This study aimed to explore the molecular mechanism in tumor invasion and metastasis. The expression of matrix metalloproteinase 2, 9 (MMP 2, MMP 9), tissue inhibitor 1 of matrix metalloproteinase (TIMP 1), c...This study aimed to explore the molecular mechanism in tumor invasion and metastasis. The expression of matrix metalloproteinase 2, 9 (MMP 2, MMP 9), tissue inhibitor 1 of matrix metalloproteinase (TIMP 1), cell adhesion molecule 44 variant 6 (CD44v6), HER2/neu and p53 was investigated in 154 patients with head and neck squamous cell carcinoma (SCC) by ABC and ImmunoMax immunohistochemical method. Their clinical relevance and correlation were analysed. The expression of MMP 2, MMP 9, TIMP 1, CD44v6, HER2/neu and p53 was found in cancer cells in 87.01%, 85.71%, 68.18%, 98.05%, 55.19% and 50.65% cases respectively. Linear regression and correlation analysis revealed that there was close positive relationship ( P <0.05) between the expression of MMP 2 and MMP 9, TIMP 1 and CD44v6, HER2/neu and MMP 9, MMP 2 and p53. Up regulation of MMP 2 was accompanied by advanced T stage ( P <0.01) . There was also a trend of MMP 2 expression being related with tumor metastasis. Increased expression of HER2/neu was found in patients with tumor recurrence( P <0.05). The expression of TIMP 1 was higher in laryngeal cancer than that in pharyngeal cancer, and higher in keratinizing and non keratinizing SCC than that in basaloid SCC( P <0.05). These findings suggested that MMP 2 and MMP 9, HER2/neu and MMP 9, MMP 2 and p53 had a coordinate function in aggression of tumor; that MMP 2 had a more important function than MMP 9 in tumor invasion and metastasis; and that HER2/neu might serve as a biomarker for poor prognosis in HNSCC.展开更多
目的探讨声带癌前病变组织中基质金属蛋白酶抑制剂-1(tissue inhibitor of metalloproteinases 1,TIMP-1)、果蝇母亲DDP同源物4(drosophila mothers against DDP homolog 4,Smad4)表达水平与术后复发和恶变的相关性。方法回顾性分析2018...目的探讨声带癌前病变组织中基质金属蛋白酶抑制剂-1(tissue inhibitor of metalloproteinases 1,TIMP-1)、果蝇母亲DDP同源物4(drosophila mothers against DDP homolog 4,Smad4)表达水平与术后复发和恶变的相关性。方法回顾性分析2018年8月~2021年8月郑州大学第一附属医院收治的162例声带癌前病变患者的临床和病理资料,收集手术切除癌前病变组织(癌前病变组)及病变旁正常黏膜组织(对照组),采用免疫组织化学法检测组织中TIMP-1、Smad4表达情况。分析TIMP-1、Smad4阳性率与临床病理特征的关系,并采用Kaplan-Meier法和Cox回归分析法分析其对术后复发和恶变的影响。结果与对照组正常黏膜组织比较,癌前病变组的TIMP-1阳性率较高,Smad4阳性率较低(P<0.05)。不同病变范围、是否累及前连合、不同程度上皮异常增生患者的TIMP-1、Smad4阳性率存在差异(P<0.05)。术后随访时间24~60个月,中位随访时间36个月,随访期间失访患者6例,随访率96.30%(156/162),随访期间术后复发35例(21.60%),术后恶变16例(9.88%);Kaplan-Meier生存分析显示,TIMP-1阳性患者术后复发率和恶变率高于TIMP-1阴性患者(P<0.05);Smad4阴性患者术后复发率和恶变率高于Smad4阳性患者(P<0.05)。多因素Cox回归分析显示,喉咽反流、病变范围>1/2、中/重度异型增生、TIMP-1阳性、Smad4阴性是复发的独立危险因素(P<0.05),年龄>60岁、累及前连合、TIMP-1阳性、Smad4阴性是恶变的独立危险因素(P<0.05)。结论声带癌前病变组织中TIMP-1高表达、Smad4低表达,且TIMP-1阳性、Smad4阴性表达者术后复发和恶变风险较高。展开更多
The identification of novel biomarkers for early prostate cancer diagnosis is highly important because early detection and treatment are critical for the medical management of patients. Disruption in the continuity of...The identification of novel biomarkers for early prostate cancer diagnosis is highly important because early detection and treatment are critical for the medical management of patients. Disruption in the continuity of both the basal cell layer and basement membrane is essential for the progression of high-grade prostatic intraepithelial neoplasia （HGPIN） to invasive adenocarcinoma in human prostate. The molecules involved in the conversion to an invasive phenotype are the subject of intense scrutiny. We have previously reported that matrix metalloproteinase-26 （MMP-26） promotes the invasion of human prostate cancer cells via the cleavage of basement membrane proteins and by activating the zymogen form of MMP-9. Furthermore, we have found that tissue inhibitor of metalloproteinases-4 （TIMP-4） is the most potent endogenous inhibitor of MMP-26. Here we demonstrate higher （p〈0.0001） MMP-26 and TIMP-4 expression in HGPIN and cancer, compared to non-neoplastic acini. Their expression levels are highest in HGPIN, but decline in invasive cancer （p〈0.001 for each） in the same tissues. Immunohistochemical staining of serial prostate cancer tissue sections suggests colocalization of MMP-26 and TIMP-4. The present study indicates that MMP-26 and TIMP-4 may play an integral role during the conversion of HGPIN to invasive cancer and may also serve as markers for early prostate cancer diagnosis.展开更多
