Abstract
Ferroptosis, a newly discovered form of programmed cell death characterized by lipid peroxidation, crafts a new perspective on cancer treatment. Serine and arginine rich splicing factor 9 (SFRS9) is frequently described as a proto-oncogene in cervical and bladder cancer. However, the role of SFRS9 in colorectal cancer (CRC) and whether SFRS9 exerts its function associated with ferroptosis is largely unknown. Herein, we found that the expression of SFRS9 mRNA and protein in the CRC tissues was obviously higher than that in the paracancerous tissues. Function assays revealed that SFRS9 overexpression (SFRS9-OE) significantly promoted cell viability, cell cycle progression and colony formation of CRC cells. While SFRS9 knockdown by shRNAs transfection inhibited these progressions. Furthermore, cell death and lipid peroxidation induced by ferroptosis inducers erastin and sorafenib were suppressed by SFRS9-OE. Bioinformatics analysis indicated that SFRS9 can bind to peroxidase 4 (GPX4) mRNA which is a central regulator of ferroptosis. Western blot showed that GPX4 protein expression was clearly elevated upon SFRS9-OE, while it was decreased in SFRS9-inhibited CRC cells. RNA immunoprecipitation experiment was carried out in HCT116 cells to confirm the binding of SFRS9 and GPX4 mRNA specifically. SiGPX4 transfection reversed the inhibitory effects of SFRS9-OE on the erastin and sorafenib-induced ferroptosis. Consistent with our in vitro observations, SFRS9 promoted the growth of tumors while SFRS9 knockdown significantly inhibited tumor growth in nude mice. In conclusion, SFRS9 represents an obstructive factor to ferroptosis by upregulating GPX4 protein expression, and knocking down SFRS9 might be an effective treatment for CRC.
Highlights
Colorectal cancer (CRC) is one of the most deadly cancers and it causes almost 700,000 deaths every year [1]
HCT116 CRC cells showed best SFRS9 mRNA expression, while Caco-2 cells showed relatively lower SFRS9 mRNA expression compared with other CRC cells (Figure 2A)
To illustrate the function of SFRS9 in CRC tumorigenesis, we firstly confirmed that SFRS9-OE vector transfection could significantly enhanced SFRS9 expression both at mRNA and protein levels in Caco-2 CRC cells (Figures 2B, C)
Summary
Colorectal cancer (CRC) is one of the most deadly cancers and it causes almost 700,000 deaths every year [1]. Environmental and genetic factors are considered to play a major role in the pathogenesis of CRC. CRC is a serious disease that poses a significant threat to human health. New therapeutic strategies such as laparoscopic surgery for primary disease, more-aggressive resection of metastatic disease, radiotherapy for rectal cancer and neoadjuvant chemotherapies have been continuously developed, providing more treatment options for CRC patients [2]. Exploring new therapeutic targets to prevent the tumorigenesis of CRC is urgently needed
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