过表达claudin-6对乳腺癌细胞MCF-7生物学行为的影响及作用机制的研究
摘要
目的:探讨claudin-6(CLDN6)过表达对乳腺癌细胞MCF-7生物学表型的影响及相关的分子机制。
方法:用脂质体法将含有CLDN6的真核表达载体转染乳腺癌细胞系MCF-7后,采用RT-PCR、Western blot和细胞免疫荧光方法进行稳定克隆的筛选和鉴定;采用MTT法、克隆形成实验和流式细胞术检测细胞生长情况;采用TUNEL法、Annexin-V/PI双染法和DAPI染色法检测细胞凋亡情况;采用划痕法、Transwell小室法和粘附实验检测细胞迁移、侵袭和粘附性;通过跨上皮电阻检测估计紧密连接功能;建立小鼠肾被膜下移植侵袭模型检测体内侵袭能力;应用Western blot、TUNEL法、划痕法、Transwell小室法检测相关信号途径的变化对细胞凋亡、迁移和侵袭能力的影响。
结果:建立了稳定表达CLDN6基因的4株单克隆;CLDN6主要表达于细胞膜;过表达CLDN6的细胞生长缓慢、克隆形成能力降低;诱导细胞凋亡;细胞的迁移性和体内外侵袭性被抑制;细胞间紧密连接功能增强;过表达CLDN6上调磷酸化p38蛋白的表达,p38抑制剂逆转CLDN6对细胞凋亡和侵袭能力。
结论:CLDN6能够明显抑制细胞增殖,诱导细胞凋亡,抑制迁移和侵袭能力,增强紧密连接功能。CLDN6对MCF-7细胞生物学行为的影响可能与p38信号转导途径的激活有关。
Breast cancer is a kind of malignant tumor which originates from mammary gland duct epithelium. Its morbidity and mortality are increasing year by year. And now breast cancer is on the top of female malignant tumors list. Most important reasons for patients death are metastasis and recurrence of tumor. There is little well-pleasing remedy for such of patients. More and more researches reported that abnormal expression of tight junction(TJ) protein claudin(CLDN) play important roles in tumor occurrence and metastasis. So, it is valuable to study on the effects of CLDNs in the development of cancers.
Junctional complex regulate the interactions between cells in epithelium and endothelium. TJ located on the top of junctional complex play barrier and grating functions as multiple complexes. Besides, TJ possess cell adhesion, maintain cell polarity and permeability, and help signal transductional protein regulating cell biological behaviour. These functions of TJ are very important for the structures of epithelium and endothelium, also for the internal environment homeostasis maintaining.
TJs are composed of three kind of transmembrane proteins which are occludin, CLDN and junctional adhesion molecules(JAM) and periphery plasmosin zonula occludens(ZO). Among the total, CLDNs are the most important backbone protein. CLDNs are a kind of transmembrane protein family. There are at least 24 members in this family. All of the members have four transmembrane domains and two extracellular rings. Molecular weight is between17-27kDa。CLDNs play determinative roles in the structure and function maintain of TJ in epithelium and endothelium, and in the process of signal transduction.
Recently, more and more researches showed that the down-regulation or loss of CLDN protein and other TJ protein are important mechanisms in tumor development and metastasis, which result in cell adhesion lost, cohesion decreased, dedifferentiation and invasiveness increase. CLDNs family is a kind of transmembrane protein. There are PDZ combination domains on C-terminal in intracytoplasm. CLDNs could regulate cell physiological events by contact with cell backbone or signal protein through PDZ domains. Until now, very few reports on the signal pathway involved CLDNs family. As CLDN5 up-regulation may activate PI3K/Akt pathway; CLDN1 down-regulation may active Erk1/2 pathway; CLDN7 up-regulation may activate p38 MAPK pathway. Besides above-mentioned pathways, CLDN could also take part in cancer developmet byinducing epithelium leakge.CLDNs could interact with and activate membrane-type matrix metalloproteinases to promote the invasive ability of cancer cells. The expresson of CLDN is related with cell survival increases, which is very important for the early and late tumor formation. There is little knowledge about the mechanism and effect of CLDN6 in cancer development.
