Abstract
BackgroundThe microRNA miR-101 is downregulated in several cancers, including bladder cancer. However, miR-101’s role in the invasion, metastasis, and chemosensitivity of bladder cancer cells remains unclear. This study was conducted to determine miR-101’s role on the lymphangiogenic molecule vascular endothelial growth factor C (VEGF-C) and their effects upon bladder cancer cell migration, invasion, and chemosensitivity to cisplatin.MethodsTwo bladder cancer cell lines (T24 and 5637) and the tool cell line 293T were employed here. Bladder cancer cells were transfected with either a miR-101 overexpression vector or a scrambled-sequence lentivirus, both of which exhibited a high transfection efficiency. Non-transfection was used as a mock negative control. Wound healing and Transwell assays were performed to measure cell migration and invasiveness. A luciferase reporter assay was performed to validate miR-101’s interaction with VEGF-C’s 3′ untranslated region followed by RT-PCR and Western blot confirmation. An MTS assay was used to evaluate the cisplatin sensitivity of the cell lines.ResultsmiR-101 overexpression significantly inhibited the migration and invasiveness while significantly enhancing cisplatin sensitivity. miR-101 negatively regulated VEGF-C protein expression, and VEGF-C overexpression rescued the effects of miR-101 overexpression, indicating that miR-101 negatively regulates VEGF-C protein expression post-transcriptionally. miR-101 and VEGF-C interference independently enhanced cisplatin cytotoxicity in bladder cancer cells.ConclusionsmiR-101 suppresses VEGF-C expression, inhibits cell migration and invasion, and increases cisplatin sensitivity in bladder cancer cells. This study provides new insight into miR-101’s role in bladder cancer and shows miR-101’s promise as a potential molecular target for bladder cancer.
Highlights
Bladder cancer is the most common urinary tract malignancy, producing approximately 150,000 annual deaths worldwide [1] and is clinically characterized by its progression, recurrence, metastasis, and drug resistance [2, 3]
Results miR-101 overexpression significantly inhibited the migration and invasiveness while significantly enhancing cisplatin sensitivity. miR-101 negatively regulated vascular endothelial growth factor C (VEGF-C) protein expression, and vascular endothelial growth factor (VEGF)-C overexpression rescued the effects of miR-101 overexpression, PLOS ONE | DOI:10.1371/journal.pone
The sensitivity of T24 and 5637 cells to cisplatin increased after VEGF-C interference, with the IC50 value increasing from 2.56 ± 0.31 mg/l to 8.23 ± 0.83 mg/l and from 3.01 ± 0.5 5mg/l to 5.42 x 0.52 mg/l, respectively (Fig. 5B, 5C). These results suggest that VEGF-C downregulation, as the downstream target of miR-101, enhances bladder cancer cell sensitivity to cisplatin
Summary
Bladder cancer is the most common urinary tract malignancy, producing approximately 150,000 annual deaths worldwide [1] and is clinically characterized by its progression, recurrence, metastasis, and drug resistance [2, 3]. Cisplatin is the first-line chemotherapy for advanced bladder cancer, the cisplatin/gemcitabine (GC) regimen has a median time-to-progression of only six months and has no effect on overall survival after radical cystectomy in high-risk patients [7]. Despite radical cystectomy or preoperative chemotherapy, uncontrolled lymphovascular invasion of bladder cancer continues to yield a poor clinical prognosis [8,9,10]. MiR-101’s role in the invasion, metastasis, and chemosensitivity of bladder cancer cells remains unclear. This study was conducted to determine miR-101’s role on the lymphangiogenic molecule vascular endothelial growth factor C (VEGF-C) and their effects upon bladder cancer cell migration, invasion, and chemosensitivity to cisplatin
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