SARI抑制上皮间质转化及肺腺癌转移的作用及机制研究
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摘要
目前肺癌已成为癌症死亡的主要原因,在许多地区其发病率、死亡率都上升为恶性肿瘤的首位。其原因除了肺癌的生物学特性十分复杂,恶性程度较高外,更重要的是肺癌患者在临床诊断时已发生了局部或广泛的转移,肺癌发生、转移机制及相应的治疗研究是现代肿瘤研究的一个重要方向。近年来肺腺癌在肺癌中所占比例明显增加,成为最常见的组织学类型之一,且肺腺癌容易发生转移。
上皮细胞间质转化(epithelial-mesenchyma transition, EMT)是以上皮细胞极性丧失及间质细胞特性获得为主要特征,存在于人体多个的生理病理过程中。EMT是上皮细胞来源肿瘤局部浸润和远处转移的一个重要途径,并且在其间扮演重要角色。目前,EMT在肿瘤转移中的作用成为研究热点,其发生及调控机制对于寻找恶性肿瘤浸润转移的靶点,进行临床干预有重要意义。
激活蛋白-1抑制因子(SARI,受干扰素调节),是一种以亮氨酸拉链为基本结构,且含有I型干扰素诱导结构的早期反应基因,可以发挥选择性癌细胞生长抑制作用,常可在特定的正常细胞检测出表达,包括黑色素细胞,神经节细胞,胰腺间质细胞,乳腺及前列腺上皮细胞,但在其对应的上皮恶性肿瘤中而未见表达,所以通常认为SARI可作为一种肿瘤抑制基因。
SARI在肺腺癌中的表达情况尚未见报道,本论文将通过3部分对SARI介导肺腺癌细胞EMT现象及在肺腺癌进展转移的过程中发挥的作用及机制加以阐述：
第一部分探究了肺腺癌患者中SARI表达与EMT标志物的关系,我们按照术前PET-CT结果,将有淋巴结转移和无淋巴结转移的患者分别入组。根据术后肺癌TNM分期系统,共筛选了6例Ⅰ期腺癌患者,及7例Ⅲ期患者,采用常规H&E染色对有淋巴结转移的和无淋巴结转移组的肺腺癌标本及转移淋巴结病灶进行观察,发现原发病灶与转移灶癌细胞类型一致。与非转移组比较,在有淋巴结转移的肺腺癌患者中,可见SARI高表达及E-cadherin的缺失,却见vimentin、 P-GSK-3β及β-catenin表达增强。在所有被检验标本中,SARI和E-cadherin之间有显著的相关性(r=0.8390),而SARI和vimentin之间却是具有明显负相关(r=0.7255)。
第二部分进一步探讨了SARI体外调节EMT的效应及其机制,我们在一系列肺腺癌细胞系检测了SARI的表达,发现在NCI-1650、NCI-H1299及CRL5908中SARI是高表达的；在NCI-H1975、 Calu-3及A549中相对较低表达；而在GLC-82、PG49及HTB-55中几乎不表达,当转染SARI至GLC-82及PG49细胞时,细胞形态发生改变,由长锤形的纤维细胞样的间质型(控制组)转化成卵石状上皮表型(实验组),相邻细胞间连接变得紧密,细胞极性也增强。在GLC-82及PG49细胞,SARI表达的效应是增强E-cadherin及降低vimentin的表达。相反,当内源性的SARI基因被敲除后,以肺腺癌NCI-H1650和NCI-H1299为例,二者可被检测到EMT的过程,细胞形态和生物标记物发生改变。
为理解SARI调节EMT的可能机制,我们检测了SARI在GSK-3β-catenin信号通路中的效应。通过siRNA,使SARI基因表达下调,我们观察到胞浆内β-catenin的积聚及向胞核内的易位,同时连于胞膜的β-catenin表达也下降,此外,当转染SARI至GLC-82时,基于免疫沉淀实验,GSK-3p与SARI密切联系。由于SARI不是磷酸化酶,SARI激活GSK-3β的机制可能是由一个独立的磷酸化酶介导并与该复合物密切联系。而且基于Ser9(S9,负性调节部位)的磷酸化作用,GSK-3β水平显著升高及β-catenin/TCF转录活性(TOP/FOP)下降,同样的,通过瞬时转染SARI-siRNA至NCI-H1650细胞下调SARI的表达可以提高GSK-3p磷酸化作用(S9)及β-catenin/TCF转录活性,经Wnt培养液处理后,效果更加明显。因此,SARI通过减少S9的磷酸化作用来激活GSK-3β,从而调节GSK-3β-catenin信号。虽然Wnt仅轻微引发NCI-H1650细胞的EMT,但是当采用SARI-siRNA对细胞内SARI基因进行敲除后,EMT标记物显著增加。反之,恢复SARI在GLC-82细胞(不表达SARI)中的表达,可防止Wnt诱导的EMT。这表明SARI是Wnt介导的EMT的拮抗剂。由于SARI能激活GSK-3β活性,从而降解胞浆β-catenin及降低胞核β-catenin转录活性,但是对于过表达的β-catenin是否能逆转SARI的抑制作用却是未知的,我们在这方面做了检测。在转染SARI的细胞里,逐渐提高β-catenin cDNA剂量可提高β-catenin转录活性,恢复EMT的标记物,及改变细胞形态。相似的,在敲除SARI的NCI-H1650细胞里,过表达的β-catenin及过活跃的β-catenin转录可诱发EMT,呈现出剂量依赖性,细胞形态也发生了改变。
