Laboratory of Medical Investigation (LIM55), Urology Department, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, Brazil.
Laboratory of Medical Investigation (LIM55), Urology Department, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, Brazil; Minas Gerais State University (UEMG), Passos, Minas Gerais, Brazil.
Cancer Genet. 2024 Jun;284-285:20-29. doi: 10.1016/j.cancergen.2024.03.006. Epub 2024 Mar 16.
Search for new clinical biomarkers targets in prostate cancer (PC) is urgent. Telomeres might be one of these targets. Telomeres are the extremities of linear chromosomes, essential for genome stability and control of cell divisions. Telomere homeostasis relies on the proper functioning of shelterin and CST complexes. Telomeric dysfunction and abnormal expression of its components are reported in most cancers and are associated with PC. Despite this, there are only a few studies about the expression of the main telomere complexes and their relationship with PC progression. We aimed to evaluate the role of shelterin (POT1, TRF2, TPP1, TIN2, and RAP1) and CST (CTC1, STN1, and TEN1) genes and telomere length in the progression of PC.
We evaluated genetic alterations of shelterin and CST by bioinformatics in samples of localized (n = 499) and metastatic castration-resistant PC (n = 444). We also analyzed the expression of the genes using TCGA (localized PC n = 497 and control n = 152) and experimental approaches, with surgical specimens (localized PC n = 81 and BPH n = 10) and metastatic cell lines (LNCaP, DU145, PC3 and PNT2 as control) by real-time PCR. Real-time PCR also determined the telomere length in the same experimental samples. All acquired data were associated with clinical parameters.
Genetic alterations are uncommon in PC, but POT1, TIN2, and TEN1 showed significantly more amplifications in the metastatic cancer. Except for CTC1 and TEN1, which are differentially expressed in localized PC samples, we did not detect an expression pattern relative to control and cell lines. Nevertheless, except for TEN1, the upregulation of all genes is associated with a worse prognosis in localized PC. We also found that increased telomere length is associated with disease aggressiveness in localized PC.
The upregulation of shelterin and CST genes creates an environment that favors telomere elongation, giving selective advantages for localized PC cells to progress to more aggressive stages of the disease.
在前列腺癌（PC）中寻找新的临床生物标志物靶标迫在眉睫。端粒可能是这些靶标之一。端粒是线性染色体的末端，对基因组稳定性和细胞分裂控制至关重要。端粒稳态依赖于庇护体和 CST 复合物的正常功能。端粒功能障碍和其成分的异常表达在大多数癌症中都有报道，并与 PC 相关。尽管如此，关于主要端粒复合物的表达及其与 PC 进展的关系的研究很少。我们旨在评估庇护体（POT1、TRF2、TPP1、TIN2 和 RAP1）和 CST（CTC1、STN1 和 TEN1）基因的表达及其与 PC 进展的关系。
我们通过生物信息学评估了局限性（n=499）和转移性去势抵抗性 PC（n=444）样本中端粒的遗传改变。我们还使用 TCGA（局限性 PC n=497 和对照 n=152）和实验方法分析了基因的表达，使用手术标本（局限性 PC n=81 和 BPH n=10）和转移性细胞系（LNCaP、DU145、PC3 和 PNT2 作为对照）通过实时 PCR。实时 PCR 还确定了相同实验样本中的端粒长度。所有获得的数据均与临床参数相关联。
遗传改变在 PC 中并不常见，但 POT1、TIN2 和 TEN1 在转移性癌症中显示出明显更多的扩增。除了在局限性 PC 样本中表达不同的 CTC1 和 TEN1 外，我们没有检测到与对照和细胞系相对应的表达模式。尽管如此，除了 TEN1 之外，所有基因的上调都与局限性 PC 的预后不良相关。我们还发现，端粒长度的增加与局限性 PC 中的疾病侵袭性相关。
庇护体和 CST 基因的上调创造了一个有利于端粒延长的环境，为局限性 PC 细胞向疾病更具侵袭性阶段进展提供了选择性优势。
