CTEN调节EGF诱导的乳腺癌细胞上皮间质转化
摘要
目的：
乳腺癌是一种严重危害女性健康的恶性肿瘤。上皮间质转变(Epithelial-mesenchymal transition, EMT)是指上皮细胞向间充质细胞转化的现象,EMT与肿瘤侵袭转移、耐药和肿瘤干细胞密切相关。表皮生长因子(Epidermal Growth Factor, EGF)是诱发EMT的重要细胞因子之一。
CTEN(COOH-terminus tensin-like molecule)是tensin基因家族中的一员,该家族参与细胞粘附、迁移及信号转导等。CTEN在多种恶性肿瘤中表达增高,并与肿瘤侵袭、转移及患者预后相关。有报道指出,CTEN参与结肠癌细胞EMT。
目前关于CTEN的研究报道不多,缺乏CTEN在乳腺癌的深入研究。CTEN在乳腺癌的发生、发展过程中发挥怎样的作用?在本研究中,将检测CTEN在乳腺癌组织及细胞系中的表达情况,重点探讨CTEN在外源性EGF诱导的乳腺癌细胞EMT中的调控作用,分析其调控机制。通过本研究,加深对CTEN的认识,揭示新的乳腺癌侵袭及EMT相关的分子基础和作用机制。
方法：
1.免疫组织化学法检测侵润性导管癌组织中CTEN和p-ERK1/2蛋白的表达,分析蛋白表达情况与乳腺癌临床病理特征间的关系及两种蛋白之间的关联。
2.外源性EGF刺激乳腺癌MCF-7细胞,观察细胞形态变化,Western blot法检测CTEN、E-cadherin、vimentin蛋白的变化。设计特异性CTEN-siRNA,采用脂质体法转染MCF-7乳腺癌细胞,采用实时荧光定量PCR法检测CTEN mRNA的表达,筛选并鉴定干扰效率最高的siRNA进入后续实验。
3.外源性EGF刺激乳腺癌MCF-7细胞后,siRNA转染沉默CTEN表达及使用抑制剂U0126阻断ERK信号通路,观察细胞形态变化,Western blot法检测CTEN、 E-cadherin、vimentin、ERK1/2、p-ERK1/2、Raf-1及Snail蛋白的表达情况；Transwell小室侵袭实验检测各组细胞的侵袭性。
结果：
1.在乳腺癌组织标本中,CTEN蛋白表达的阳性率是88.1%,其表达水平与乳腺癌的分化程度、淋巴结转移、临床分期、肿瘤大小、PR、N-cadherin表达有关(P＜0.05)。p-ERK1/2蛋白表达的阳性率是83.3%,其表达水平与乳腺癌的分化程度、淋巴结转移、临床分期、N-cadherin表达有关(P＜0.05)。CTEN蛋白表达强度与p-ERK1/2蛋白表达强度之间呈正相关(r=0.526,P<0.01)。
2.外源性EGF刺激乳腺癌MCF-7细胞后,观察细胞形态由上皮样向间质样改变,Western blot法检测CTEN蛋白表达上调,同时E-cadherin蛋白表达下降、vimentin蛋白表达增高。CTEN-siRNA可有效抑制CTEN mRNA表达(抑制率>90%)。
3.外源性EGF刺激乳腺癌MCF-7细胞后,CTEN-siRNA转染,发现细胞形态由间质样向上皮样转变；且CTEN蛋白、vimentin蛋白、p-ERK1/2蛋白、ERK1/2蛋白、Raf-1蛋白及Snail蛋白表达减少,E-cadherin蛋白增加；使用ERK通路特异性抑制剂U0126后,p-ERK1/2蛋白及Snail蛋白均减少,Raf-1蛋白的表达无变化；转染CTEN-siRNA可抑制EGF诱导的MCF-7细胞的侵袭细胞数增加(P<0.05)。
结论：
1.癌基因CTEN的表达与乳腺癌生物学行为密切相关,且CTEN蛋白的表达与p-ERK1/2蛋白表达呈正相关。
2.EGF可促进乳腺癌MCF-7细胞发生EMT,同时上调CTEN蛋白。
3.沉默CTEN可部分逆转EGF诱导的EMT,其机制是沉默CTEN可下调Raf-1从而阻滞Ras/Raf/MEK/ERK/Snail信号通路。
4.沉默CTEN表达可部分逆转EGF诱导的MCF-7细胞侵袭力增强。
Objective
Breast cancer is a serious malignant tumor which hazards to the health of women. Epithelial-mesenchymal transition(EMT) is a transdifferentiation of epithelial cells to mesenchymal cells. There is a closely relationship between EMT and tumors' invasion, metastasis, drug resistance and cancer stem cells. Epidermal Growth Factor (EGF) is one of the cell factors which can induce EMT.