第三部分通过原位动物模型,我们比较了敲除SARI基因的NCI-H1650及对照组细胞的转移潜质。在接种细胞前,测量并保证每个亚组里的萤光酶活性一致。采用生物发光成像技术(BLI)监测肿瘤的生长及转移的始动。一周后,BLI检测到在接种NCI-H1650-KD细胞的小鼠体内不同部位有明显的肿瘤转移损害,相反,对照组小鼠5周后仅见原发部位有肿物,并未见转移征象。免疫组织化学染色显示大部分的肿瘤细胞强烈表达vimentin,但却弱表达E-cadherin和细胞角蛋白。以上实验数据为SARI体内抑制肺腺癌转移提供强有力的证据。
结论：
SARI蛋白的表达在有淋巴结转移的和无淋巴结转移的原发肺腺癌标本出现表达差异,在有淋巴结转移的肺腺癌组织中明显下调,却见vimentin、p-GSK-3β及β-catenin等EMT密切相关指标表达增强,在肺腺癌进展过程中SARI基因介导的EMT发挥了关键作用。其机制可能为SARI拮抗Wnt信号通路介导的EMT过程,由于SARI能激活GSK-3p活性,从而降解胞浆β-catenin及降低胞核β-catenin转录活性,从而发挥拮抗作用,同样,过表达的β-catenin是能逆转SARI的抑制作用,进一步体内证实SARI可以进一步抑制腺癌细胞的转移,为SARI体内抑制肺腺癌转移提供强有力的证据。SARI可以通过拮抗Wnt信号通路介导的EMT过程,发挥抑制肺腺癌进展及转移的作用,为进一步认识肺腺癌的分子病理机制及新一类的靶向治疗提供实验依据。
Lung cancer is the leading cancer all over the world, and lung adenocarcinoma is the most common kind of lung cancer. In the absence of metastasis, lung adenocarcinoma is largely a treatable disease. Thus, early diagnosis of patients who develop lung adenocarcinoma metastasis could reduce the mortality and morbidity associated with this disease. The development of metastasis depends on the migration and invasion of cancer cells from the primary tumor into the surrounding tissues. To acquire such invasive abilities, carcinoma cells may acquire unique phenotypic changes such as epithelial-mesenchymal transition (EMT). EMT is a highly conserved cellular process that allows polarized, generally immotile epithelial cells to convert to motile mesenchymal-appearing cells. This process was initially recognized during several critical stages of embryonic development and has more recently been implicated in promoting carcinoma invasion and metastasis. During EMT,3major changes occur:(i) morphological changes from a cobblestone-like monolayer of epithelial cells to dispersed, spindle-shaped mesenchymal cells with migratory protrusions;(ii) changes in the differentiation markers from cell-cell junction proteins and cytokeratin intermediate filaments to vimentin filaments and fibronectin; and (iii) acquisition of invasiveness through the extracellular matrix. Decreased E-cadherin expression or gain of vimentin expression is closely correlated with various indices of lung adenocarcinoma progression, including the grade, local invasiveness, dissemination into blood, and tumor relapse after radiotherapy.
