转录因子KLF4及DEC1诱导的细胞衰老在肿瘤中作用及机制研究
摘要
细胞衰老是指细胞在一定刺激条件下不可逆地丧失增殖能力后进入的一种相对稳定的状态。通常认为,细胞衰老在体内外发挥了阻止肿瘤发生发展的作用,但这个过程中的具体调控机制及对肿瘤的影响还有很多未知之处。转录因子在细胞的各种生命活动调控中发挥了核心作用,对细胞衰老和肿瘤同时起到了调控作用,本项目主要研究转录因子KLF4及DEC1诱导的细胞衰老在肿瘤中的作用及机制。
KLF4(Kruppel-like factor4)又称GKLF,定位于人染色体9q31,是KLF转录因子家族中一个重要的成员,与细胞增殖调控、介导细胞分化和细胞凋亡有关。KLF4作为转录因子激活或抑制多个基因的表达,参与细胞增殖调控、介导细胞分化和细胞凋亡等。KLF4在大多数肿瘤中被认为是抑癌基因,但在某些肿瘤(如乳癌)中则具有癌基因特性。在诱导多能干细胞的过程中,过表达KLF4可以诱导细胞衰老发生,但KLF4是否可以诱导肿瘤细胞衰老,KLF4诱导细胞衰老的机制及在肿瘤发生发展中的作用尚未见报道。
我们首先发现在多个肿瘤细胞系中,瞬时表达KLF4可以诱导细胞衰老的发生；随后,我们构建了KLF4可诱导表达细胞系,T-REx-293KLF4及T-REx-HeLa KLF4,发现诱导表达KLF4同样可以促进细胞衰老的发生；为了明确KLF4诱导衰老的机制,我们首先检测了一些与KLF4或细胞衰老相关的分子表达,发现了如p21、cyclin E1、E-cadherin、Survivin等蛋白表达变化；通过抑制实验证明KLF4主要通过诱导p21表达引起细胞衰老,KLF4抑制Survivin表达可间接影响p21而影响细胞衰老发生；此外,我们还利用miRNA芯片发现了一系列有可能被KLF4调控并参与细胞衰老调节的niRNA,并且证明了KLF4可以直接促进miR-203表达而抑制Survivin表达,或者促进miR-200家族表达而抑制ZEB1表达,最终直接或间接参与到细胞衰老发生之中。最后,我们又通过ChIP-Sequencing、转录组芯片等方法从全基因组、转录组的角度分析了KLF4诱导的细胞衰老中细胞整体的改变,为从整体上认识细胞衰老的过程起到了提示作用。
为了探讨细胞衰老在体内外肿瘤中的作用,我们选取了另一个重要的转录因子DEC1(Differentiated embryo-chondrocyte expressed gene1)为研究对象。DEC1位于人染色体3p26,是一个含有碱性螺旋-环-螺旋(bHLH)结构的转录因子,与细胞分化、增殖、凋亡及衰老有关,并且被认为是体内细胞衰老的一个重要生物标记物之一。同KLF4一样,DEC1可以激活或抑制多个基因的表达,并在肿瘤中具有组织特异性。
我们发现,在食管癌细胞系EC9706中过表达DEC1蛋白可以诱导衰老发生,抑制细胞增殖和集落形成。在食管癌新鲜组织冰冻切片中发现DEC1高表达与细胞衰老相关。我们对241例食管鳞癌病人食管各损伤时期DEC1表达进行了免疫组织化学染色,结果提示DEC1高表达在食管癌癌前病变及食管癌中很可能与细胞衰老相关,并且是食管癌病人生存的有利因素。此外,我们还发现DEC1诱导细胞衰老的机制可能与抑制Survivin蛋白表达及促进p21蛋白表达相关,从另一个侧面重复了我们在KLF4诱导细胞衰老中的研究成果。
总之,我们的研究结果阐明了转录因子诱导和调控细胞衰老中发挥的重要作用,并证明了细胞衰老对于肿瘤的抑制作用,为研究细胞衰老的调控机制及与肿瘤的关系提供了重要信息,也为利用细胞衰老来防治肿瘤提供了新的思路。
Cellular senescence is an irreversible state of stable growth arrest triggered by multiple stimulations, and is related to cancer and many age-related diseases. It is usually considered that senescent cells permanently lose the ability of division and suppress carcinogenesis both in vivo and in vitro. Transcription factors play central roles in both cellular senescence and tumor development, but the exact mechanism is still unclear.
