Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, USA; Division of Cancer Biology, Department of Medicine, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Division of Cancer Biology, Department of Medicine, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Environ Int. 2024 Mar;185:108494. doi: 10.1016/j.envint.2024.108494. Epub 2024 Feb 10.
Hexavalent chromium [Cr(VI)] is a common environmental pollutant and chronic exposure to Cr(VI) causes lung cancer in humans, however, the mechanism of Cr(VI) carcinogenesis has not been well understood. Lung cancer is the leading cause of cancer-related death, although the mechanisms of how lung cancer develops and progresses have been poorly understood. While long non-coding RNAs (lncRNAs) are found abnormally expressed in cancer, how dysregulated lncRNAs contribute to carcinogenesis remains largely unknown. The goal of this study is to investigate the mechanism of Cr(VI)-induced lung carcinogenesis focusing on the role of the lncRNA ABHD11 antisense RNA 1 (tail to tail) (ABHD11-AS1). It was found that the lncRNA ABHD11-AS1 expression levels are up-regulated in chronic Cr(VI) exposure-transformed human bronchial epithelial cells, chronically Cr(VI)-exposed mouse lung tissues, and human lung cancer cells as well. Bioinformatics analysis revealed that ABHD11-AS1 levels are up-regulated in lung adenocarcinomas (LUADs) tissues and associated with worse overall survival of LUAD patients but not in lung squamous cell carcinomas. It was further determined that up-regulation of ABHD11-AS1 expression plays an important role in chronic Cr(VI) exposure-induced cell malignant transformation and tumorigenesis, and the stemness of human lung cancer cells. Mechanistically, it was found that ABHD11-AS1 directly binds SART3 (spliceosome associated factor 3, U4/U6 recycling protein). The interaction of ABHD11-AS1 with SART3 promotes USP15 (ubiquitin specific peptidase 15) nuclear localization. Nuclear localized USP15 interacts with pre-mRNA processing factor 19 (PRPF19) to increase CD44 RNA alternative splicing activating β-catenin and enhancing cancer stemness. Together, these findings indicate that lncRNA ABHD11-AS1 interacts with SART3 and regulates CD44 RNA alternative splicing to promote cell malignant transformation and lung carcinogenesis.
六价铬[Cr(VI)]是一种常见的环境污染物，慢性接触 Cr(VI)会导致人类患肺癌，然而，Cr(VI)致癌的机制尚未得到很好的理解。肺癌是癌症相关死亡的主要原因，尽管肺癌的发展和进展机制尚未被很好地理解。虽然长链非编码 RNA（lncRNA）在癌症中异常表达，但失调的 lncRNA 如何促进致癌作用在很大程度上仍然未知。本研究的目的是研究 Cr(VI)诱导的肺癌发生的机制，重点研究 lncRNA ABHD11 反义 RNA 1（尾对尾）（ABHD11-AS1）的作用。研究发现，lncRNA ABHD11-AS1 的表达水平在慢性 Cr(VI)暴露转化的人支气管上皮细胞、慢性 Cr(VI)暴露的小鼠肺组织以及人肺癌细胞中上调。生物信息学分析显示，ABHD11-AS1 水平在肺腺癌（LUAD）组织中上调，并与 LUAD 患者的总生存时间较差相关，但与肺鳞状细胞癌无关。进一步确定，ABHD11-AS1 表达的上调在慢性 Cr(VI)暴露诱导的细胞恶性转化和肿瘤发生以及人肺癌细胞的干性中起着重要作用。机制上，发现 ABHD11-AS1 直接与 SART3（剪接体相关因子 3，U4/U6 回收蛋白）结合。ABHD11-AS1 与 SART3 的相互作用促进 USP15（泛素特异性肽酶 15）核定位。核定位的 USP15 与 pre-mRNA 加工因子 19（PRPF19）相互作用，增加 CD44 RNA 可变剪接激活 β-连环蛋白并增强癌症干性。总之，这些发现表明 lncRNA ABHD11-AS1 与 SART3 相互作用，并调节 CD44 RNA 可变剪接，以促进细胞恶性转化和肺癌发生。
