Foxo3a-dependent miR-633 regulates chemotherapeutic sensitivity in gastric cancer by targeting Fas-associated death...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Chemotherapeutic drug resistance, including to doxorubicin (DOX) and cisplatin (DDP), is a significant obstacle in gastric cancer treatment.
• MicroRNAs (miRNAs) are increasingly recognized for their role in modulating cellular responses to chemotherapy.

Purpose of the Study:

• To investigate the function of the oncogenic microRNA, miR-633, in the context of gastric cancer chemoresistance.
• To elucidate the molecular mechanisms underlying miR-633's involvement in chemoresistance and identify potential therapeutic targets.

Main Methods:

• Expression analysis of miR-633 and FADD in gastric cancer tissues and cell lines.
• In vitro studies involving miR-633 inhibition and assessment of apoptosis.
• In vivo experiments using miR-633 antagomirs in combination with doxorubicin.
• Investigation of the regulatory relationship between Foxo3a and miR-633 transcription.

Main Results:

• miR-633 expression was elevated in gastric cancer and inversely correlated with FADD protein levels.
• Inhibition of miR-633 increased FADD expression, enhanced apoptosis, and improved chemosensitivity in vitro.
• Administration of miR-633 antagomir combined with DOX reduced tumor growth in vivo.
• Forkhead box O 3 (Foxo3a) was identified as a transcriptional repressor of miR-633, and its nuclear accumulation upon DOX treatment suppressed miR-633.

Conclusions:

• The miR-633/FADD axis is a key mediator of chemoresistance in gastric cancer.
• Foxo3a regulates this axis by suppressing miR-633 transcription, particularly in response to chemotherapy.
• Targeting miR-633 with antagomirs represents a promising therapeutic strategy to overcome chemoresistance in gastric cancer.