CLDN6 was one of CLDNs family which had 24 members. It locates at chromosome 16p13.3 coding 219 amino acids and synthesizing 23kDa protein. The functional researches of CLDN6 before were limited to epithelium or epidermis level, ion permeability, barrier protection and the regulation of junction between cells. We cloned and identified CLDN6 as breast cancer phenotypic suppression gene in our previous work and found that the level of CLDN6 was undetectable or down-regulated in human and rat mammary cancer tissues and cell lines. CLDN6 was obviously down-regulated in breast cancer tissues with lymph nodes metastasis suggesting that CLDN6 may play essential roles in breast cancer development forbidden. Until now, there was little knowledge about the relation between CLDN6 and breast cancer.
Methods:
To explore the effects of up-regulation of CLDN6 on breast cancer cell lines MCF-7, we gained MCF-7 sublines with high levels of CLDN6 by transfection with a pcDNA3.1-CLDN6 expression vector. The detected the effect of CLDN6 on cell growth, cycle, cloned forming ability, apoptosis, invasive and migration ability, the structure and function of tight junction, then analysis the mechanism of effects above. The results showed as follows.
Results:
(1) Screen and identification of CLDN6 expression clone by transfection: RT-PCR and Western blot screen four clones with CLDN6 stable exression which named C1, C2, C3 and C4. The cytoimmunity stain results show that CLDN6 locates on the cell membrane of stable expression clone. There is no CLDN6 expression in control and vector groups.
(2) The effects of CLDN6 over expression on MCF-7 cell growth: MTT results show the control and vector groups have similar cell proliferation speed and over expression group have a lower speed. Plate ans soft agar clone forming assay shows over expression group has fewer clones than control and vector groups. Flow cytometry cell cycle assay result shows over expression group have a higher rate of S phase cell than control and vector groups. Above all, CLDN6 transfection may decrease cell two and three clone forming ability and change cell cycle.
(3)The effects of CLDN6 on MCF-7 cell apoptosis: TUNEL assay shows the rate of cell apoptosis in over expression group is higher than control and vector groups. Annexin-V/PI double stain results show that the rate of early and late apoptosis in over expression group is also higher than control and vector groups. DAPI stain further proves the results above that there are obvious cell apoptosis in over expression group. Above all, CLDN6 may induce cell apoptosis.
(4)The effects of CLDN6 on MCF-7 cell metastatic ability: Wound healing assay found that cell migration rate was lower in CLDN6 expression cells. Transwell assay showed that invasive depth and rate were lower in CLDN6 expression cells. Above all, CLDN6 may decrease the cell migration and invasive ability. Cell adhesion assay in vitro showed there was no difference in groups.
(5)The effects of CLDN6 on the tight junction fuction of MCF-7 cell: Monolayer culture transepithelial electric resistance detection showed a higher resistance in CLDN6 expression cells. It is means that CLDN6 may tighten the structure and function of tight junction between cells.
(6)The effects of CLDN6 on MCF-7 cell invasive ability in mice: Mice renal capsule invasive inhibition mode presented that the invasive depth was lower in CLDN6 expression cells. Immunohistochemistry stain results show that CLDN6 only expression in over expression groups. Above all, CLDN6 could inhibite MCF-7 cell local infiltration.
(7)The mechanisms of CLDN6’s effects on MCF-7 cell biological behaviour: Western blot assay showed that the level of phospho-p38 was higher in CLDN6 expression cells. p38 inhibitor could not only obviously inhibit the activation of p38 pathway, but also partly inverse the effect of CLDN6 expression on cell apoptosis, migration and invasive ability, yet with no effect on CLDN6 expression. Above all, p38 locates at downstream of CLDN6 signal pathway and the effects of CLDN6 on cell apoptosis, migration and invasive ability are coming true by p38 pathway.
Conclusions:
(1)CLDN6 can inhibit MCF-7 cell proliferation, migration and invasive ability, induce cell apoptosis.
(2)CLDN6 can inhibit cell metastatic ability by tightening the tight junction.
