α_1抗胰蛋白酶在肺癌发生发展中的作用
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摘要
肺癌是当今世界发病和死亡率最高的恶性肿瘤。在我国城市居民中其死亡率高居癌症死亡的首位。尽管随着基础与临床医学的发展,肺癌的病因、诊断及治疗水平有了很大提高,但对其发生与发展的认识以及治疗的效果远未达到令人满意的程度。
α_1AT是一种重要的血浆蛋白酶抑制剂。研究发现多种恶性肿瘤细胞可以合成α_1AT,并且组织局部的α_1AT具有明显抑制肿瘤细胞生长、转移和实体瘤血管形成的特点。因此,α_1AT被认为是肿瘤诊断与治疗的潜在靶点。
研究目的:观察α_1AT在非小细胞肺癌组织中的表达,研究α_1AT对人肺癌细胞株A549生长的影响。
研究方法:
1、用免疫组织化学Envision法检测72例非小细胞肺癌组织中α_1AT的表达。
2、培养人肺癌细胞A549,采用RT-PCR的方法克隆人α_1AT基因编码区cDNA,构建国α_1AT的真核表达载体;转染A549细胞,G418筛选稳
Carcinoma of the lung has been the leading cause of cancer incidence and death up to now. Its mortality has been the top of all malignant tumors in citizen of China. With the development of basic and clinical medicine, great progress has been achieved in the diagnosis and treatment of lung cancer, however it is far from satisfied in understanding the development of lung cancer, neither the outcome of therapy of the disease.α_1 AT, an important serum protease inhibitor, has been found to be synthesized by many malignant carcinoma cells. It is reported that α_1AT locally suppressed tumor cell proliferation, metastasis and angiogenesis in the solid tumors. So it is believed that the α_1AT might play an important role in the diagnosis and treatment of the tumors.Objective: To investigate the expression of α_1AT in non-small cell lung carcinoma (NSCLC) and its effect on cell proliferation in human lung adenocarcinoma cell line A549.Methods:
1: α_1AT expression was detected using Envision immunohistochemical staining in 72 specimens of the NSCLC prepared with paraffin embedding.2: The human lung cancer cell line A549 was cultured and the coding sequence of α_1 AT cDNA was cloned by RT-PCR to construct α_1AT eukaryotic expression vector. When the vector was constructed and selected by G418, A549 cells were transfected with pcDNA3.1(+)(as control)vector or pcDNA3.1(+)-α_1AT. These cells were cultured on cover slips and observed respectively through HE staining and electron microscopy. All the cells were cultured and counted every other day, thus the growth curve was drawn. α_1AT mRNA and protein levels were measured with RT-PCR, immunofluorescence microscopy and western blotting. Apoptosis was detected by AnnexinV staining and Hoechst staining.3. BALB/c nude mice were injected subcutaneously with A549, A549-pcDNA(3.1+), A549-pcDNA(3.1+)-α_1AT cell suspension respectively to construct nude mouse lung carcinoma animal model. The formation and proliferation of the tumors were observed by measuring the tumor volume and weight.Results:Part I : α_1AT protein expression was observed in 66 of 72 cases of NSCLC. It was highly expressed in lung cancer tissues (91.6%) than in para-carcinoma tissues (41.6%)(P<0.05), which may be due to the synthesis of NSCLC cells themselves. aiAT level was much more higher in stage I—II cases than in stage III-IV cases, which might imply that α_1AT was related with lung cancer clinical staging. Positive correlation was found between the expression and the cell differentiation. The lower was the tumor cell grade, the less was α_1AT expression; There was no significant difference between
moderate- and high-differentiated NSCLC samples in the expression, but it was found that staining was more intensive in later group. Negative correlation was found between the expression and the tumor size. The bigger was the tumor the less was the expression. There were no correlation between α_1AT expression and sex, age and NSCLC histologic types.Part II: cDNA coding otiAT about 1200bp was generated by reverse transcription-PCR. The purified PCR product was inserted into the BamH I and EcoR V sites of pcDNA3.1(+). Sequence analysis showed that it was the same as the α_1AT sequence reported. Then α_1AT PCR product was cloned reversal into pcDNA3.1(+) vector. The A549 stable transfectants with either control vector pcDNA3.1(+), or pcDNA3.1(+)-α_1AT were established. Morphology of A549/ pcDNA3.1(+)-ctiAT under electron microscopy displayed signs of apoptosis, such as plasma membrane blebbing and multiplied nuclei. Cell growth curve showed A549/pcDNA3.1(+)-α_1AT proliferated slowly than other kinds of cells.0.5 × 10~5 different kinds of cells were cultured in 6-well plates respectively. In day 7, the number of A549/ pcDNA3.1(+)-α_1AT was just 3.12 × 105 but all other cells was 6.83 × 105. A549/pcDNA3.1(+)-aiAT had significantly decreased in cell number compared with the other two groups.Strong and diffuse green staining of α_1AT emerged in pcDNA3.1 (+)-α_1AT transfected cells by indirect immunofluorescence staining, but in negative control and the native A549 the staining was very weak or absent.The mRNA of α_1AT in A549 and A549/ pcDNA3.1(+) cells were nearly undetectable by RT-PCR. In contrast, the mRNA level of α_1AT was detected obviously in A549/pcDNA3.1(+)-α_1AT cells. At the same time , β -actin mRNA had not been changed in all kinds of cells. The similar change was
