PDF(Pubmed)
Abstract：
As a major cancer hallmark, there is a sustained interest in understanding the telomerase contribution to carcinogenesis in order to therapeutically target this enzyme. This is particularly relevant in primary cutaneous T-cell lymphomas (CTCL), a malignancy showing telomerase dysregulation with few investigative data available. In CTCL, we examined the mechanisms involved in telomerase transcriptional activation and activity regulation. We analyzed 94 CTCL patients from a Franco-Portuguese cohort, as well as 8 cell lines, in comparison to 101 healthy controls. Our results showed that not only polymorphisms (SNPs) located at the promoter of human telomerase reverse transcriptase (hTERT) gene (rs2735940 and rs2853672) but also an SNP located within the coding region (rs2853676) could influence CTCL occurrence. Furthermore, our results sustained that the post-transcriptional regulation of hTERT contributes to CTCL lymphomagenesis. Indeed, CTCL cells present a different pattern of hTERT spliced transcripts distribution from the controls, mostly marked by an increase in the hTERT β+ variants proportion. This increase seems to be associated with CTCL development and progression. Through hTERT splicing transcriptome modulation with shRNAs, we observed that the decrease in the α-β+ transcript induced a decrease in the cell proliferation and tumorigenic capacities of T-MF cells in vitro. Taken together, our data highlight the major role of post-transcriptional mechanisms regulating telomerase non canonical functions in CTCL and suggest a new potential role for the α-β+ hTERT transcript variant.
摘要：
作为癌症的主要标志，人们对了解端粒酶对致癌作用的贡献有持续的兴趣，以便在治疗上靶向该酶。这在原发性皮肤T细胞淋巴瘤（CTCL）中特别相关，显示端粒酶失调的恶性肿瘤，研究数据很少。在CTCL中,我们研究了端粒酶转录激活和活性调节的机制。我们分析了来自法国-葡萄牙队列的94名CTCL患者，以及8个细胞系，与101名健康对照相比。我们的结果表明，不仅位于人端粒酶逆转录酶（hTERT）基因启动子的多态性（SNP）（rs2735940和rs2853672），而且位于编码区（rs2853676）内的SNP也可能影响CTCL的发生。此外，我们的结果认为,hTERT的转录后调控有助于CTCL淋巴生成.的确,CTCL细胞呈现与对照不同的hTERT剪接转录物分布模式，主要以hTERTβ+变体比例增加为标志。这种增加似乎与CTCL的发展和进展有关。通过shRNA的hTERT剪接转录组调节，我们观察到，在体外，α-β转录物的减少诱导了T-MF细胞的细胞增殖和致瘤能力的降低。一起来看,我们的数据强调了调节CTCL中端粒酶非规范功能的转录后机制的主要作用，并提示了α-β+hTERT转录变体的新潜在作用。