(3)The effects of CLDN6 on MCF-7 biological phenotype are relateed with the activation of p38 MAPK signal pathway.
方法:用脂质体法将含有CLDN6的真核表达载体转染乳腺癌细胞系MCF-7后,采用RT-PCR、Western blot和细胞免疫荧光方法进行稳定克隆的筛选和鉴定;采用MTT法、克隆形成实验和流式细胞术检测细胞生长情况;采用TUNEL法、Annexin-V/PI双染法和DAPI染色法检测细胞凋亡情况;采用划痕法、Transwell小室法和粘附实验检测细胞迁移、侵袭和粘附性;通过跨上皮电阻检测估计紧密连接功能;建立小鼠肾被膜下移植侵袭模型检测体内侵袭能力;应用Western blot、TUNEL法、划痕法、Transwell小室法检测相关信号途径的变化对细胞凋亡、迁移和侵袭能力的影响。
结果:建立了稳定表达CLDN6基因的4株单克隆;CLDN6主要表达于细胞膜;过表达CLDN6的细胞生长缓慢、克隆形成能力降低;诱导细胞凋亡;细胞的迁移性和体内外侵袭性被抑制;细胞间紧密连接功能增强;过表达CLDN6上调磷酸化p38蛋白的表达,p38抑制剂逆转CLDN6对细胞凋亡和侵袭能力。
结论:CLDN6能够明显抑制细胞增殖,诱导细胞凋亡,抑制迁移和侵袭能力,增强紧密连接功能。CLDN6对MCF-7细胞生物学行为的影响可能与p38信号转导途径的激活有关。
Breast cancer is a kind of malignant tumor which originates from mammary gland duct epithelium. Its morbidity and mortality are increasing year by year. And now breast cancer is on the top of female malignant tumors list. Most important reasons for patients death are metastasis and recurrence of tumor. There is little well-pleasing remedy for such of patients. More and more researches reported that abnormal expression of tight junction(TJ) protein claudin(CLDN) play important roles in tumor occurrence and metastasis. So, it is valuable to study on the effects of CLDNs in the development of cancers.
Junctional complex regulate the interactions between cells in epithelium and endothelium. TJ located on the top of junctional complex play barrier and grating functions as multiple complexes. Besides, TJ possess cell adhesion, maintain cell polarity and permeability, and help signal transductional protein regulating cell biological behaviour. These functions of TJ are very important for the structures of epithelium and endothelium, also for the internal environment homeostasis maintaining.
TJs are composed of three kind of transmembrane proteins which are occludin, CLDN and junctional adhesion molecules(JAM) and periphery plasmosin zonula occludens(ZO). Among the total, CLDNs are the most important backbone protein. CLDNs are a kind of transmembrane protein family. There are at least 24 members in this family. All of the members have four transmembrane domains and two extracellular rings. Molecular weight is between17-27kDa。CLDNs play determinative roles in the structure and function maintain of TJ in epithelium and endothelium, and in the process of signal transduction.
Recently, more and more researches showed that the down-regulation or loss of CLDN protein and other TJ protein are important mechanisms in tumor development and metastasis, which result in cell adhesion lost, cohesion decreased, dedifferentiation and invasiveness increase. CLDNs family is a kind of transmembrane protein. There are PDZ combination domains on C-terminal in intracytoplasm. CLDNs could regulate cell physiological events by contact with cell backbone or signal protein through PDZ domains. Until now, very few reports on the signal pathway involved CLDNs family. As CLDN5 up-regulation may activate PI3K/Akt pathway; CLDN1 down-regulation may active Erk1/2 pathway; CLDN7 up-regulation may activate p38 MAPK pathway. Besides above-mentioned pathways, CLDN could also take part in cancer developmet byinducing epithelium leakge.CLDNs could interact with and activate membrane-type matrix metalloproteinases to promote the invasive ability of cancer cells. The expresson of CLDN is related with cell survival increases, which is very important for the early and late tumor formation. There is little knowledge about the mechanism and effect of CLDN6 in cancer development.
