Abstract
Steroid receptor RNA activator 1 (SRA1) has been described as a novel transcriptional co-activator that affects the migration of cancer cells. Through RT-PCR, we identified that skipping exon 3 of SRA1 produces two isoforms, including the truncated short isoform, SRA1-S, and the long isoform, SRA1-L. However, the effect of these two isomers on the migration of HCC cells, as well as the specific mechanism of exon 3 skipping remain unclear. In this study, we found up regulated expression of SRSF1 and SRA1-L in highly metastatic HCCLM3, as well as in HCCs with SRSF1 demonstrating the strongest correlation with SRA1-L. In contrast, we observed a constitutively low expression of SRA1-S and SRSF1 in lowly metastatic HepG2 cells. Overexpression of SRSF1 or SRA1-L promoted migration and invasion by increasing the expression of CD44, while SRA1-S reversed the effect of SRSF1 and SRA1-L in vitro. In addition, lung metastasis in mice revealed that, knockdown of SRSF1 or SRA1-L inhibited the migration of HCC cells, while SRA1-L overexpression abolished the effect of SRSF1 knockout and instead promoted HCC cells migration in vivo. More importantly, RNA immunoprecipitation and Cross-link immunoprecipitation analyses showed that SRSF1 interacts with exon 3 of SRA1 to up regulate the expression of SRA1-L in HCC cells. RNA pull-down results indicated that SRSF1 could also bind to exon 3 of SRA1 in vitro. Finally, minigene -MS2 mutation experiments showed that mutation of the SRA1 exon 3 binding site for SRSF1 prevented the binding of SRA1 pre-mRNA. In summary, our results provide experimental evidence that SRA1 exon 3 inclusion is up regulated by SRSF1 to promote tumor invasion and metastasis in hepatocellular carcinoma.
Highlights
Liver cancer is a common cancer in the world
We selected several genes related to tumor metastasis through the NCBI database and literature, including Steroid receptor RNA activator 1 (SRA1), DBF4 zinc finger B (DBF4B), ZNFX1 antisense RNA 1 (ZFAS1), colorectal neoplasia differentially expressed (CRNDE), endoplasmic reticulum lectin (OS9), and others
From the detection of clinical samples of HCCs, we found that the expression of SRA1-L in HCCs was higher than that in adjacent tissues (Fig. 1D)
Summary
Liver cancer is a common cancer in the world. Many deaths of cancer patients are caused by liver cancer[1]. In 90% of solid cancer cases, metastasis is the main reason for mortality[2]. It can be seen that inhibiting tumor metastasis is an effective way to improve the survival rate of patients. Studies have shown that alternative splicing (AS) plays an important role in cancer metastasis[3,4,5,6]. Many abnormal alternative splicing events of mRNA have been reported, few articles have reported on alternative splicing events that simultaneously producecoding proteins isoforms and non-coding isoforms[7]. Further study of alternative splicing will improve our understanding of liver cancer metastasis and promote the development of more effective targeted therapies
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