High-risk human papillomavirus oncoproteins E6 and E7 are the major etiological factors of cervical cancer but are insufficient for malignant transformation of cervical cancer. Dysregulated alternative splicing, mainly ascribed to aberrant splicing factor levels and activities, contributes to most cancer hallmarks. However, do E6 and E7 regulate the expression of splicing factors? Does alternative splicing acts as an "accomplice" of E6E7 to promote cervical cancer progression? Here, we identified that the splicing factor SRSF10, which promotes tumorigenesis of cervix, was upregulated by E6E7 via E2F1 transcriptional activation. SRSF10 modulates the alternate terminator of interleukin-1 receptor accessory protein exon 13 to increase production of the membrane form of interleukin-1 receptor accessory protein. SRSF10-mediated mIL1RAP upregulates the expression of the "don't eat me" signal CD47 to inhibit macrophage phagocytosis by promoting nuclear factor-κB activation, which is pivotal in inflammatory, immune, and tumorigenesis processes. Altogether, these data reveal a close relationship among HPV infection, alternative splicing and tumor immune evasion, and also suggests that the SRSF10-mIL1RAP-CD47 axis could be an attractive therapeutic target for the treatment of cervical cancer.

中文翻译：

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SRSF10介导的IL1RAP选择性剪接通过mIL1RAP-NF-κB-CD47轴调控子宫颈癌的发生。

高危型人乳头瘤病毒癌蛋白E6和E7是宫颈癌的主要病因，但不足以进行宫颈癌的恶性转化。异常剪接的剪接，主要归因于异常的剪接因子水平和活性，是导致大多数癌症的标志。但是，E6和E7是否调节剪接因子的表达？选择性剪接是否可作为E6E7的“帮凶”来促进子宫颈癌的进展？在这里，我们确定，促进子宫颈癌发生的剪接因子SRSF10被E6E7通过E2F1转录激活上调。SRSF10调节白介素-1受体辅助蛋白外显子13的交替终止子，以增加白介素-1受体辅助蛋白的膜形式的产生。SRSF10介导的mIL1RAP上调“不要吃我”信号CD47的表达，以通过促进核因子-κB的活化来抑制巨噬细胞的吞噬作用，这在炎症，免疫和肿瘤发生过程中至关重要。总而言之，这些数据揭示了HPV感染，选择性剪接和肿瘤免疫逃逸之间的密切关系，并且还表明SRSF10-mIL1RAP-CD47轴可能是治疗宫颈癌的有吸引力的治疗靶标。