FXR1 Microtubule Axis: Key Driver and Target in Oral Cancer

Objectives: Gene expression is intricately regulated by RNA-based circuits by interacting with proteins, and its dysregulation is a key factor in tumor growth and proliferation.Fragile X-related protein 1 (FXR1), a member of the Fragile-X protein family, is known for its role in regulating RNA stability and translation. There is evidence of FXR1’s involvement in several malignancies, including oral squamous cell carcinoma. Our recent research has shown that FXR1 binds to numerous mRNAs in UMSCC 74B cells, particularly MAP1B, AHNAK, and AHNAK2. These proteins play a crucial role in maintaining cellular integrity by regulating Ca2+ channels and microtubule (MT) formation. MT dynamics are essential for all processes in cytoskeleton, such as cell migration, differentiation, and invasion. This study delved into the function of FXR1 in regulating mRNAs associated with MT production and stabilization, thereby influencing tumor growth and proliferation.
Methods: We employed an FXR1-silenced murine cancer cell line to examine the molecular mechanism by which FXR1 modulates its target mRNAs and affects their translation. Additionally, we utilized FXR1 knockout mice and 4NQO-induced tumor models to investigate the function of FXR1 in carcinogenesis via the modulation of MTs. We used next-generation sequencing and Spatial OMICS methodology to elucidate the molecular mechanism that facilitates OSCC progression.
Results: Immunoblot and immunofluorescence studies demonstrated that the silencing of FXR1 markedly modifies the protein levels of MAP1B, AHNAK, and AHNAK2 in Moc2 cells and mouse tongue tissues. Further we shown that the inhibition of FXR1 significantly modified the microtubule density and stability in both cellular lines and murine models. Notably, 4NQO-induced FXR1 knockout significantly decreased the tumor burden compared to the wild-type tongue tissues.
Conclusions: The FXR1-microtubule axis may contribute to oral cancer progression, indicating potential for targeting this axis as a therapeutic strategy for managing OSCC.