To investigate the effects of TGF-β1 on the two gelatinases （MMP-2 and MMP-9）, and their roles in lung remodeling after irradiation-induced lung injury. Expressions of TGF-β1 were measured with western blot, and e...To investigate the effects of TGF-β1 on the two gelatinases （MMP-2 and MMP-9）, and their roles in lung remodeling after irradiation-induced lung injury. Expressions of TGF-β1 were measured with western blot, and expressions of MMP-2 and MMP-9 were analyzed with zymography in a TGF-β1 transgenic mouse model after thoracic irradiation with 12 Gy. We found expressions of TGF-β1 in the lung from the transgenic mice were three folds as compared to those from control mice. With densitometrical analysis, we found a significant decrease in MMP-9 activity in lung homogenates from the transgenic mice as compared with those from non-transgenic control mice 8 weeks after sham-irradiation （relative MMP-9 activity： C： 1. 000±0. 1091; TG： 0. 4772±0. 470 （n=8, P〈0.05）. But MMP-2 was constitutively expressed in the lung homogenates from the transgenic mice as compared to those from control mice 8 weeks after sham-irradiation （relative MMP-2 activity 8 weeks after sham-irradiation： C： 1. 000±0. 1556, TG： 1. 0075±0. 1472）. Eight weeks after thoracic irradiation with 12 Gy, we observed a significant increase of MMP-2 and MMP-9 activity in lung homogenates from both transgenic and normal mice. In TGF-β1 transgenic mice relative MMP-9 activity was increased to 1. 5321±0. 2217 folds 8 weeks after thoracic irradiation with 12 Gy as compared to those after sham-irradiation （1. 000±0. 2153）, and relative MMP-2 activity was increased to 1. 7142 ± 0. 4231 folds. Our results show that TGF-β1 itself down-regulates activity of MMP-9, thereby decreases ECM degradation in lungs of TGF-β1 transgenic mice. Also we find that ionizing irradiation upregulates both MMP-2 and MMP-9 activity. Over-expressions of MMP-9 and MMP-2 after lung irradiation are involved in the inflammatory response associated with radiation-induced lung injury, and maybe further in radiation-induced lung fibrosis.展开更多
Objective:To determine the effects of a recombinant replication-deficient adenovirus encoding human tissue inhibitor of metalloproteinase-4(Ad.TIMP-4) on vascular smooth muscle cell(VSMC) function in vitro and neointi...Objective:To determine the effects of a recombinant replication-deficient adenovirus encoding human tissue inhibitor of metalloproteinase-4(Ad.TIMP-4) on vascular smooth muscle cell(VSMC) function in vitro and neointimal development in the injured rat carotid artery.Methods:Western blotting,gelatin zymography and reverse zymography were used to characterize the expression and functional activity of the TIMP-4 secreted by Ad.TIMP-4-infected VSMCs.The migration and proliferation of VSMCs in vitro were separately detected by using Millicell-PCF invasion chambers and [3H]-thymidine incorporation assay.Immunohistochemistry and morphometric analysis were used to determine the local expression of TIMP-4 and its effect on neointima development in a rat carotid artery balloon injury model.Results:VSMCs infected with Ad.TIMP-4 expressed functionally active human TIMP-4 which increased with the duration of infection.TIMP-4 expression inhibited VSMC migration,but not significantly affect VSMC proliferation.In a balloon-injured rat carotid artery model,a significant 62% reduction in neointimal area was found in Ad.TIMP-4-infected vessels at 14 days after injury.Ad.TIMP-4 infection had no effect on medial area.Conclusion:Our results indicated TIMP-4 over expression can significantly inhibit the migration of cultured VSMCs and prevent neointimal formation after vascular injury.Our findings provide additional evidence that TIMP-4 could play an important role in vascular pathophysiology,and may be an important therapeutic target for future drug development.展开更多