CTEN(COOH-terminus tensin-like molecule) gene is a member of the tension genes family, which participates in cell adhesion, migration and signal transmitting. Over-expression of CTEN is associated correlated with invasion and migration of the malignant tumor and the prognosis of the patients. Researches showed that, CTEN participated in the EMT of colorectal cancer.
There are no deep investigations on CTEN and its influences on breast cancer. How does CTEN influence the generation of breast cancer? In this study, we tested the CTEN expression in breast cancer tissues and cell lines, and discussed the possible mechanism of CTEN on EMT. It will increase the recognition to CTEN and uncover new molecular mechanism of the EMT in breast cancer.
Methods
1. The expression of CTEN and p-ERK1/2was detected in invasive breast cancer by immunohistochemistry, then analysising the relationship between protein expression and clinicopathological parameters, and the association of two proteins.
2. Exogenous EGF was used to stimulate MCF-7cells, then morphological changes of cells were observed, and the expression of CTEN, E-cadherin and vimentin was detected by Western blot. The specific CTEN-small interference RNA (siRNA) was constructed and transfected into MCF-7cells using lipofectamine, the expression of CTEN mRNA was detected by real-time fluorescence quantitative PCR, finally the most efficient siRNA was screened out for the follow-up experiments.
3. EGF was used to stimulate MCF-7cells, then transfecting CTEN-siRNA and using U0126to blocking the ERK signal pathway, the morphological changes of cells were observed, and the expression of CTEN, E-cadherin, vimentin, ERK1/2, p-ERK1/2, Raf-1and Snail protein was detected by Western blot. The number of invasive cells was determined by Transwell assay.
Results
1. The positive rate of CTEN in breast cancer was88.1%, while p-ERK1/2was83.3%. CTEN and p-ERK1/2both associated with the loss of tumor differentiation, clinical stage, lymph node metastasis and N-cadherin expression (P＜0.05). There was a significant positive correlation between the expression strength of CTEN and p-ERK1/2(r=0.526, P＜0.01).
2. After EGF was used to stimulate MCF-7cells, epithelial-like to mesenchymal-like changes in cells morphology were observed, and the expression of CTEN and vimentin protein was increased, as well as E-cadherin protein was decreased. CTEN-siRNA can suppress CTEN mRNA expression effectively (inhibition＞90%).
3. EGF was used to stimulate MCF-7cells. After transfection, it was found that mesenchymal-like to epithelial-like changes in cells morphology, and the expression of CTEN, vimentin, ERK1/2, p-ERK1/2, Raf-1and Snail protein was decreased, E-cadherin protein was increased. The expression of p-ERK1/2and Snail protein was decreased, but Raf-1protein expression did not change after using U0126.After transfection, the number of invasive cells did not significantly increase even if using exogenous EGF to stimulate MCF-7cells (P＜0.05).
Conclusion
1. It suggested that the expression level of CTEN protein was closely related to biological behavior of breast cancer, and there was a significant positive correlation between the expression strength of CTEN and p-ERK1/2.
2. Exogenous EGF could promote breast cancer MCF-7cells occurring EMT, and the expression of CTEN protein was increased after occurring EMT.
3. Suppressing CTEN expression could partly inverse EMT by EGF-induced, because CTEN silencing could block activation of Ras/Raf/MEK/ERK/Snail signal pathways due to reducing Raf-1protein expression.