SARI, also known as suppressor of AP-1, is regulated by IFN and has been implicated in cell-growth inhibition and apoptosis. SARI is down-regulated in various types of human cancers and plays an important role in tumor development.
Thus, it is very likely that SARI functions as a tumor suppressor in cancer development; however, its role and mechanism in lung adenocarcinoma metastasis is largely unknown. In the current study, we have shown that loss of SARI facilitates EMT, leading to lung adenocarcinoma metastasis:
The first part explores the SARI and EMT markers expression in lung adenocarcinoma patients. In accordance with the preoperative PET-CT results, we will have lymph node metastasis and non-lymph node metastasis groups. According to postoperative lung cancer TNM staging system,6cases of stage I patients with adenocarcinoma, and7cases of stage III patients were screened using the conventional H&E staining of lymph node metastasis and lymph node metastasis of lung adenocarcinoma specimens and metastatic lymph node lesions. We found that the primary lesions and metastases of the cancer are the same cells type. Compared with the non-metastasis group, lymph node metastasis of lung adenocarcinoma patients were showing that SARI was high expression but E-cadherin missing.We also find positive for vimentin, p-GSK-3β and (3-catenin, increased expression. In all test specimens, a significant correlation (r=0.8390) between SARI and E-cadherin, and SARI and vimentin has a significant negative correlation (r=0.7255).
The second part to further explore the effect and mechanism of regulation of EMT by SARI in vitro.SARI expression is detected in a series of lung adenocarcinoma cell line, found a high-expression in the NCI-1650, NCI-of H1299and CRL5908SARI; in NCI-H1975, Calu-3and A549, are the relatively low expression; GLC-82, PG49and HTB-55, are almost no expression. When transfected SARI to GLC-82and PG49cells, cell morphology changed from long hammer-shaped fibroblast-like mesenchymal type (control group) into a pebble-like epithelial phenotype (experimental group), the connection between adjacent cells become closer, and also enhances cell polarity. GLC-82and PG49cells, effect of SARI expression is to enhance the E-cadherin and reduce expression of vimentin. Conversely, when endogenous SARI gene knockout, lung adenocarcinoma cell lines NCI-H1650and NCI-of H1299, for example, both can be detected the process of EMT, changed cell morphology and biomarkers.