KLF4(Kriippel-like factor4or GKLF), an important member of KLF transcription factor family, locates at9q31, and involves in regulation of cell proliferation, differentiation, and apoptosis. As a transcription factor, KLF4can activate or repress gene expression in a cell-context dependent manner and functions as a tumor suppressor or oncogene in different kind of cancers. During the research of induced pluripotent stem (iPS) cells, it was found that overexpression of KLF4could induce cell senescence. However, the mechanisms of KLF4-induced senescence and its roles in cancer have not been reported yet.
Firstly, we observed that transient expression of KLF4could induce senescence in different kinds of tumor cell lines. Then, we constructed KLF4inducible cell lines in T-REx-293and T-REx-HeLa cells, and named as T-REx-293KLF4and T-REx-HeLa KLF4, respectively. Cellular senescence was observed, and cell proliferation was inhibited while KLF4was induced. The protein levels of cyclin E1, E-cadherin and survivin, were changed. Then we confirmed that p21induced by KLF4could promote senescence, and survivin inhibited by KLF4could indirectly induced p21and senescence. By miRNA microarray, we found a series of miRNAs regulated by KLF4and involved in senescence. We demonstrated that KLF4could upregulate miR-203which inhibited survivin expression, and KLF4could promote expression of miR-200family members which inhibited ZEB1expression. Thus, miRNAs directly or indirectly involved in senescence induced by KLF4. Also, we analyzed the transcription activity, and gene expression pattern during KLF4induced senescence by ChIP-Sequencing assay and transcriptome microarray, and found some valuable indications for understanding the whole process of senescence.
DEC1(Differentiated embryo-chondrocyte expressed gene1), locates at3p26, is a basic helix-loop-helix (bHLH) transcription factor, and related to cell differentiation, proliferation, apoptosis and senescence. DEC1is considered as one of the important senescence biomarkers in vivo. Like KLF, DEC1can also activate or repress gene expression in a cell-context dependent manner and functions as a tumor suppressor or oncogene in different kind of cancers.
When DEC1was overexpressed in ESCC cell line EC9706, senescence, as well as inhibition of both cell proliferation and colony formation was observed. We also found that strongly positive expression of DEC1was correlated to senescent cells in fresh tissue samples from patients with esophageal cancer. DEC1immunohistochemical analysis was performed in ESCC and adjacent tissues of241patients, and the result suggested that high expression of DEC1in ESCC and its precursor lesions was positively correlated with cell senescence, and was a biomarker to predict better prognosis. Besides, we found that DEC1induced survivin inhibition and p21overexpression, which might be the molecular mechanism of DEC1-induced senescence, and was similar to our results in KLF4-induced senescence.
In summary, our results elucidated the molecular mechanism of transcription factor in regulating cell senescence, and the role of senescence in cancer. This offers plausible approaches to the development of novel therapeutic strategies to inhibit tumor growth by inducing cellular senescence.
KLF4(Kruppel-like factor4)又称GKLF,定位于人染色体9q31,是KLF转录因子家族中一个重要的成员,与细胞增殖调控、介导细胞分化和细胞凋亡有关。KLF4作为转录因子激活或抑制多个基因的表达,参与细胞增殖调控、介导细胞分化和细胞凋亡等。KLF4在大多数肿瘤中被认为是抑癌基因,但在某些肿瘤(如乳癌)中则具有癌基因特性。在诱导多能干细胞的过程中,过表达KLF4可以诱导细胞衰老发生,但KLF4是否可以诱导肿瘤细胞衰老,KLF4诱导细胞衰老的机制及在肿瘤发生发展中的作用尚未见报道。
我们首先发现在多个肿瘤细胞系中,瞬时表达KLF4可以诱导细胞衰老的发生；随后,我们构建了KLF4可诱导表达细胞系,T-REx-293KLF4及T-REx-HeLa KLF4,发现诱导表达KLF4同样可以促进细胞衰老的发生；为了明确KLF4诱导衰老的机制,我们首先检测了一些与KLF4或细胞衰老相关的分子表达,发现了如p21、cyclin E1、E-cadherin、Survivin等蛋白表达变化；通过抑制实验证明KLF4主要通过诱导p21表达引起细胞衰老,KLF4抑制Survivin表达可间接影响p21而影响细胞衰老发生；此外,我们还利用miRNA芯片发现了一系列有可能被KLF4调控并参与细胞衰老调节的niRNA,并且证明了KLF4可以直接促进miR-203表达而抑制Survivin表达,或者促进miR-200家族表达而抑制ZEB1表达,最终直接或间接参与到细胞衰老发生之中。最后,我们又通过ChIP-Sequencing、转录组芯片等方法从全基因组、转录组的角度分析了KLF4诱导的细胞衰老中细胞整体的改变,为从整体上认识细胞衰老的过程起到了提示作用。
为了探讨细胞衰老在体内外肿瘤中的作用,我们选取了另一个重要的转录因子DEC1(Differentiated embryo-chondrocyte expressed gene1)为研究对象。DEC1位于人染色体3p26,是一个含有碱性螺旋-环-螺旋(bHLH)结构的转录因子,与细胞分化、增殖、凋亡及衰老有关,并且被认为是体内细胞衰老的一个重要生物标记物之一。同KLF4一样,DEC1可以激活或抑制多个基因的表达,并在肿瘤中具有组织特异性。