4. Suppressing CTEN expression could partly inverse invasive ability of MCF-7cells enhancing by EGF-induced.
乳腺癌是一种严重危害女性健康的恶性肿瘤。上皮间质转变(Epithelial-mesenchymal transition, EMT)是指上皮细胞向间充质细胞转化的现象,EMT与肿瘤侵袭转移、耐药和肿瘤干细胞密切相关。表皮生长因子(Epidermal Growth Factor, EGF)是诱发EMT的重要细胞因子之一。
CTEN(COOH-terminus tensin-like molecule)是tensin基因家族中的一员,该家族参与细胞粘附、迁移及信号转导等。CTEN在多种恶性肿瘤中表达增高,并与肿瘤侵袭、转移及患者预后相关。有报道指出,CTEN参与结肠癌细胞EMT。
目前关于CTEN的研究报道不多,缺乏CTEN在乳腺癌的深入研究。CTEN在乳腺癌的发生、发展过程中发挥怎样的作用?在本研究中,将检测CTEN在乳腺癌组织及细胞系中的表达情况,重点探讨CTEN在外源性EGF诱导的乳腺癌细胞EMT中的调控作用,分析其调控机制。通过本研究,加深对CTEN的认识,揭示新的乳腺癌侵袭及EMT相关的分子基础和作用机制。
方法：
1.免疫组织化学法检测侵润性导管癌组织中CTEN和p-ERK1/2蛋白的表达,分析蛋白表达情况与乳腺癌临床病理特征间的关系及两种蛋白之间的关联。
2.外源性EGF刺激乳腺癌MCF-7细胞,观察细胞形态变化,Western blot法检测CTEN、E-cadherin、vimentin蛋白的变化。设计特异性CTEN-siRNA,采用脂质体法转染MCF-7乳腺癌细胞,采用实时荧光定量PCR法检测CTEN mRNA的表达,筛选并鉴定干扰效率最高的siRNA进入后续实验。
3.外源性EGF刺激乳腺癌MCF-7细胞后,siRNA转染沉默CTEN表达及使用抑制剂U0126阻断ERK信号通路,观察细胞形态变化,Western blot法检测CTEN、 E-cadherin、vimentin、ERK1/2、p-ERK1/2、Raf-1及Snail蛋白的表达情况；Transwell小室侵袭实验检测各组细胞的侵袭性。
结果：
1.在乳腺癌组织标本中,CTEN蛋白表达的阳性率是88.1%,其表达水平与乳腺癌的分化程度、淋巴结转移、临床分期、肿瘤大小、PR、N-cadherin表达有关(P＜0.05)。p-ERK1/2蛋白表达的阳性率是83.3%,其表达水平与乳腺癌的分化程度、淋巴结转移、临床分期、N-cadherin表达有关(P＜0.05)。CTEN蛋白表达强度与p-ERK1/2蛋白表达强度之间呈正相关(r=0.526,P<0.01)。
2.外源性EGF刺激乳腺癌MCF-7细胞后,观察细胞形态由上皮样向间质样改变,Western blot法检测CTEN蛋白表达上调,同时E-cadherin蛋白表达下降、vimentin蛋白表达增高。CTEN-siRNA可有效抑制CTEN mRNA表达(抑制率>90%)。
3.外源性EGF刺激乳腺癌MCF-7细胞后,CTEN-siRNA转染,发现细胞形态由间质样向上皮样转变；且CTEN蛋白、vimentin蛋白、p-ERK1/2蛋白、ERK1/2蛋白、Raf-1蛋白及Snail蛋白表达减少,E-cadherin蛋白增加；使用ERK通路特异性抑制剂U0126后,p-ERK1/2蛋白及Snail蛋白均减少,Raf-1蛋白的表达无变化；转染CTEN-siRNA可抑制EGF诱导的MCF-7细胞的侵袭细胞数增加(P<0.05)。
结论：
1.癌基因CTEN的表达与乳腺癌生物学行为密切相关,且CTEN蛋白的表达与p-ERK1/2蛋白表达呈正相关。
2.EGF可促进乳腺癌MCF-7细胞发生EMT,同时上调CTEN蛋白。
3.沉默CTEN可部分逆转EGF诱导的EMT,其机制是沉默CTEN可下调Raf-1从而阻滞Ras/Raf/MEK/ERK/Snail信号通路。
4.沉默CTEN表达可部分逆转EGF诱导的MCF-7细胞侵袭力增强。
Objective
Breast cancer is a serious malignant tumor which hazards to the health of women. Epithelial-mesenchymal transition(EMT) is a transdifferentiation of epithelial cells to mesenchymal cells. There is a closely relationship between EMT and tumors' invasion, metastasis, drug resistance and cancer stem cells. Epidermal Growth Factor (EGF) is one of the cell factors which can induce EMT.
