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目前,不断有证据证明肿瘤源自组织成体干细胞或其祖细胞的恶性转化,这些转化的干(祖)细胞称为肿瘤起始细胞(tumor-initiating cells)或肿瘤干细胞(cancer stem cells,CSC)。但肺癌CSC细胞的起源尚不清楚。该实验室曾报道人体肺腺癌中存在一类表达OCT4(octamer-binding transcription factor 4)的细支气管肺泡干细胞(bronchioalveolar stem cell,BASC)样CSC。该研究采用RNA干扰技术灭活了此类癌细胞中的锌指蛋白转录因子编码基因多形腺瘤样基因2(pleiomorphic adenoma gene-like 2,PLAGL2),证明该基因表达沉默驱使肺腺癌CSC分化形成了I型肺泡细胞(alveolartype 1 cells,AT1)样细胞并失去致瘤能力。借助基因芯片筛查技术平台,发现肺腺癌CSC具有与人体肺脏未分化干细胞和肺泡祖细胞相似的分子表型,提示此类肺干(祖)细胞可能是肺腺癌潜在的细胞起源。此外,该研究结果还揭示肺腺癌CSC的分化受TTF-1(甲状腺转录因子-1)和PLAGL2的双重调控,通过基因操作以及药理性诱导可以驱使此类癌细胞分化。这些结果为针对肺癌CSC的靶向治疗提供了新的思路。
Currently, there is constant evidence that tumors originate from the malignant transformation of tissue-derived adult stem cells or their progenitor cells. These transformed stem (progenitor) cells are called tumor-initiating cells or cancer stem cells (CSCs) . However, the origin of lung cancer CSC cells is not clear. The laboratory has reported the presence of a class of bronchioalveolar stem cell (BASC) -like CSCs that express octamer-binding transcription factor 4 (OCT4) in human lung adenocarcinomas. This study used RNA interference technology to inactivate the pleiomorphic adenoma gene-like 2 (PLAGL2) encoding zinc finger protein transcription factor in these cancer cells, and proved that the gene silencing drives lung adenocarcinoma CSC Differentiation formed alveolar type 1 cells (AT1) -like cells and lost tumorigenicity. Using gene chip screening technology platform, it was found that lung adenocarcinoma CSC has similar molecular phenotype to human lung undifferentiated stem cells and alveolar progenitor cells, suggesting that such lung stem (progenitor) cells may be potential cellular origins of lung adenocarcinoma. In addition, the results of this study also revealed that the differentiation of CSC from lung adenocarcinoma is double regulated by TTF-1 (thyroid transcription factor-1) and PLAGL2, and such cancer cells can be driven to differentiate by genetic manipulation and pharmacological induction. These results provide a new idea for the targeted therapy of CSC in lung cancer.