found in the level of α_1AT protein through western blotting.The pcDNA3.1(+)-α_1AT transfected cells showed more typical apoptotic characters, such as shrinkage nuclei, chromatin condensation, plasma membrane blebbing and chromatin breakage fragments by Hoechst staining under fluorescence microscope than the negative control and the native A549 cells. The same scene was found under transmission electron microscope. The apoptosis rate in the pcDNA3.1(+)-α_1AT cells was significantly higher than that of the negative control and the native A549 cells. A549 cell's apoptosis was increased significantly after transfected with α_1AT.Partlll: When tumor cells were seeded in nude mice, the tumorigenesis was found in day 16 in those injected with A549/ pcDNA3.1(+)-α_1AT cell suspension transfected by α_1AT gene , as the other two groups was in day 7. The incubation period of tumors was lengthened in the experimental group than in the control and the tumor volume was significant decreased either. The tumor-inhibiting rate was 55.5%. It indicated that α_1AT could inhibit thesubcutaneous tumorigenic of A549 in nude mice. Conclusion1.Our study showed that the expression of α_1AT in NSCLC tissues were significant higher than in para-carcinoma tissues, and the expression of α_1AT was not correlated with the age, gender and histological types. Its expression level was negatively correlated with NSCLC clinical TNM staging but positively with cell differentiation. The lower was the tumor cell differentiation and the clinical TNM staging, the less was α_1AT expression. On the other hand, the smaller was the tumor size, the higher was the expression, which could also be found in clinical staging. So α_1AT might be an index for estimating the degree of malignant and progression of the
α_1AT是一种重要的血浆蛋白酶抑制剂。研究发现多种恶性肿瘤细胞可以合成α_1AT,并且组织局部的α_1AT具有明显抑制肿瘤细胞生长、转移和实体瘤血管形成的特点。因此,α_1AT被认为是肿瘤诊断与治疗的潜在靶点。
研究目的:观察α_1AT在非小细胞肺癌组织中的表达,研究α_1AT对人肺癌细胞株A549生长的影响。
研究方法:
1、用免疫组织化学Envision法检测72例非小细胞肺癌组织中α_1AT的表达。
2、培养人肺癌细胞A549,采用RT-PCR的方法克隆人α_1AT基因编码区cDNA,构建国α_1AT的真核表达载体;转染A549细胞,G418筛选稳
Carcinoma of the lung has been the leading cause of cancer incidence and death up to now. Its mortality has been the top of all malignant tumors in citizen of China. With the development of basic and clinical medicine, great progress has been achieved in the diagnosis and treatment of lung cancer, however it is far from satisfied in understanding the development of lung cancer, neither the outcome of therapy of the disease.α_1 AT, an important serum protease inhibitor, has been found to be synthesized by many malignant carcinoma cells. It is reported that α_1AT locally suppressed tumor cell proliferation, metastasis and angiogenesis in the solid tumors. So it is believed that the α_1AT might play an important role in the diagnosis and treatment of the tumors.Objective: To investigate the expression of α_1AT in non-small cell lung carcinoma (NSCLC) and its effect on cell proliferation in human lung adenocarcinoma cell line A549.Methods:
1: α_1AT expression was detected using Envision immunohistochemical staining in 72 specimens of the NSCLC prepared with paraffin embedding.2: The human lung cancer cell line A549 was cultured and the coding sequence of α_1 AT cDNA was cloned by RT-PCR to construct α_1AT eukaryotic expression vector. When the vector was constructed and selected by G418, A549 cells were transfected with pcDNA3.1(+)(as control)vector or pcDNA3.1(+)-α_1AT. These cells were cultured on cover slips and observed respectively through HE staining and electron microscopy. All the cells were cultured and counted every other day, thus the growth curve was drawn. α_1AT mRNA and protein levels were measured with RT-PCR, immunofluorescence microscopy and western blotting. Apoptosis was detected by AnnexinV staining and Hoechst staining.3. BALB/c nude mice were injected subcutaneously with A549, A549-pcDNA(3.1+), A549-pcDNA(3.1+)-α_1AT