For understanding the possible mechanisms SARI adjustment EMT, we examined the effect of SARI in GSK-3β-β-catenin signaling pathway. SARI gene downregulated by siRNA, and we observed in the cytoplasm of (3-catenin accumulation and translocation to the nucleus, which attached to the membrane of (3-catenin,which expression was also decreased when transfected SARI to GLC-82. Based on immunoprecipitation experiments, GSK-3β and SARI are in close contaction. The mechanism may be due to the SARI is not a phosphorylase, so SARI activation of GSK-3β is mediated by an independent phosphorylase that is in close contact with the compound. And based on Ser9(S9, a negative regulator of the site) phosphorylation of GSK-3β level was significantly increased but β-catenin/TCF transcriptional activity (TOP/FOP) decreased. Similarly, by transient transfection SARI-siRNA to NCI-H1650cells, SARI expression can increase GSK-3β phosphorylation (S9) and β-catenin/TCF transcriptional activity by Wnt medium processing, the effect is much more pronounced. Therefore, SARI is used to activate the by S9reduction phosphate into GSK-3β, thereby regulating GSK-3β-β-catenin signal. Although Wnt was only a slight to the EMT in the NCI-H1650cells, but SARI-siRNA knockout of EMT markers increased significantly. Conversely, the restoration of the SARI expression in GLC-82cells was to prevent Wnt-induced EMT. This indicates that the SARI is the antagonist of the Wnt-mediated EMT. SARI can activate GSK-3β activity and thus degradation of cytoplasmic P-catenin and reduce the nucleus of P-catenin transcriptional activity, but overexpression of P-catenin can reverse SARI inhibition is unknown, in this regard to do the testing. In cells transfected with SARI, a gradual increasing of β-catenin cDNA dose increase beta-catenin transcriptional activity, restore the EMT markers and changes in cell morphology. Similar in the knockout the SARI NCI-H1650cells, overexpression of P-catenin and active beta-catenin transcription can be induced by the EMT, showing a dose-dependent, and cell morphology changed.
The third part in situ animal models, we compare the knockout the SARI genes in the NCI-H1650cells and the control group transfer potential in situ animal models,. Before the inoculated cells, we must make sure that the fluorescence activity in each subgroup was consistent. Using bioluminescence imaging (BLI), we monitor tumor growth and metastasis initiating. A week later, the BLI detected in different parts of the mice inoculated with NCI-H1650cells-the KD obvious tumor metastasis damage. On the contrary, the control mice only can see the original tumor site and no transfer of signs after5weeks. The immunohistochemical staining revealed that most of the tumor cells strongly positive for vimentin, but weak expression of E-cadherin and cytokeratin. The above experimental data provide strong evidence that SARI in vivo inhibition of lung adenocarcinoma metastasis. Conclusion:
This study delineates the functional role of SARI in EMT, which also explains how loss of SARI in lung adenocarcinoma underlines the onset of aggressive metastatic lung adenocarcinoma. We believe that the assessment of SARI expression in lung adenocarcinoma specimens can be a valuable prognostic biomarker for the risk of lung adenocarcinoma metastasis, and that the delineation of SARI function could provide a potential intervention strategy for lung adenocarcinoma metastasis.
上皮细胞间质转化(epithelial-mesenchyma transition, EMT)是以上皮细胞极性丧失及间质细胞特性获得为主要特征,存在于人体多个的生理病理过程中。EMT是上皮细胞来源肿瘤局部浸润和远处转移的一个重要途径,并且在其间扮演重要角色。目前,EMT在肿瘤转移中的作用成为研究热点,其发生及调控机制对于寻找恶性肿瘤浸润转移的靶点,进行临床干预有重要意义。
激活蛋白-1抑制因子(SARI,受干扰素调节),是一种以亮氨酸拉链为基本结构,且含有I型干扰素诱导结构的早期反应基因,可以发挥选择性癌细胞生长抑制作用,常可在特定的正常细胞检测出表达,包括黑色素细胞,神经节细胞,胰腺间质细胞,乳腺及前列腺上皮细胞,但在其对应的上皮恶性肿瘤中而未见表达,所以通常认为SARI可作为一种肿瘤抑制基因。
SARI在肺腺癌中的表达情况尚未见报道,本论文将通过3部分对SARI介导肺腺癌细胞EMT现象及在肺腺癌进展转移的过程中发挥的作用及机制加以阐述：
第一部分探究了肺腺癌患者中SARI表达与EMT标志物的关系,我们按照术前PET-CT结果,将有淋巴结转移和无淋巴结转移的患者分别入组。根据术后肺癌TNM分期系统,共筛选了6例Ⅰ期腺癌患者,及7例Ⅲ期患者,采用常规H&E染色对有淋巴结转移的和无淋巴结转移组的肺腺癌标本及转移淋巴结病灶进行观察,发现原发病灶与转移灶癌细胞类型一致。与非转移组比较,在有淋巴结转移的肺腺癌患者中,可见SARI高表达及E-cadherin的缺失,却见vimentin、 P-GSK-3β及β-catenin表达增强。在所有被检验标本中,SARI和E-cadherin之间有显著的相关性(r=0.8390),而SARI和vimentin之间却是具有明显负相关(r=0.7255)。
第二部分进一步探讨了SARI体外调节EMT的效应及其机制,我们在一系列肺腺癌细胞系检测了SARI的表达,发现在NCI-1650、NCI-H1299及CRL5908中SARI是高表达的；在NCI-H1975、 Calu-3及A549中相对较低表达；而在GLC-82、PG49及HTB-55中几乎不表达,当转染SARI至GLC-82及PG49细胞时,细胞形态发生改变,由长锤形的纤维细胞样的间质型(控制组)转化成卵石状上皮表型(实验组),相邻细胞间连接变得紧密,细胞极性也增强。在GLC-82及PG49细胞,SARI表达的效应是增强E-cadherin及降低vimentin的表达。相反,当内源性的SARI基因被敲除后,以肺腺癌NCI-H1650和NCI-H1299为例,二者可被检测到EMT的过程,细胞形态和生物标记物发生改变。
为理解SARI调节EMT的可能机制,我们检测了SARI在GSK-3β-catenin信号通路中的效应。通过siRNA,使SARI基因表达下调,我们观察到胞浆内β-catenin的积聚及向胞核内的易位,同时连于胞膜的β-catenin表达也下降,此外,当转染SARI至GLC-82时,基于免疫沉淀实验,GSK-3p与SARI密切联系。由于SARI不是磷酸化酶,SARI激活GSK-3β的机制可能是由一个独立的磷酸化酶介导并与该复合物密切联系。而且基于Ser9(S9,负性调节部位)的磷酸化作用,GSK-3β水平显著升高及β-catenin/TCF转录活性(TOP/FOP)下降,同样的,通过瞬时转染SARI-siRNA至NCI-H1650细胞下调SARI的表达可以提高GSK-3p磷酸化作用(S9)及β-catenin/TCF转录活性,经Wnt培养液处理后,效果更加明显。因此,SARI通过减少S9的磷酸化作用来激活GSK-3β,从而调节GSK-3β-catenin信号。虽然Wnt仅轻微引发NCI-H1650细胞的EMT,但是当采用SARI-siRNA对细胞内SARI基因进行敲除后,EMT标记物显著增加。反之,恢复SARI在GLC-82细胞(不表达SARI)中的表达,可防止Wnt诱导的EMT。这表明SARI是Wnt介导的EMT的拮抗剂。由于SARI能激活GSK-3β活性,从而降解胞浆β-catenin及降低胞核β-catenin转录活性,但是对于过表达的β-catenin是否能逆转SARI的抑制作用却是未知的,我们在这方面做了检测。在转染SARI的细胞里,逐渐提高β-catenin cDNA剂量可提高β-catenin转录活性,恢复EMT的标记物,及改变细胞形态。相似的,在敲除SARI的NCI-H1650细胞里,过表达的β-catenin及过活跃的β-catenin转录可诱发EMT,呈现出剂量依赖性,细胞形态也发生了改变。
第三部分通过原位动物模型,我们比较了敲除SARI基因的NCI-H1650及对照组细胞的转移潜质。在接种细胞前,测量并保证每个亚组里的萤光酶活性一致。采用生物发光成像技术(BLI)监测肿瘤的生长及转移的始动。一周后,BLI检测到在接种NCI-H1650-KD细胞的小鼠体内不同部位有明显的肿瘤转移损害,相反,对照组小鼠5周后仅见原发部位有肿物,并未见转移征象。免疫组织化学染色显示大部分的肿瘤细胞强烈表达vimentin,但却弱表达E-cadherin和细胞角蛋白。以上实验数据为SARI体内抑制肺腺癌转移提供强有力的证据。
结论：
SARI蛋白的表达在有淋巴结转移的和无淋巴结转移的原发肺腺癌标本出现表达差异,在有淋巴结转移的肺腺癌组织中明显下调,却见vimentin、p-GSK-3β及β-catenin等EMT密切相关指标表达增强,在肺腺癌进展过程中SARI基因介导的EMT发挥了关键作用。其机制可能为SARI拮抗Wnt信号通路介导的EMT过程,由于SARI能激活GSK-3p活性,从而降解胞浆β-catenin及降低胞核β-catenin转录活性,从而发挥拮抗作用,同样,过表达的β-catenin是能逆转SARI的抑制作用,进一步体内证实SARI可以进一步抑制腺癌细胞的转移,为SARI体内抑制肺腺癌转移提供强有力的证据。SARI可以通过拮抗Wnt信号通路介导的EMT过程,发挥抑制肺腺癌进展及转移的作用,为进一步认识肺腺癌的分子病理机制及新一类的靶向治疗提供实验依据。