CTEN(COOH-terminus tensin-like molecule) gene is a member of the tension genes family, which participates in cell adhesion, migration and signal transmitting. Over-expression of CTEN is associated correlated with invasion and migration of the malignant tumor and the prognosis of the patients. Researches showed that, CTEN participated in the EMT of colorectal cancer.
There are no deep investigations on CTEN and its influences on breast cancer. How does CTEN influence the generation of breast cancer? In this study, we tested the CTEN expression in breast cancer tissues and cell lines, and discussed the possible mechanism of CTEN on EMT. It will increase the recognition to CTEN and uncover new molecular mechanism of the EMT in breast cancer.
Methods
1. The expression of CTEN and p-ERK1/2was detected in invasive breast cancer by immunohistochemistry, then analysising the relationship between protein expression and clinicopathological parameters, and the association of two proteins.
2. Exogenous EGF was used to stimulate MCF-7cells, then morphological changes of cells were observed, and the expression of CTEN, E-cadherin and vimentin was detected by Western blot. The specific CTEN-small interference RNA (siRNA) was constructed and transfected into MCF-7cells using lipofectamine, the expression of CTEN mRNA was detected by real-time fluorescence quantitative PCR, finally the most efficient siRNA was screened out for the follow-up experiments.
3. EGF was used to stimulate MCF-7cells, then transfecting CTEN-siRNA and using U0126to blocking the ERK signal pathway, the morphological changes of cells were observed, and the expression of CTEN, E-cadherin, vimentin, ERK1/2, p-ERK1/2, Raf-1and Snail protein was detected by Western blot. The number of invasive cells was determined by Transwell assay.
Results
1. The positive rate of CTEN in breast cancer was88.1%, while p-ERK1/2was83.3%. CTEN and p-ERK1/2both associated with the loss of tumor differentiation, clinical stage, lymph node metastasis and N-cadherin expression (P＜0.05). There was a significant positive correlation between the expression strength of CTEN and p-ERK1/2(r=0.526, P＜0.01).
2. After EGF was used to stimulate MCF-7cells, epithelial-like to mesenchymal-like changes in cells morphology were observed, and the expression of CTEN and vimentin protein was increased, as well as E-cadherin protein was decreased. CTEN-siRNA can suppress CTEN mRNA expression effectively (inhibition＞90%).
3. EGF was used to stimulate MCF-7cells. After transfection, it was found that mesenchymal-like to epithelial-like changes in cells morphology, and the expression of CTEN, vimentin, ERK1/2, p-ERK1/2, Raf-1and Snail protein was decreased, E-cadherin protein was increased. The expression of p-ERK1/2and Snail protein was decreased, but Raf-1protein expression did not change after using U0126.After transfection, the number of invasive cells did not significantly increase even if using exogenous EGF to stimulate MCF-7cells (P＜0.05).
Conclusion
1. It suggested that the expression level of CTEN protein was closely related to biological behavior of breast cancer, and there was a significant positive correlation between the expression strength of CTEN and p-ERK1/2.
2. Exogenous EGF could promote breast cancer MCF-7cells occurring EMT, and the expression of CTEN protein was increased after occurring EMT.
3. Suppressing CTEN expression could partly inverse EMT by EGF-induced, because CTEN silencing could block activation of Ras/Raf/MEK/ERK/Snail signal pathways due to reducing Raf-1protein expression.
4. Suppressing CTEN expression could partly inverse invasive ability of MCF-7cells enhancing by EGF-induced.
引文
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