TBX1 functions as a putative oncogene of breast cancer through promoting cell cycle progression.
TBX1 functions as a putative oncogene of breast cancer through promoting cell cycle progression.
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TBX1 通过促进细胞周期进展发挥乳腺癌假定癌基因的作用。
DOI：
10.1093/carcin/bgab111
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发表时间：
2022
期刊：
影响因子：
4.7
通讯作者：
Cai,Qiuyin
中科院分区：
文献类型：
--
作者：
Huang,Shuya;Shu,Xiang;Ping,Jie;Wu,Jie;Wang,Jifeng;Shidal,Chris;Guo,Xingyi;Bauer,JoshuaA;Long,Jirong;Shu,Xiao-Ou;Zheng,Wei;Cai,Qiuyin
我们先前在一项全基因组关联研究中发现了22q11.21位点的一种遗传变异rs34331122与乳腺癌风险相关。这种新的变体位于T-box转录因子1（TBX 1）基因的内含子区域。顺式表达数量性状位点分析表明，TBX 1基因的表达受rs34331122变异体的调控。在本研究中，我们探讨了TBX 1在乳腺癌中的生物学功能和潜在的分子机制。TBX 1在乳腺癌组织中的表达显著高于癌旁正常乳腺组织，且随肿瘤分期的增加而增加（P < 0.05）。我们进一步用小分子干扰RNA（small interfering RNA，siRNA）敲低了TBX 1基因在MDA-MB-231、MCF-7和T47 D三种乳腺癌细胞系中的表达，并检测了细胞致瘤性和基因表达的变化，结果发现TBX 1基因敲低可显著抑制乳腺癌细胞的增殖、集落形成、迁移和侵袭。RNA测序和流式细胞术分析显示，乳腺癌细胞中TBX 1的敲低通过破坏细胞周期途径中相关基因的表达而诱导细胞周期停滞在G1期。此外，使用在线Kaplan-Meier Plotter进行的生存分析表明，在乳腺癌患者中，TBX 1表达水平越高，预后越差，尤其是雌激素受体阳性的乳腺癌，总生存期（OS）和无远处转移生存期（DMFS）的HR（95%CI）分别为1.5（1.05-2.15）和1.55（1.10-2.18）。以上结果提示，TBX 1基因可能通过调控细胞周期相关基因的表达，在乳腺癌中发挥作用。
We have previously identified a genetic variant, rs34331122 in the 22q11.21 locus, as being associated with breast cancer risk in a genome-wide association study. This novel variant is located in the intronic region of the T-box transcription factor 1 (TBX1) gene. Cis-expression quantitative trait loci analysis showed that expression ofTBX1was regulated by the rs34331122 variant. In the current study, we investigated biological functions and potential molecular mechanisms ofTBX1in breast cancer. We found thatTBX1expression was significantly higher in breast cancer tumor tissues than adjacent normal breast tissues and increased with tumor stage (P < 0.05). We further knocked-downTBX1gene expression in three breast cancer cell lines, MDA-MB-231, MCF-7 and T47D, using small interfering RNAs and examined consequential changes on cell oncogenicity and gene expression.TBX1knock-down significantly inhibited breast cancer cell proliferation, colony formation, migration and invasion. RNA sequencing and flow cytometry analysis revealed thatTBX1knock-down in breast cancer cells induced cell cycle arrest in the G1 phase through disrupting expression of genes involved in the cell cycle pathway. Furthermore, survival analysis using the online Kaplan–Meier Plotter suggested that higherTBX1expression was associated with worse outcomes in breast cancer patients, especially for estrogen receptor-positive breast cancer, with HRs (95% CIs) for overall survival (OS) and distant metastasis free survival (DMFS) of 1.5 (1.05–2.15) and 1.55 (1.10–2.18), respectively. In conclusion, our results suggest that theTBX1gene may act as a putative oncogene of breast cancer through regulating expressions of cell cycle-related genes.