Lung cancer is the leading cancer all over the world, and lung adenocarcinoma is the most common kind of lung cancer. In the absence of metastasis, lung adenocarcinoma is largely a treatable disease. Thus, early diagnosis of patients who develop lung adenocarcinoma metastasis could reduce the mortality and morbidity associated with this disease. The development of metastasis depends on the migration and invasion of cancer cells from the primary tumor into the surrounding tissues. To acquire such invasive abilities, carcinoma cells may acquire unique phenotypic changes such as epithelial-mesenchymal transition (EMT). EMT is a highly conserved cellular process that allows polarized, generally immotile epithelial cells to convert to motile mesenchymal-appearing cells. This process was initially recognized during several critical stages of embryonic development and has more recently been implicated in promoting carcinoma invasion and metastasis. During EMT,3major changes occur:(i) morphological changes from a cobblestone-like monolayer of epithelial cells to dispersed, spindle-shaped mesenchymal cells with migratory protrusions;(ii) changes in the differentiation markers from cell-cell junction proteins and cytokeratin intermediate filaments to vimentin filaments and fibronectin; and (iii) acquisition of invasiveness through the extracellular matrix. Decreased E-cadherin expression or gain of vimentin expression is closely correlated with various indices of lung adenocarcinoma progression, including the grade, local invasiveness, dissemination into blood, and tumor relapse after radiotherapy.
SARI, also known as suppressor of AP-1, is regulated by IFN and has been implicated in cell-growth inhibition and apoptosis. SARI is down-regulated in various types of human cancers and plays an important role in tumor development.
Thus, it is very likely that SARI functions as a tumor suppressor in cancer development; however, its role and mechanism in lung adenocarcinoma metastasis is largely unknown. In the current study, we have shown that loss of SARI facilitates EMT, leading to lung adenocarcinoma metastasis:
The first part explores the SARI and EMT markers expression in lung adenocarcinoma patients. In accordance with the preoperative PET-CT results, we will have lymph node metastasis and non-lymph node metastasis groups. According to postoperative lung cancer TNM staging system,6cases of stage I patients with adenocarcinoma, and7cases of stage III patients were screened using the conventional H&E staining of lymph node metastasis and lymph node metastasis of lung adenocarcinoma specimens and metastatic lymph node lesions. We found that the primary lesions and metastases of the cancer are the same cells type. Compared with the non-metastasis group, lymph node metastasis of lung adenocarcinoma patients were showing that SARI was high expression but E-cadherin missing.We also find positive for vimentin, p-GSK-3β and (3-catenin, increased expression. In all test specimens, a significant correlation (r=0.8390) between SARI and E-cadherin, and SARI and vimentin has a significant negative correlation (r=0.7255).