Objective:To investigate the effect of resveratrol on the expression of tissue inhibitors of metalloproteinases-1 (TIMP-1) mRNA, Bax and Wnt-4 protein in kidney of rats with renal failure.Methods: Seventy SD rats were...Objective:To investigate the effect of resveratrol on the expression of tissue inhibitors of metalloproteinases-1 (TIMP-1) mRNA, Bax and Wnt-4 protein in kidney of rats with renal failure.Methods: Seventy SD rats were randomly divided into control group (group A), model group (group B), losartan group (group C), low-dose resveratrol group (group D) and high-dose resveratrol group (group E), with 14 rats in each group. Except for the blank control group, the rats in the other groups were given adenine intragastric administration to make chronic renal failure rat models. After successful modeling, the rats in losartan group, low-dose resveratrol group and high-dose resveratrol group were given losartan and resveratrol respectively. HE staining was used to observe the morphological structure of renal tissue cells of rats in each group. The expressions of TIMP-1 mRNA, Bax mRNA, Bax protein and Wnt4 protein were detected and compared.Results: HE staining showed that there were significant pathological changes in the kidney tissues of rats in group B, while those in group C, D and E were significantly improved compared with those in model group. The levels of serum creatinine and urea nitrogen in group B were significantly higher than those in group A and albumin were significantly lower than those in group A, while the levels of serum creatinine and urea nitrogen in group C, D and E were significantly lower than those in group B and albumin was significantly higher than those in group B. The expression levels of TIMP-1 gene and Bax gene mRNA in kidney of rats in group B were significantly increased, and the expression levels of Bax and Wnt protein were also significantly increased. The expression levels of TIMP-1 gene, Bax gene mRNA and Bax and Wnt protein in kidney of rats in group C, D and E were significantly lower than those of rats in group B, with the greatest decrease in group D. The difference between group E and group D, group C and group D were not significant.Conclusion:Low dose resveratrol can alleviate renal fibrosis damage, inhibit apoptosis and protect kidney by inhibiting the expression of timp-1, Bax gene and Wtn4 protein, thus delaying the progression of chronic renal failure.展开更多
文摘This study aimed to explore the molecular mechanism in tumor invasion and metastasis. The expression of matrix metalloproteinase 2, 9 (MMP 2, MMP 9), tissue inhibitor 1 of matrix metalloproteinase (TIMP 1), cell adhesion molecule 44 variant 6 (CD44v6), HER2/neu and p53 was investigated in 154 patients with head and neck squamous cell carcinoma (SCC) by ABC and ImmunoMax immunohistochemical method. Their clinical relevance and correlation were analysed. The expression of MMP 2, MMP 9, TIMP 1, CD44v6, HER2/neu and p53 was found in cancer cells in 87.01%, 85.71%, 68.18%, 98.05%, 55.19% and 50.65% cases respectively. Linear regression and correlation analysis revealed that there was close positive relationship ( P <0.05) between the expression of MMP 2 and MMP 9, TIMP 1 and CD44v6, HER2/neu and MMP 9, MMP 2 and p53. Up regulation of MMP 2 was accompanied by advanced T stage ( P <0.01) . There was also a trend of MMP 2 expression being related with tumor metastasis. Increased expression of HER2/neu was found in patients with tumor recurrence( P <0.05). The expression of TIMP 1 was higher in laryngeal cancer than that in pharyngeal cancer, and higher in keratinizing and non keratinizing SCC than that in basaloid SCC( P <0.05). These findings suggested that MMP 2 and MMP 9, HER2/neu and MMP 9, MMP 2 and p53 had a coordinate function in aggression of tumor; that MMP 2 had a more important function than MMP 9 in tumor invasion and metastasis; and that HER2/neu might serve as a biomarker for poor prognosis in HNSCC.
