Benzyl isothiocyanate promotes miR-99a expression through ERK/AP-1-dependent pathway in bladder cancer cells

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Benzyl isothiocyanate (BITC), a natural compound from cruciferous vegetables, shows anticancer properties.
• BITC suppresses bladder cancer progression via IGF1R, FGFR3, and mTOR, mediated by miR-99a.
• The precise molecular mechanism regulating miR-99a expression by BITC in bladder cancer requires elucidation.

Purpose of the Study:

• To identify the signaling pathway responsible for BITC-induced miR-99a upregulation in bladder cancer.
• To investigate the role of transcription factors in mediating BITC's effect on miR-99a expression.
• To establish the mechanistic link between BITC, signaling pathways, and miR-99a in bladder cancer.

Main Methods:

• Bladder cancer cell lines were treated with varying BITC concentrations.
• Extracellular signal-regulated protein kinase (ERK) and c-jun N-terminal kinase (JNK) activation were assessed.
• Chemical inhibitors (U0126) were used to probe pathway involvement.
• c-Jun/AP-1 activation was confirmed via immunofluorescence and luciferase reporter assays.

Main Results:

• BITC treatment dose-dependently increased miR-99a expression in bladder cancer cells.
• BITC activated both ERK and JNK signaling pathways.
• Only the ERK pathway was essential for BITC-induced miR-99a expression.
• BITC treatment led to dose-dependent activation and nuclear translocation of c-Jun/AP-1.
• Inhibition of ERK signaling abrogated BITC-induced c-Jun phosphorylation and AP-1 transcriptional activity.

Conclusions:

• BITC upregulates miR-99a expression in bladder cancer cells through the ERK/c-Jun signaling pathway.
• This ERK/c-Jun-mediated miR-99a induction is a key mechanism underlying BITC's previously observed antitumor effects.
• The findings provide a mechanistic explanation for BITC's biological function in bladder cancer.