The second part to further explore the effect and mechanism of regulation of EMT by SARI in vitro.SARI expression is detected in a series of lung adenocarcinoma cell line, found a high-expression in the NCI-1650, NCI-of H1299and CRL5908SARI; in NCI-H1975, Calu-3and A549, are the relatively low expression; GLC-82, PG49and HTB-55, are almost no expression. When transfected SARI to GLC-82and PG49cells, cell morphology changed from long hammer-shaped fibroblast-like mesenchymal type (control group) into a pebble-like epithelial phenotype (experimental group), the connection between adjacent cells become closer, and also enhances cell polarity. GLC-82and PG49cells, effect of SARI expression is to enhance the E-cadherin and reduce expression of vimentin. Conversely, when endogenous SARI gene knockout, lung adenocarcinoma cell lines NCI-H1650and NCI-of H1299, for example, both can be detected the process of EMT, changed cell morphology and biomarkers.
For understanding the possible mechanisms SARI adjustment EMT, we examined the effect of SARI in GSK-3β-β-catenin signaling pathway. SARI gene downregulated by siRNA, and we observed in the cytoplasm of (3-catenin accumulation and translocation to the nucleus, which attached to the membrane of (3-catenin,which expression was also decreased when transfected SARI to GLC-82. Based on immunoprecipitation experiments, GSK-3β and SARI are in close contaction. The mechanism may be due to the SARI is not a phosphorylase, so SARI activation of GSK-3β is mediated by an independent phosphorylase that is in close contact with the compound. And based on Ser9(S9, a negative regulator of the site) phosphorylation of GSK-3β level was significantly increased but β-catenin/TCF transcriptional activity (TOP/FOP) decreased. Similarly, by transient transfection SARI-siRNA to NCI-H1650cells, SARI expression can increase GSK-3β phosphorylation (S9) and β-catenin/TCF transcriptional activity by Wnt medium processing, the effect is much more pronounced. Therefore, SARI is used to activate the by S9reduction phosphate into GSK-3β, thereby regulating GSK-3β-β-catenin signal. Although Wnt was only a slight to the EMT in the NCI-H1650cells, but SARI-siRNA knockout of EMT markers increased significantly. Conversely, the restoration of the SARI expression in GLC-82cells was to prevent Wnt-induced EMT. This indicates that the SARI is the antagonist of the Wnt-mediated EMT. SARI can activate GSK-3β activity and thus degradation of cytoplasmic P-catenin and reduce the nucleus of P-catenin transcriptional activity, but overexpression of P-catenin can reverse SARI inhibition is unknown, in this regard to do the testing. In cells transfected with SARI, a gradual increasing of β-catenin cDNA dose increase beta-catenin transcriptional activity, restore the EMT markers and changes in cell morphology. Similar in the knockout the SARI NCI-H1650cells, overexpression of P-catenin and active beta-catenin transcription can be induced by the EMT, showing a dose-dependent, and cell morphology changed.
The third part in situ animal models, we compare the knockout the SARI genes in the NCI-H1650cells and the control group transfer potential in situ animal models,. Before the inoculated cells, we must make sure that the fluorescence activity in each subgroup was consistent. Using bioluminescence imaging (BLI), we monitor tumor growth and metastasis initiating. A week later, the BLI detected in different parts of the mice inoculated with NCI-H1650cells-the KD obvious tumor metastasis damage. On the contrary, the control mice only can see the original tumor site and no transfer of signs after5weeks. The immunohistochemical staining revealed that most of the tumor cells strongly positive for vimentin, but weak expression of E-cadherin and cytokeratin. The above experimental data provide strong evidence that SARI in vivo inhibition of lung adenocarcinoma metastasis. Conclusion:
This study delineates the functional role of SARI in EMT, which also explains how loss of SARI in lung adenocarcinoma underlines the onset of aggressive metastatic lung adenocarcinoma. We believe that the assessment of SARI expression in lung adenocarcinoma specimens can be a valuable prognostic biomarker for the risk of lung adenocarcinoma metastasis, and that the delineation of SARI function could provide a potential intervention strategy for lung adenocarcinoma metastasis.
引文
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