An NF90/long noncoding RNA-LET/miR-548k feedback amplification loop controls esophageal squamous cell carcinoma...

Area of Science:

• Molecular Biology
• Oncology
• Gene Regulation

Background:

• Previous studies identified microRNA-548k (miR-548k) as oncogenic in esophageal squamous cell carcinoma (ESCC) by targeting long noncoding RNA-LET (lncRNA-LET) and nuclear factor 90 (NF90).
• The upstream regulators of miR-548k in ESCC remained largely unknown.

Purpose of the Study:

• To elucidate the upstream regulatory mechanisms controlling miR-548k expression in ESCC.
• To investigate the functional role of NF90 in ESCC.
• To characterize the feedback loop involving NF90, miR-548k, and lncRNA-LET.

Main Methods:

• Investigated the direct binding of NF90 to pri-miR-548k using molecular assays.
• Performed gain-of-function and loss-of-function experiments to assess the roles of NF90 and miR-548k in ESCC cell proliferation and migration.
• Validated the regulatory feedback loop through expression analysis and functional assays.
• Assessed the impact of manipulating the feedback loop on ESCC cell growth in vitro and in vivo.

Main Results:

• NF90 directly binds to pri-miR-548k, enhancing its stability and upregulating miR-548k expression.
• NF90 promotes ESCC cell proliferation and migration, mirroring the oncogenic functions of miR-548k.
• A feedback loop was identified where NF90 upregulates miR-548k and downregulates lncRNA-LET; miR-548k downregulates lncRNA-LET and upregulates NF90; lncRNA-LET downregulates NF90 and miR-548k.
• Activation of this loop promotes ESCC progression, while its inhibition suppresses tumor growth.

Conclusions:

• A novel oncogenic feedback amplification loop comprising NF90, miR-548k, and lncRNA-LET was identified in ESCC.
• This regulatory loop significantly drives ESCC cell proliferation, migration, and tumor growth.
• The NF90/miR-548k/lncRNA-LET feedback loop represents a potential therapeutic target for esophageal squamous cell carcinoma.