B7-H3 is spliced by SRSF3 in colorectal cancer

Colorectal Cancer
28/07/2020

Cancer Immunol Immunother. 2020 Jul 27. doi: 10.1007/s00262-020-02683-9. Online ahead of print.

ABSTRACT

B7-H3, an important co-inhibitor, is abnormally highly expressed in a variety of malignancies. The antibodies targeting B7-H3 have exhibited beneficial therapeutic effects in clinical trials. Therefore, discovery of the regulatory factors in B7-H3 expression may provide new strategies for tumor therapy. Here, we investigated the splicing factors involved in the splicing of B7-H3. By individual knockdown of the splicing factors in colorectal cancer (CRC) cells, we found that B7-H3 expression was


markedly inhibited by SRSF3 and SRSF8, especially SRSF3. Then we found that both SRSF3 and B7-H3 were highly expressed in CRC tissues. Moreover, high-expression of either SRSF3 or B7-H3 was significantly correlated with poor prognosis of patients. The expression of B7-H3 mRNA and protein were evidently reduced by SRSF3 silence, but were enhanced by overexpression of SRSF3 in both HCT-116 and HCT-8 cells. The results from the RNA immunoprecipitation (RIP) assays demonstrated that SRSF3 protein directly binds to B7-H3 mRNA. In addition, we constructed a minigene recombinant plasmid for expressing B7-H3 exons 3-6. We found that SRSF3 contributed to the retention of B7-H3 exon 4. These findings demonstrate that SRSF3 involves in the splicing of B7-H3 by directly binding to its exon 4 and/or 6. It may provide novel insights into the regulatory mechanisms of B7-H3 expression and potential strategies for the treatment of CRC.