文摘目的探讨声带癌前病变组织中基质金属蛋白酶抑制剂-1(tissue inhibitor of metalloproteinases 1,TIMP-1)、果蝇母亲DDP同源物4(drosophila mothers against DDP homolog 4,Smad4)表达水平与术后复发和恶变的相关性。方法回顾性分析2018年8月~2021年8月郑州大学第一附属医院收治的162例声带癌前病变患者的临床和病理资料,收集手术切除癌前病变组织(癌前病变组)及病变旁正常黏膜组织(对照组),采用免疫组织化学法检测组织中TIMP-1、Smad4表达情况。分析TIMP-1、Smad4阳性率与临床病理特征的关系,并采用Kaplan-Meier法和Cox回归分析法分析其对术后复发和恶变的影响。结果与对照组正常黏膜组织比较,癌前病变组的TIMP-1阳性率较高,Smad4阳性率较低(P<0.05)。不同病变范围、是否累及前连合、不同程度上皮异常增生患者的TIMP-1、Smad4阳性率存在差异(P<0.05)。术后随访时间24~60个月,中位随访时间36个月,随访期间失访患者6例,随访率96.30%(156/162),随访期间术后复发35例(21.60%),术后恶变16例(9.88%);Kaplan-Meier生存分析显示,TIMP-1阳性患者术后复发率和恶变率高于TIMP-1阴性患者(P<0.05);Smad4阴性患者术后复发率和恶变率高于Smad4阳性患者(P<0.05)。多因素Cox回归分析显示,喉咽反流、病变范围>1/2、中/重度异型增生、TIMP-1阳性、Smad4阴性是复发的独立危险因素(P<0.05),年龄>60岁、累及前连合、TIMP-1阳性、Smad4阴性是恶变的独立危险因素(P<0.05)。结论声带癌前病变组织中TIMP-1高表达、Smad4低表达,且TIMP-1阳性、Smad4阴性表达者术后复发和恶变风险较高。
文摘The identification of novel biomarkers for early prostate cancer diagnosis is highly important because early detection and treatment are critical for the medical management of patients. Disruption in the continuity of both the basal cell layer and basement membrane is essential for the progression of high-grade prostatic intraepithelial neoplasia （HGPIN） to invasive adenocarcinoma in human prostate. The molecules involved in the conversion to an invasive phenotype are the subject of intense scrutiny. We have previously reported that matrix metalloproteinase-26 （MMP-26） promotes the invasion of human prostate cancer cells via the cleavage of basement membrane proteins and by activating the zymogen form of MMP-9. Furthermore, we have found that tissue inhibitor of metalloproteinases-4 （TIMP-4） is the most potent endogenous inhibitor of MMP-26. Here we demonstrate higher （p〈0.0001） MMP-26 and TIMP-4 expression in HGPIN and cancer, compared to non-neoplastic acini. Their expression levels are highest in HGPIN, but decline in invasive cancer （p〈0.001 for each） in the same tissues. Immunohistochemical staining of serial prostate cancer tissue sections suggests colocalization of MMP-26 and TIMP-4. The present study indicates that MMP-26 and TIMP-4 may play an integral role during the conversion of HGPIN to invasive cancer and may also serve as markers for early prostate cancer diagnosis.
