Abstract
One of the most challenging problems in colorectal cancer (CRC) is resistance to chemotherapy drugs such as doxorubicin (DOX). The programmed death ligand-1 (PD-L1) is related to chemoresistance and is overexpressed in several human cancer cell types. Here, we investigated the changes in the expression of PD-L1 in DOX-treated CRC and breast cancer (BRC) cells. Also, to address PD-L1 regulation, we assessed expression levels of miR-140 and miR-34a, two microRNAs that can target the 3’ UTR region of the gene encoding PD-L1. HCT116 CRC and MDA-MB-231 BRC cells were treated with various doses of DOX in culture and PD-L1 expression was quantified using qRT-PCR, flow cytometry, and western blot analysis. We also evaluated PD-L1 localization in HCT116 cells by immunofluorescence. Next, we assessed expression of miR-140 and miR-34a in DOX-treated HCT116 and MDA-MB-231 cells. Finally, we investigated whether miR-140 targets the 3’ UTR of the gene encoding PD-L1 in HCT116 cells using the p2FP-RNAi RNAi reporter vector system. PD-L1 expression in HCT116 cells, while low at baseline, can be induced by treatment with 0.5 µM DOX. MDA-MB-231 baseline PD-L1 expression exceeded HCT116 cell maximal expression and decreased following DOX treatment. We further demonstrated that PD-L1 localizes to the cell surface in DOX-treated HCT116 cells. While miR-140 expression decreased in DOX-treated HCT116 cells, it increased in DOX-treated MDA-MB-231 cells. MiR-34a expression increased in both DOX-treated cell types. Finally, we present evidence for the regulation of PD-L1 by miR-140 in HCT116 cells. PD-L1 expression can increase following treatment with DOX in HCT116 cells but decrease in MDA-MB-231 cells, suggesting a distinct response to DOX in these two different cancer types. Also, a negative correlation between PD-L1 and miR-140 was observed in DOX-treated HCT116 cells, but not in MDA-MB-231 cells.
Highlights
Colorectal cancer is reported as the leading cause of cancer-related death worldwide (Torre et al, 2012)
Earlier studies reported that DOX downregulates programmed death ligand-1 (PD-L1) expression on the cell surface of MDA-MB-231 breast cancer cells (Ghebeh et al, 2010)
Because the DOX effect on PD-L1 expression in colorectal cancer (CRC) cells is not known, we investigated the expression level of PD-L1 on DOX treatment in HCT116 colon cancer cells
Summary
Colorectal cancer is reported as the leading cause of cancer-related death worldwide (Torre et al, 2012). Most patients with CRC are diagnosed in advanced stages, where the main option for the treatment is chemotherapy (Moertel et al, 1994). Chemotherapeutic drugs such as 5-fluorouracil and oxaliplatin are used in CRC treatment despite their severe side effects like risk of infection, anemia, and peripheral neuropathy (Midgley et al, 2005). Doxorubicin (DOX), which belongs to the anthracycline family, is used for the treatment of various cancer types including breast cancer, lung cancer, gastric cancer, and leukemia, but not for CRC (Minotti et al, 2004). Developed immunotherapies, which aim to block the PD-1/PD-L1 pathway using specific monoclonal antibodies, dramatically improve antitumor immune responses in various cancer types like skin cancer
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