CLDN6 was one of CLDNs family which had 24 members. It locates at chromosome 16p13.3 coding 219 amino acids and synthesizing 23kDa protein. The functional researches of CLDN6 before were limited to epithelium or epidermis level, ion permeability, barrier protection and the regulation of junction between cells. We cloned and identified CLDN6 as breast cancer phenotypic suppression gene in our previous work and found that the level of CLDN6 was undetectable or down-regulated in human and rat mammary cancer tissues and cell lines. CLDN6 was obviously down-regulated in breast cancer tissues with lymph nodes metastasis suggesting that CLDN6 may play essential roles in breast cancer development forbidden. Until now, there was little knowledge about the relation between CLDN6 and breast cancer.
Methods:
To explore the effects of up-regulation of CLDN6 on breast cancer cell lines MCF-7, we gained MCF-7 sublines with high levels of CLDN6 by transfection with a pcDNA3.1-CLDN6 expression vector. The detected the effect of CLDN6 on cell growth, cycle, cloned forming ability, apoptosis, invasive and migration ability, the structure and function of tight junction, then analysis the mechanism of effects above. The results showed as follows.
Results:
(1) Screen and identification of CLDN6 expression clone by transfection: RT-PCR and Western blot screen four clones with CLDN6 stable exression which named C1, C2, C3 and C4. The cytoimmunity stain results show that CLDN6 locates on the cell membrane of stable expression clone. There is no CLDN6 expression in control and vector groups.
(2) The effects of CLDN6 over expression on MCF-7 cell growth: MTT results show the control and vector groups have similar cell proliferation speed and over expression group have a lower speed. Plate ans soft agar clone forming assay shows over expression group has fewer clones than control and vector groups. Flow cytometry cell cycle assay result shows over expression group have a higher rate of S phase cell than control and vector groups. Above all, CLDN6 transfection may decrease cell two and three clone forming ability and change cell cycle.
(3)The effects of CLDN6 on MCF-7 cell apoptosis: TUNEL assay shows the rate of cell apoptosis in over expression group is higher than control and vector groups. Annexin-V/PI double stain results show that the rate of early and late apoptosis in over expression group is also higher than control and vector groups. DAPI stain further proves the results above that there are obvious cell apoptosis in over expression group. Above all, CLDN6 may induce cell apoptosis.
(4)The effects of CLDN6 on MCF-7 cell metastatic ability: Wound healing assay found that cell migration rate was lower in CLDN6 expression cells. Transwell assay showed that invasive depth and rate were lower in CLDN6 expression cells. Above all, CLDN6 may decrease the cell migration and invasive ability. Cell adhesion assay in vitro showed there was no difference in groups.
(5)The effects of CLDN6 on the tight junction fuction of MCF-7 cell: Monolayer culture transepithelial electric resistance detection showed a higher resistance in CLDN6 expression cells. It is means that CLDN6 may tighten the structure and function of tight junction between cells.
(6)The effects of CLDN6 on MCF-7 cell invasive ability in mice: Mice renal capsule invasive inhibition mode presented that the invasive depth was lower in CLDN6 expression cells. Immunohistochemistry stain results show that CLDN6 only expression in over expression groups. Above all, CLDN6 could inhibite MCF-7 cell local infiltration.
(7)The mechanisms of CLDN6’s effects on MCF-7 cell biological behaviour: Western blot assay showed that the level of phospho-p38 was higher in CLDN6 expression cells. p38 inhibitor could not only obviously inhibit the activation of p38 pathway, but also partly inverse the effect of CLDN6 expression on cell apoptosis, migration and invasive ability, yet with no effect on CLDN6 expression. Above all, p38 locates at downstream of CLDN6 signal pathway and the effects of CLDN6 on cell apoptosis, migration and invasive ability are coming true by p38 pathway.
Conclusions:
(1)CLDN6 can inhibit MCF-7 cell proliferation, migration and invasive ability, induce cell apoptosis.
(2)CLDN6 can inhibit cell metastatic ability by tightening the tight junction.
(3)The effects of CLDN6 on MCF-7 biological phenotype are relateed with the activation of p38 MAPK signal pathway.
引文
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