The human Integrator complex is a set of 15 subunits that mediates processing of small nuclear RNAs (snRNAs), and which later participates in splicing messenger RNAs (mRNAs). In addition, it controls the pause and release of RNA polymerase II (RNA pol II) at specific gene promoters in response to growth factors. Mutations in Integrator-complex subunit 6 (INTS6) are associated with different types of tumors. However, theINTS6gene product does not have a significant prognostic value as a biomarker for tumor progression. Here we show that Integrator-complex deregulation is involved in 8.3% of the colorectal cancer cases diagnosed from the population screen carried out in La Rioja (Spain) from the years 2017 to 2019. Lack of Integrator-complex function, measured by an increased level of unprocessed snRNA, is a prognostic biomarker and correlates with a poorer prognosis in colorectal-cancer patients. The transcriptomic profile of all analyzed colorectal tumors shows a strong alteration of the metabolic state of tumor cells, which compromises standard energy production through mitochondrial respiration, known as the Warburg effect. Furthermore, there is a significant upregulation of genes involved in extracellular matrix organization and collagen rearrangement. This is consistent with tissue reorganization in a growing tumor forming a polyp. Crossing the molecular data generated in this study with the follow-up of patients from population screening indicates that population screening combined with early typing of tumors appears to be the most efficient way to increase patient survival.
人类整合子复合体由15个亚基组成，主要负责小核RNA（snRNA）的加工处理，并参与后续信使RNA（mRNA）的剪接过程。此外，该复合体还能响应生长因子信号，调控RNA聚合酶II（RNA pol II）在特定基因启动子处的暂停与释放。整合子复合体第六亚基（INTS6）的突变与多种肿瘤类型相关，但INTS6基因产物作为肿瘤进展的生物标志物尚未显示出显著的预后价值。本研究通过对西班牙拉里奥哈地区2017至2019年人群筛查确诊的结直肠癌病例分析发现，8.3%的病例存在整合子复合体功能失调。通过检测未加工snRNA水平升高所表征的整合子复合体功能缺失，可作为结直肠癌患者的预后生物标志物，其与患者不良预后显著相关。所有分析结直肠肿瘤的转录组谱显示，肿瘤细胞的代谢状态发生剧烈改变，导致线粒体呼吸的标准产能途径受损，即瓦博格效应。同时，细胞外基质组织和胶原重排相关基因显著上调，这与生长中肿瘤形成息肉时的组织重构过程相符。将本研究产生的分子数据与人群筛查患者的随访资料交叉分析表明，人群筛查结合肿瘤早期分型是提高患者生存率的最有效途径。
肿瘤(癌症)患者之家