Human artificial chromosome carrying 3p21.3-p22.2 region suppresses hTERT transcription in oral cancer cells.

IF 2.4 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Takahito Ohira, Kaho Yoshimura, Hiroyuki Kugoh
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Abstract

Telomerase is a ribonucleoprotein ribonucleic enzyme that elongates telomere repeat sequences at the ends of chromosomes and contributes to cellular immortalization. The catalytic component of telomerase, human telomerase reverse transcriptase (hTERT), has been observed to be reactivated in immortalized cells. Notably, most cancer cells have been found to have active hTERT mRNA transcription, resulting in continuous cell division, which is crucial for malignant transformation. Therefore, discovering mechanisms underlying the regulation of hTERT transcription is an attractive target for cancer-specific treatments.Loss of heterozygosity (LOH) of chromosome 3p21.3 has been frequently observed in human oral squamous cell carcinoma (OSCC). Moreover, we previously reported that HSC3 OSCC microcell hybrid clones with an introduced human chromosome 3 (HSC3#3) showed inhibition of hTERT transcription compared with the parental HSC3 cells. This study examined whether hTERT transcription regulators are present in the 3p21.3 region. We constructed a human artificial chromosome (HAC) vector (3p21.3-HAC) with only the 3p21.3-p22.2 region and performed functional analysis using the 3p21.3-HAC. HSC3 microcell hybrid clones with an introduced 3p21.3-HAC exhibited significant suppression of hTERT transcription, similar to the microcell hybrid clones with an intact chromosome 3. In contrast, HSC3 clones with truncated chromosome 3 with deletion of the 3p21.3 region (3delp21.3) showed no effect on hTERT expression levels. These results provide direct evidence that hTERT suppressor gene(s) were retained in the 3p21.3 region, suggesting that the presence of regulatory factors that control telomerase enzyme activity may be involved in the development of OSCC.

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Abstract Image

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携带 3p21.3-p22.2 区域的人类人工染色体可抑制口腔癌细胞中 hTERT 的转录。
端粒酶是一种核糖核蛋白核糖核酶,能延长染色体末端的端粒重复序列,促进细胞永生。据观察,端粒酶的催化成分--人类端粒酶逆转录酶(hTERT)在永生化细胞中被重新激活。值得注意的是,已发现大多数癌细胞的 hTERT mRNA 转录活跃,导致细胞持续分裂,这对恶性转化至关重要。因此,发现 hTERT 转录的调控机制是癌症特异性治疗的一个有吸引力的目标。在人类口腔鳞状细胞癌(OSCC)中经常观察到染色体 3p21.3 的杂合性缺失(LOH)。此外,我们以前还报道过,与亲代HSC3细胞相比,带有引入的人类3号染色体(HSC3#3)的HSC3 OSCC微细胞杂交克隆显示出抑制hTERT转录的作用。本研究考察了 3p21.3 区域是否存在 hTERT 转录调控因子。我们构建了一个仅包含 3p21.3-p22.2 区域的人类人工染色体(HAC)载体(3p21.3-HAC),并利用 3p21.3-HAC 进行了功能分析。导入了3p21.3-HAC的HSC3微细胞杂交克隆表现出明显的hTERT转录抑制作用,这与带有完整3号染色体的微细胞杂交克隆相似。与此相反,带有3p21.3区域缺失的截短3号染色体(3delp21.3)的HSC3克隆对hTERT表达水平没有影响。这些结果提供了在3p21.3区域保留hTERT抑制基因的直接证据,表明控制端粒酶活性的调节因子的存在可能与OSCC的发生有关。
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来源期刊
Chromosome Research
Chromosome Research 生物-生化与分子生物学
CiteScore
4.70
自引率
3.80%
发文量
31
审稿时长
1 months
期刊介绍: Chromosome Research publishes manuscripts from work based on all organisms and encourages submissions in the following areas including, but not limited, to: · Chromosomes and their linkage to diseases; · Chromosome organization within the nucleus; · Chromatin biology (transcription, non-coding RNA, etc); · Chromosome structure, function and mechanics; · Chromosome and DNA repair; · Epigenetic chromosomal functions (centromeres, telomeres, replication, imprinting, dosage compensation, sex determination, chromosome remodeling); · Architectural/epigenomic organization of the genome; · Functional annotation of the genome; · Functional and comparative genomics in plants and animals; · Karyology studies that help resolve difficult taxonomic problems or that provide clues to fundamental mechanisms of genome and karyotype evolution in plants and animals; · Mitosis and Meiosis; · Cancer cytogenomics.
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