistant MCF-7/TAX cells with miR-152-3p mimics, we analyzed the function of miR-152-3p in these cells by MTT assay and flow cytometry. We screened the target gene, endothelial PAS domain-containing protein 1 (EPAS1), using bioinformatics analysis and verified it with the dual luciferase reporter gene experiment. The relationship between EPAS1 and miR-152-3p and their roles in paclitaxel resistance of breast cancer were further investigated using RNA interference and transfection techniques. Results: The expression of miR-152-3p in normal breast tissues and cells was markedly higher than that in breast cancer. Overexpression of miR-152-3p decreased the survival rate and increased the apoptosis rate and sensitivity of MCF-7/TAX cells to paclitaxel. We confirmed that EPAS1 is the target of miR-152-3p and is negatively regulated by this miRNA. Moreover, transfection with EPAS1 siRNA enhanced the susceptibility and apoptosis rate of MCF-7/TAX cells to paclitaxel. Co-transfection of miR-152-3p mimics and EPAS1 increased paclitaxel sensitivity and apoptosis induced by the drug. Conclusion: miR-152-3p inhibits the survival of MCF-7/TAX cells and promotes their apoptosis by targeting the expression of EPAS1, thereby, enhancing the sensitivity of these breast cancer cells to paclitaxel.

Genetic variants in primary cilia‐related genes associated with the prognosis of first‐line chemotherapy in colorectal cancer

“…10 Single nucleotide polymorphisms (SNPs) in the folic acid metabolic pathway and DNA repair system genes were related to prediction of CRC chemotherapy efficacy. 11,12 Primary cilia are tentacle-like structures on the surface of the cells, regulating the signal conduction between cells and the matrix, which affects cell proliferation, migration, and differentiation. 13 Additionally, primary cilia were associated with several important paracellular pathways between tumor microenvironment (TME) cells.…”

“…KRAS mutation predicts non‐response to EGFR‐targeted drugs is a breakthrough in CRC molecular markers 10 . Single nucleotide polymorphisms (SNPs) in the folic acid metabolic pathway and DNA repair system genes were related to prediction of CRC chemotherapy efficacy 11,12 …”