Poly(rC) Binding Protein 1 Represses the Translation of STAT3 through 5' UTR

Area of Science:

• Molecular Biology
• Cancer Research
• RNA Biology

Background:

• Signal transducer and activator of transcription 3 (STAT3) is a frequently overexpressed oncogene in various cancers.
• The precise regulatory mechanisms governing STAT3 expression remain incompletely understood.
• Poly(rC)-binding protein 1 (PCBP1), an RNA-binding protein, acts as a tumor suppressor by inhibiting the translation of oncogenic mRNAs.

Purpose of the Study:

• To elucidate the regulatory mechanisms of STAT3 expression.
• To investigate the role of PCBP1 in controlling STAT3 gene expression.
• To identify specific domains or residues within PCBP1 crucial for STAT3 regulation.

Main Methods:

• Utilized reporter gene systems (GFP) with STAT3 5' UTR and 3' UTR to assess PCBP1's inhibitory effects.
• Employed deletion and point mutations within the STAT3 5' UTR to pinpoint essential regulatory sequences.
• Analyzed PCBP1 protein mutations using cBioPortal and evaluated their impact on STAT3 expression and cancer cell phenotypes in OSCC cell lines.

Main Results:

• PCBP1 inhibits STAT3 mRNA translation through a specific motif located in the 5' UTR of STAT3.
• Identified two critical leucine residues (Leu100 and Leu102) in PCBP1 that are frequently mutated in cancers.
• These PCBP1 mutations abrogated its inhibitory effect on STAT3 translation and unexpectedly promoted cancer cell proliferation and colony formation.

Conclusions:

• PCBP1 functions as a tumor suppressor by inhibiting STAT3 expression via its 5' UTR.
• The identified leucine residues (Leu100 and Leu102) in PCBP1 are essential for its tumor-suppressive activity.
• Dysregulation of PCBP1 through these mutations contributes to cancer progression by reactivating STAT3 signaling.