HPV alternative splicing in cervical cancer radiation response

项目摘要/摘要 人乳头瘤病毒(HPV)感染是宫颈癌的主要原因。局部进展期宫颈 癌症(LACC)是无法治愈的，在标准护理放化疗(CRT)后复发率很高。 高危HPV基因类型已经进化出复杂的调控策略来严格控制病毒基因的表达 和另一种剪接。最近的研究表明，一些选择性剪接的hpv基因具有不同的 在宫颈肿瘤复制和致癌中的功能比其全长癌基因同义物。该比率 全长和选择性剪接的HPV转录本在具有不同高危因素的宫颈肿瘤中可能存在差异 HPV基因分型。我们手动检查了整个转录组测序(rna-seq)数据，发现 包含选择性剪接的HPV转录本和长的非基因间隔期的复发性HPV-人类基因融合 编码蛋白质的人类RNA(LncRNA)。人乳头瘤病毒选择性剪接在宫颈癌生物学中具有重要意义； 然而，目前仍不清楚交替剪接的HPV转录本是否会影响 宫颈癌患者。拟议中的研究将确定选择性剪接的HPV转录本 对宫颈癌患者的预后和机制有重要意义。具体来说，我们将 确定选择性剪接的HPV转录本是否通过HPV转化来调节辐射反应 宫颈癌细胞和端粒酶逆转录酶(HTERT)转化宫颈上皮细胞。我们 还将评估选择性剪接的HPV转录本是否可以作为不同HPV的生物标志物 利用已建立的LACC患者队列中的基因捕获测序数据和临床数据进行基因分型 统一采用治疗性CRT治疗。最后，我们将开发新的算法来识别病毒宿主基因 并使用RNA-SEQ数据和临床结果数据检查其功能后果。成功 完成这项翻译研究将确定可替代剪接的HPV转录本是准确的 LACC的预后分子生物标志物和合适的新靶点。确立机械系统的功能 HPV选择性剪接在宫颈癌放射反应中的作用最终将促进 优化治疗，改善患者预后。

PROJECT SUMMARY/ABSTRACT Human papillomavirus (HPV) infection is the primary cause of cervical carcinoma. Locally advanced cervical cancer (LACC) is incurable with a high recurrence rate after standard-of-care chemoradiation therapy (CRT). High-risk HPV genotypes have evolved complex regulatory strategies to tightly control viral gene expression and alternative splicing. Recent studies indicate that some alternatively spliced HPV genes have different functions in cervical tumor replication and oncogenesis than their full-length oncogene counterparts. The ratio of full-length and alternatively spliced HPV transcripts can vary in cervical tumors harboring different high-risk HPV genotypes. We manually inspected whole transcriptome sequencing (RNA-seq) data and discovered recurrent HPV-human gene fusions containing alternatively spliced HPV transcripts and long intergenic non- protein-coding human RNAs (lncRNA). HPV alternative splicing is important in cervical cancer biology; however, it is still unclear whether alternatively spliced HPV transcripts affect the chemoradiation response in cervical cancer patients. The proposed research will determine whether alternatively spliced HPV transcripts have prognostic and mechanistic significance for patient outcomes in cervical cancer. Specifically, we will determine whether alternatively spliced HPV transcripts modulate radiation response using HPV-transformed cervical cancer cells and telomerase-reverse-transcriptase (hTERT) transformed cervical epithelial cells. We will also evaluate whether alternatively spliced HPV transcripts can serve as biomarkers for different HPV genotypes using cDNA capture sequencing data and clinical data from an established cohort of LACC patients uniformly treated with curative-intent CRT. Finally, we will develop novel algorithms to identify viral-host gene fusions and examine their functional consequences using RNA-seq data and clinical outcome data. Successful completion of this translational research will identify alternatively spliced HPV transcripts as accurate prognostic molecular biomarkers and suitable novel targets in LACC. Establishing the mechanistic function of HPV alternative splicing in cervical cancer radiation response will ultimately facilitate the development of optimized therapies and improve patient outcomes.