文摘To investigate the effects of TGF-β1 on the two gelatinases （MMP-2 and MMP-9）, and their roles in lung remodeling after irradiation-induced lung injury. Expressions of TGF-β1 were measured with western blot, and expressions of MMP-2 and MMP-9 were analyzed with zymography in a TGF-β1 transgenic mouse model after thoracic irradiation with 12 Gy. We found expressions of TGF-β1 in the lung from the transgenic mice were three folds as compared to those from control mice. With densitometrical analysis, we found a significant decrease in MMP-9 activity in lung homogenates from the transgenic mice as compared with those from non-transgenic control mice 8 weeks after sham-irradiation （relative MMP-9 activity： C： 1. 000±0. 1091; TG： 0. 4772±0. 470 （n=8, P〈0.05）. But MMP-2 was constitutively expressed in the lung homogenates from the transgenic mice as compared to those from control mice 8 weeks after sham-irradiation （relative MMP-2 activity 8 weeks after sham-irradiation： C： 1. 000±0. 1556, TG： 1. 0075±0. 1472）. Eight weeks after thoracic irradiation with 12 Gy, we observed a significant increase of MMP-2 and MMP-9 activity in lung homogenates from both transgenic and normal mice. In TGF-β1 transgenic mice relative MMP-9 activity was increased to 1. 5321±0. 2217 folds 8 weeks after thoracic irradiation with 12 Gy as compared to those after sham-irradiation （1. 000±0. 2153）, and relative MMP-2 activity was increased to 1. 7142 ± 0. 4231 folds. Our results show that TGF-β1 itself down-regulates activity of MMP-9, thereby decreases ECM degradation in lungs of TGF-β1 transgenic mice. Also we find that ionizing irradiation upregulates both MMP-2 and MMP-9 activity. Over-expressions of MMP-9 and MMP-2 after lung irradiation are involved in the inflammatory response associated with radiation-induced lung injury, and maybe further in radiation-induced lung fibrosis.
基金Supported by the National Natural Science Foundation of China (30630056)
文摘Objective:To determine the effects of a recombinant replication-deficient adenovirus encoding human tissue inhibitor of metalloproteinase-4(Ad.TIMP-4) on vascular smooth muscle cell(VSMC) function in vitro and neointimal development in the injured rat carotid artery.Methods:Western blotting,gelatin zymography and reverse zymography were used to characterize the expression and functional activity of the TIMP-4 secreted by Ad.TIMP-4-infected VSMCs.The migration and proliferation of VSMCs in vitro were separately detected by using Millicell-PCF invasion chambers and [3H]-thymidine incorporation assay.Immunohistochemistry and morphometric analysis were used to determine the local expression of TIMP-4 and its effect on neointima development in a rat carotid artery balloon injury model.Results:VSMCs infected with Ad.TIMP-4 expressed functionally active human TIMP-4 which increased with the duration of infection.TIMP-4 expression inhibited VSMC migration,but not significantly affect VSMC proliferation.In a balloon-injured rat carotid artery model,a significant 62% reduction in neointimal area was found in Ad.TIMP-4-infected vessels at 14 days after injury.Ad.TIMP-4 infection had no effect on medial area.Conclusion:Our results indicated TIMP-4 over expression can significantly inhibit the migration of cultured VSMCs and prevent neointimal formation after vascular injury.Our findings provide additional evidence that TIMP-4 could play an important role in vascular pathophysiology,and may be an important therapeutic target for future drug development.
文摘Objective:To investigate the effect of resveratrol on the expression of tissue inhibitors of metalloproteinases-1 (TIMP-1) mRNA, Bax and Wnt-4 protein in kidney of rats with renal failure.Methods: Seventy SD rats were randomly divided into control group (group A), model group (group B), losartan group (group C), low-dose resveratrol group (group D) and high-dose resveratrol group (group E), with 14 rats in each group. Except for the blank control group, the rats in the other groups were given adenine intragastric administration to make chronic renal failure rat models. After successful modeling, the rats in losartan group, low-dose resveratrol group and high-dose resveratrol group were given losartan and resveratrol respectively. HE staining was used to observe the morphological structure of renal tissue cells of rats in each group. The expressions of TIMP-1 mRNA, Bax mRNA, Bax protein and Wnt4 protein were detected and compared.Results: HE staining showed that there were significant pathological changes in the kidney tissues of rats in group B, while those in group C, D and E were significantly improved compared with those in model group. The levels of serum creatinine and urea nitrogen in group B were significantly higher than those in group A and albumin were significantly lower than those in group A, while the levels of serum creatinine and urea nitrogen in group C, D and E were significantly lower than those in group B and albumin was significantly higher than those in group B. The expression levels of TIMP-1 gene and Bax gene mRNA in kidney of rats in group B were significantly increased, and the expression levels of Bax and Wnt protein were also significantly increased. The expression levels of TIMP-1 gene, Bax gene mRNA and Bax and Wnt protein in kidney of rats in group C, D and E were significantly lower than those of rats in group B, with the greatest decrease in group D. The difference between group E and group D, group C and group D were not significant.Conclusion:Low dose resveratrol can alleviate renal fibrosis damage, inhibit apoptosis and protect kidney by inhibiting the expression of timp-1, Bax gene and Wtn4 protein, thus delaying the progression of chronic renal failure.
