PO.ET01.02 · 实验与分子治疗
长链非编码RNA浆细胞瘤变异易位1的选择性剪接在前列腺癌发生中的作用
Long non coding RNA plasmacytoma variant translocation 1 alternative splicing in prostate carcinogenesis
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
前列腺癌仍然是全球主要的健康问题，并且不成比例地影响黑人男性/非洲血统男性（MoAA）。与欧洲血统男性（MoEA）相比，MoAA的前列腺癌发病率更高，死亡率也显著升高。根据美国癌症协会近期的报告，MoAA的前列腺癌发病率高出67%，且死于该疾病的可能性是MoEA的两倍多。虽然社会经济和医疗可及性因素对这些差异有所贡献，但越来越多的证据表明潜在的分子机制也发挥着关键作用。一个新出现的分子因素是长链非编码RNA浆细胞瘤变异易位1（PVT1），它在MoAA的前列腺肿瘤中持续过表达。既往研究表明PVT1第9外显子参与促进肿瘤发生和进展。在前列腺癌模型中实验性过表达第9外显子会增加肿瘤侵袭性并增强恶性细胞行为，支持其在疾病严重程度中的功能性作用。此外，PVT1第9外显子诱导前列腺上皮细胞的恶性转化。然而，最近的研究结果表明PVT1并非以单一转录本形式表达，而是以一组多样化的选择性剪接异构体表达，这提示特定的变异体可能对观察到的种族差异有所贡献。我们假设这些选择性剪接的PVT1转录本中有一部分在MoAA中差异表达，并对该人群中观察到的前列腺癌发病率和死亡率升高有所贡献。为研究这一点，我们使用来自两项独立研究（包括TCGA）的前列腺癌数据集分析了PVT1剪接谱。我们鉴定出ENST00000666076，这是一个位于8号染色体27,975,972-27,995,613区域的选择性剪接PVT1转录本，与MoEA相比在MoAA中显著过表达。该转录本包含五个外显子：ENSE00004271579、ENSE00004271636、ENSE00002081483、ENSE00002020395和ENSE00004271500。总之，我们的分析支持了以下结论：不同的PVT1剪接变异体可能参与前列腺癌的发生。
查看英文原文 English abstract
Prostate cancer remains a major global health concern and disproportionately affects Black men/men of African ancestry (MoAA). Compared to men of European ancestry (MoEA), MoAA experience both a higher incidence of prostate cancer and significantly elevated mortality rates. According to recent American Cancer Society reports, MoAA have a 67% higher incidence of prostate cancer and are more than twice as likely to die from the disease. While socioeconomic and healthcare access factors contribute to these disparities, growing evidence suggests that underlying molecular mechanisms also play a critical role. One emerging molecular factor is the long non-coding RNA Plasmacytoma Variant Translocation 1 (PVT1), which is consistently overexpressed in prostate tumors from MoAA. Prior studies have implicated PVT1 exon 9 in promoting tumor development and progression. Experimental overexpression of exon 9 in prostate cancer models increases tumor aggressiveness and enhances malignant cellular behavior, supporting a functional role in disease severity. In addition, PVT1 exon 9 induces malignant transformation of prostate epithelial cells. However, recent findings indicate that PVT1 is not expressed as a single transcript, but rather as a diverse set of alternatively spliced isoforms, raising the possibility that specific variants may contribute to the observed racial disparities. We hypothesize that a subset of these alternatively spliced PVT1 transcripts is differentially expressed in MoAA and contributes to the increased prostate cancer incidence and mortality observed in this population. To investigate this, we analyzed PVT1 splicing profiles using prostate cancer datasets from two independent studies, including TCGA. We identified ENST00000666076, an alternatively spliced PVT1 transcript located on Chromosome 8: 27,975,972-27,995,613, as being significantly overexpressed in MoAA compared to MoEA. This transcript includes five exons: ENSE00004271579, ENSE00004271636, ENSE00002081483, ENSE00002020395, and ENSE00004271500. In conclusion, our analysis supports the conclusion that distinct PVT1 splice variants may be involved in prostate carcinogenesis.
利益披露 Disclosure
S. Adams, None..
D. Weatherall, None.