Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with poor prognosis, and understanding the molecular mechanisms underlying its progression is crucial for developing effective therapies. A recent study has uncovered a critical role of the BOLA3 gene and its exon 3 inclusion, which is promoted by the heterogeneous nuclear ribonucleoprotein C (HNRNPC), in accelerating ESCC progression. This discovery provides new insights into the molecular pathology of ESCC and may have implications for the development of targeted therapies.

The study focused on the regulation of BOLA3 exon 3 inclusion by HNRNPC and its impact on ESCC cell behavior. BOLA3, a protein involved in various cellular processes, has been implicated in cancer development, but its precise role in ESCC has been unclear. HNRNPC, known for its role in pre-mRNA splicing, was found to enhance the inclusion of BOLA3 exon 3, leading to increased BOLA3 protein levels and promoting ESCC cell proliferation, migration, and invasion. The researchers hypothesized that this dysregulation contributes significantly to ESCC progression.

To investigate this, the team conducted a series of experiments using ESCC cell lines and clinical samples. They first confirmed the elevated levels of HNRNPC in ESCC tissues compared to normal esophageal tissues. The overexpression of HNRNPC was associated with poor differentiation and advanced tumor stage, indicating a potential role in tumor aggressiveness. Further experiments demonstrated that HNRNPC directly binds to the pre-mRNA of BOLA3, facilitating the inclusion of exon 3 and resulting in increased BOLA3 protein production.

The functional consequences of this interaction were then assessed. The study showed that the enforced inclusion of BOLA3 exon 3, driven by HNRNPC, enhanced the malignant properties of ESCC cells, including their ability to form colonies, invade, and migrate. Conversely, the suppression of HNRNPC or BOLA3 reduced these capabilities, suggesting that the HNRNPC-BOLA3 axis is a key determinant of ESCC aggressiveness.

To explore the clinical relevance of these findings, the researchers analyzed the correlation between HNRNPC and BOLA3 expression levels in ESCC patient samples. They found a positive correlation, suggesting that the HNRNPC-mediated regulation of BOLA3 exon 3 inclusion may be a common event in ESCC. The study also examined the prognostic significance of HNRNPC and BOLA3 expression levels and found that high levels were associated with shorter overall survival, highlighting the potential of these proteins as prognostic markers.

In conclusion, this study has identified a novel molecular mechanism involving HNRNPC and BOLA3 that drives ESCC progression. The findings suggest that targeting the HNRNPC-BOLA3 axis may represent a promising therapeutic strategy for ESCC patients. Further research is needed to validate these findings and to explore the potential of HNRNPC and BOLA3 as therapeutic targets and biomarkers in ESCC.
DOI: 10.1007/s11684-024-1068-4