Abstract
Many studies have proven that splicing factors are crucial for human malignant tumor development. However, as a classical splicing factor, the expression of SF3B4 is not clear, and its biological function needs to be further clarified in ovarian cancer (OC). We determined that SF3B4 was obviously upregulated and its high expression was associated with poor prognosis in OC patients. In vitro and in vivo assays suggested that SF3B4 overexpression promoted OC cell proliferation and mobility, and downregulation of SF3B4 had the opposite effect. Further studies found that miR-509–3p decreased SF3B4 mRNA expression by binding to the 3’ -UTR of SF3B4 directly. Importantly, we revealed that RAD52 was a potential target of SF3B4 through alternative splicing events analysis. Loss of SF3B4 led to decreased expression of RAD52, owing to intron 8 retention and generation of premature termination codons. Moreover, decreased expression of RAD52 partially counteracted the tumor-promoting effect of SF3B4 overexpression. In conclusion, our results suggested that SF3B4, negatively regulated by miR-509–3p, promoted OC progression through effective splicing of RAD52. Therefore, SF3B4 may be a promising biomarker and effective therapeutic target for OC.
Highlights
ovarian cancer (OC) is the most lethal gynecologic malignancy [1]
SF3B4 is overexpressed in OC and correlates with poor prognosis To search for critical splicing factors involved in the initiation and development of OC, overlapping analysis of 2611 upregulated genes, genes related to poor prognosis, and 406 classical RNAbinding proteins revealed 3 potential genes, including IGF2BP2, IGF2BP3, and SF3B4 (Fig. 1A)
Knockdown of RAD52 impaired the phenotype of SF3B4 overexpression we investigated the biological function of RAD52 by transiently transfecting OC cells with siNC and RAD52-targeted siRNA to knock down RAD52
Summary
OC is the most lethal gynecologic malignancy [1]. More than 60% of patients are diagnosed at an advanced stage due to a lack of early diagnostic technology and rapid progression [2], and the five-year survival rate is approximately 45% [2]. The mechanism of initiation and development of OC needs to be elucidated further. More than 95% of genes exhibit AS [7]. Many diseases, including human malignant tumors, are associated with abnormal gene splicing [8]. Multiple studies have confirmed that some RBPs are involved in OC development. RBP USP39 promotes OC progression by targeting HMGA2 [9]. IGF2BP3 and Lin28B are associated with drug resistance in OC patients [10]. SORBS2 suppresses immune evasion of OC [12]
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