cell suspension respectively to construct nude mouse lung carcinoma animal model. The formation and proliferation of the tumors were observed by measuring the tumor volume and weight.Results:Part I : α_1AT protein expression was observed in 66 of 72 cases of NSCLC. It was highly expressed in lung cancer tissues (91.6%) than in para-carcinoma tissues (41.6%)(P<0.05), which may be due to the synthesis of NSCLC cells themselves. aiAT level was much more higher in stage I—II cases than in stage III-IV cases, which might imply that α_1AT was related with lung cancer clinical staging. Positive correlation was found between the expression and the cell differentiation. The lower was the tumor cell grade, the less was α_1AT expression; There was no significant difference between
moderate- and high-differentiated NSCLC samples in the expression, but it was found that staining was more intensive in later group. Negative correlation was found between the expression and the tumor size. The bigger was the tumor the less was the expression. There were no correlation between α_1AT expression and sex, age and NSCLC histologic types.Part II: cDNA coding otiAT about 1200bp was generated by reverse transcription-PCR. The purified PCR product was inserted into the BamH I and EcoR V sites of pcDNA3.1(+). Sequence analysis showed that it was the same as the α_1AT sequence reported. Then α_1AT PCR product was cloned reversal into pcDNA3.1(+) vector. The A549 stable transfectants with either control vector pcDNA3.1(+), or pcDNA3.1(+)-α_1AT were established. Morphology of A549/ pcDNA3.1(+)-ctiAT under electron microscopy displayed signs of apoptosis, such as plasma membrane blebbing and multiplied nuclei. Cell growth curve showed A549/pcDNA3.1(+)-α_1AT proliferated slowly than other kinds of cells.0.5 × 10~5 different kinds of cells were cultured in 6-well plates respectively. In day 7, the number of A549/ pcDNA3.1(+)-α_1AT was just 3.12 × 105 but all other cells was 6.83 × 105. A549/pcDNA3.1(+)-aiAT had significantly decreased in cell number compared with the other two groups.Strong and diffuse green staining of α_1AT emerged in pcDNA3.1 (+)-α_1AT transfected cells by indirect immunofluorescence staining, but in negative control and the native A549 the staining was very weak or absent.The mRNA of α_1AT in A549 and A549/ pcDNA3.1(+) cells were nearly undetectable by RT-PCR. In contrast, the mRNA level of α_1AT was detected obviously in A549/pcDNA3.1(+)-α_1AT cells. At the same time , β -actin mRNA had not been changed in all kinds of cells. The similar change was
found in the level of α_1AT protein through western blotting.The pcDNA3.1(+)-α_1AT transfected cells showed more typical apoptotic characters, such as shrinkage nuclei, chromatin condensation, plasma membrane blebbing and chromatin breakage fragments by Hoechst staining under fluorescence microscope than the negative control and the native A549 cells. The same scene was found under transmission electron microscope. The apoptosis rate in the pcDNA3.1(+)-α_1AT cells was significantly higher than that of the negative control and the native A549 cells. A549 cell's apoptosis was increased significantly after transfected with α_1AT.Partlll: When tumor cells were seeded in nude mice, the tumorigenesis was found in day 16 in those injected with A549/ pcDNA3.1(+)-α_1AT cell suspension transfected by α_1AT gene , as the other two groups was in day 7. The incubation period of tumors was lengthened in the experimental group than in the control and the tumor volume was significant decreased either. The tumor-inhibiting rate was 55.5%. It indicated that α_1AT could inhibit thesubcutaneous tumorigenic of A549 in nude mice. Conclusion1.Our study showed that the expression of α_1AT in NSCLC tissues were significant higher than in para-carcinoma tissues, and the expression of α_1AT was not correlated with the age, gender and histological types. Its expression level was negatively correlated with NSCLC clinical TNM staging but positively with cell differentiation. The lower was the tumor cell differentiation and the clinical TNM staging, the less was α_1AT expression. On the other hand, the smaller was the tumor size, the higher was the expression, which could also be found in clinical staging. So α_1AT might be an index for estimating the degree of malignant and progression of the
引文
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