我们发现,在食管癌细胞系EC9706中过表达DEC1蛋白可以诱导衰老发生,抑制细胞增殖和集落形成。在食管癌新鲜组织冰冻切片中发现DEC1高表达与细胞衰老相关。我们对241例食管鳞癌病人食管各损伤时期DEC1表达进行了免疫组织化学染色,结果提示DEC1高表达在食管癌癌前病变及食管癌中很可能与细胞衰老相关,并且是食管癌病人生存的有利因素。此外,我们还发现DEC1诱导细胞衰老的机制可能与抑制Survivin蛋白表达及促进p21蛋白表达相关,从另一个侧面重复了我们在KLF4诱导细胞衰老中的研究成果。
总之,我们的研究结果阐明了转录因子诱导和调控细胞衰老中发挥的重要作用,并证明了细胞衰老对于肿瘤的抑制作用,为研究细胞衰老的调控机制及与肿瘤的关系提供了重要信息,也为利用细胞衰老来防治肿瘤提供了新的思路。
Cellular senescence is an irreversible state of stable growth arrest triggered by multiple stimulations, and is related to cancer and many age-related diseases. It is usually considered that senescent cells permanently lose the ability of division and suppress carcinogenesis both in vivo and in vitro. Transcription factors play central roles in both cellular senescence and tumor development, but the exact mechanism is still unclear.
KLF4(Kriippel-like factor4or GKLF), an important member of KLF transcription factor family, locates at9q31, and involves in regulation of cell proliferation, differentiation, and apoptosis. As a transcription factor, KLF4can activate or repress gene expression in a cell-context dependent manner and functions as a tumor suppressor or oncogene in different kind of cancers. During the research of induced pluripotent stem (iPS) cells, it was found that overexpression of KLF4could induce cell senescence. However, the mechanisms of KLF4-induced senescence and its roles in cancer have not been reported yet.
Firstly, we observed that transient expression of KLF4could induce senescence in different kinds of tumor cell lines. Then, we constructed KLF4inducible cell lines in T-REx-293and T-REx-HeLa cells, and named as T-REx-293KLF4and T-REx-HeLa KLF4, respectively. Cellular senescence was observed, and cell proliferation was inhibited while KLF4was induced. The protein levels of cyclin E1, E-cadherin and survivin, were changed. Then we confirmed that p21induced by KLF4could promote senescence, and survivin inhibited by KLF4could indirectly induced p21and senescence. By miRNA microarray, we found a series of miRNAs regulated by KLF4and involved in senescence. We demonstrated that KLF4could upregulate miR-203which inhibited survivin expression, and KLF4could promote expression of miR-200family members which inhibited ZEB1expression. Thus, miRNAs directly or indirectly involved in senescence induced by KLF4. Also, we analyzed the transcription activity, and gene expression pattern during KLF4induced senescence by ChIP-Sequencing assay and transcriptome microarray, and found some valuable indications for understanding the whole process of senescence.
DEC1(Differentiated embryo-chondrocyte expressed gene1), locates at3p26, is a basic helix-loop-helix (bHLH) transcription factor, and related to cell differentiation, proliferation, apoptosis and senescence. DEC1is considered as one of the important senescence biomarkers in vivo. Like KLF, DEC1can also activate or repress gene expression in a cell-context dependent manner and functions as a tumor suppressor or oncogene in different kind of cancers.
When DEC1was overexpressed in ESCC cell line EC9706, senescence, as well as inhibition of both cell proliferation and colony formation was observed. We also found that strongly positive expression of DEC1was correlated to senescent cells in fresh tissue samples from patients with esophageal cancer. DEC1immunohistochemical analysis was performed in ESCC and adjacent tissues of241patients, and the result suggested that high expression of DEC1in ESCC and its precursor lesions was positively correlated with cell senescence, and was a biomarker to predict better prognosis. Besides, we found that DEC1induced survivin inhibition and p21overexpression, which might be the molecular mechanism of DEC1-induced senescence, and was similar to our results in KLF4-induced senescence.
In summary, our results elucidated the molecular mechanism of transcription factor in regulating cell senescence, and the role of senescence in cancer. This offers plausible approaches to the development of novel therapeutic strategies to inhibit tumor growth by inducing cellular senescence.
引文
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