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MiR-223 regulates CDDP resistance in pancreatic cancer via targeting FoxO3a
1Center for Clinical Laboratory, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang Uygur Autonomous Region, China. muliang621527826@yeah.net.
Objective:
FoxO3a is a well-defined tumor suppressor gene in the forkhead transcription factor O subfamily (FoxO), and its reduction is related to the occurrence of various tumors. It was found that miR-223 expression is abnormally elevated in pancreatic cancer tissues. Bioinformatics analysis revealed a targeted complementary binding relationship between miR-223 and FoxO3a. This study explored whether miR-155 regulates the expression of FoxO3a and affects the proliferation, apoptosis, and cisplatin (CDDP) resistance of oral cancer cells.
Materials And Methods:
Dual-Luciferase reporter gene assay validated the targeted relationship between miR-223 and FoxO3a. The CDDP-resistant pancreatic cancer cell line BXPC3/CDDP was established, and the expressions of miR-223 and FoxO3a were compared. BXPC3/CDDP cells were divided into miR-NC group and miR-223 inhibitor group. QRT-PCR was adopted to test miR-223 and FoxO3a mRNA expressions. Western blot was performed to determine FoxO3a protein expression. Cell apoptosis was detected by flow cytometry and cell proliferation was detected by EdU staining.
Results:
There was a targeted regulatory relationship between miR-223 and FoxO3a mRNA. The expression of miR-223 was significantly higher, while the expression of FoxO3a mRNA and protein was significantly lower in BXPC3/CDDP cells than that in BXPC3 cells. Cell Counting Kit-8 (CCK-8) experiments showed that the same concentration of CDDP exhibited significantly lower proliferation inhibition in BXPC3/CDDP cells than BXPC3 cells. Compared with miR-NC group, transfection of miR-223 inhibitor significantly increased the expression of FoxO3a in BXPC3/CDDP cells, which significantly attenuated cell proliferation and enhanced apoptosis in CDDP-treated cells.
Conclusions:
Increased expression of miR-233 was associated with CDDP resistance in pancreatic cancer cells. Inhibition of miR-223 expression upregulated FoxO3a expression, restrained pancreatic cancer cell proliferation, promoted cell apoptosis, and enhanced CDDP sensitivity in pancreatic cancer cells.
Insights
Elevated miR-223 expression promotes pancreatic cancer cell proliferation and cisplatin resistance by downregulating FoxO3a. Inhibiting miR-223 restores FoxO3a, enhancing apoptosis and sensitivity to cisplatin.
Area of Science:
- Oncology
- Molecular Biology
- Gene Regulation
Background:
- Forkhead box O3a (FoxO3a) is a tumor suppressor gene, and its reduced expression is linked to various cancers.
- MicroRNA-223 (miR-223) is abnormally elevated in pancreatic cancer tissues.
- Bioinformatics analysis suggests a direct targeting relationship between miR-223 and FoxO3a.
Purpose of the Study:
- To investigate the role of miR-223 in regulating FoxO3a expression.
- To determine the effect of miR-223 on pancreatic cancer cell proliferation, apoptosis, and cisplatin resistance.
Main Methods:
- Dual-Luciferase reporter assay to confirm the miR-223 and FoxO3a interaction.
- Establishment of a cisplatin-resistant pancreatic cancer cell line (BXPC3/CDDP).
- Quantitative real-time PCR (QRT-PCR) and Western blot to assess mRNA and protein expression levels of miR-223 and FoxO3a.
- Flow cytometry for apoptosis analysis and EdU staining for proliferation assays.
Main Results:
- A direct regulatory relationship between miR-223 and FoxO3a was confirmed.
- Cisplatin-resistant cells (BXPC3/CDDP) exhibited significantly higher miR-223 expression and lower FoxO3a expression compared to parental cells.
- Inhibition of miR-223 in BXPC3/CDDP cells led to increased FoxO3a expression, reduced cell proliferation, and enhanced apoptosis, particularly in the presence of cisplatin.
Conclusions:
- Elevated miR-223 expression is associated with cisplatin resistance in pancreatic cancer.
- Inhibiting miR-223 upregulates FoxO3a, suppresses pancreatic cancer cell proliferation, promotes apoptosis, and increases sensitivity to cisplatin.
