Downregulation of SRSF3 by antisense oligonucleotides sensitizes oral squamous cell carcinoma and breast cancer cells to paclitaxel treatment

Purpose: Paclitaxel (PTX) is widely used in the chemotherapy of many cancers, including breast Cancer and oral squamous cell carcinoma (OSCC). However, many patients respond poorly to PTX treatment. The SRSF3 oncogene and several splicing factors play important roles in OSCC tumorigenesis. This study aimed to understand the function of splicing factors in PTX treatment and improve the therapeutic effects of PTX treatment.

Methods: Splicing factors regulated by PTX treatment were screened in CAL 27 cell by reverse transcription polymerase chain reaction. The function of SRSF3 in PTX treatment was analyzed by gain-of-function or loss-of-function assay in OSCC cell lines CAL 27 and SCC-9 and breast Cancer cell line MCF-7. Alternative splicing of SRSF3 exon 4 in Cancer tissues or cells was analyzed by RT-PCR and online program TSVdb. SRSF3-specific antisense oligonucleotide (ASO) SR-3 was used to downregulate SRSF3 expression and enhance the effect of PTX treatment.

Results: PTX treatment decreased SRSF3 expression, and SRSF3 overexpression rescued the growth inhibition caused by PTX in both OSCC and breast Cancer cells. Moreover, we found that PTX treatment could repress SRSF3 exon 4 (containing an in-frame stop codon) exclusion and then decrease the SRSF3 protein expression. Increased exclusion of SRSF3 exon 4 is correlated with poor survival in OSCC and breast Cancer patients. SR-3 downregulated SRSF3 protein expression and significantly increased the sensitivity of Cancer cells to PTX treatment.

Conclusions: SRSF3 downregulation by ASO sensitizes Cancer cells to PTX treatment.