缺氧诱导因子-1α在肾透明细胞癌中的表达及意义
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摘要
目的与背景
HIF-1是一种在哺乳动物组织中广泛存在的转录因子,组织处于缺氧状态时,它发挥转录和基因调控作用,是缺氧状态下血管生成的核心调控因子。HIF-1由α亚基(HIF-1α)和β亚基(HIF-1β)组成。HIF-1β是HIF-1的结构性亚基,在细胞内的表达水平相对稳定；HIF-1α是HIF-1的功能亚基,正常生理条件下一般检测不到,在特定诱导条件下,细胞内HIF-1α水平增高并发挥调节作用。在肿瘤的发生和生长过程中,癌基因或抑癌基因改变会通过不同的信号传导途径激活HIF-1基因。缺氧诱导因子最先由Semenza于1992年在缺氧细胞的细胞核提取物中发现,是在缺氧条件下广泛存在于哺乳动物和人体内的一种转录因子,广泛参与哺乳动物细胞中缺氧诱导产生的特异应答。作为介导肿瘤细胞缺氧适应的关键性转录调控因子,HIF-1α在许多肿瘤细胞中高表达,并和肿瘤的生物学行为密切相关,已成为近年来肿瘤学研究中的一个新的热点。本实验诣在观察肾透明细胞癌组织中缺氧诱导因子-1(HIF-1α)的表达情况及意义。
材料与方法
收集2006年12月～2007年10月天津医科大学总医院肾癌患者术后新鲜冰冻保存标本50例,病理证实为肾透明细胞癌。所有病例术前均未经任何治疗,其中男28例,女性22例,年龄41-78岁,平均58.2岁。另取10例周围正常肾组织蜡块作为对照。全部标本均经10%福尔马林固定,常规石蜡包埋。肾癌细胞类型：透明细胞癌。临床分期(2002年AJCC分期方法)：Ⅰ期16例,Ⅱ期19例,Ⅲ期11例,Ⅳ期4例；组织学分期(Fuhrman法)：Ⅰ期18例,Ⅱ期23例,Ⅲ期9例。应用免疫组织化学的方法检测50例肾透明细胞癌和10例正常组织中HIF-1的表达。
结果
1.肾透明细胞癌中HIF-1α的表达水平明显低于正常肾组织中的表达水平,其阳性表达率分别为为62%和0%,两者之间比较有统计学差异(χ2值=12.828,P<0.01)。
2.HIF-1α的阳性表达水平与肾透明细胞癌临床分期有关。在肾透明细胞癌临床分期(Ⅰ～Ⅳ期)中,HIF-1α的阳性率分别为43.8%、57.9%、81.8%和100.0%。其中早期肾癌(Ⅰ+Ⅱ期)与晚期肾癌(Ⅲ+Ⅳ期)阳性率分别为51.4%和86.7%,二者比较有统计学差异(χ2值=5.534,P<0.05)。
3.HIF-1α的阳性表达水平与肾透明细胞癌病理分级有关。HIF-1α在肾透明细胞癌病理分级(Ⅰ～Ⅲ级)中的阳性表达率分别为38.9%、69.6%和88.9%,各分级之比较有统计学差异(χ2值=7.401,P<0.05)。
结论
1.HIF-1α在肾透明细胞癌中高度表达,说明HIF-1α可能在肾透明细胞癌发生发展的过程中起到了重要作用。
2.HIF-1α在肾透明细胞癌中的表达水平与肿瘤临床分期有关,肿瘤分期越晚HIF-1α越高表达。
3.HIF-1α在肾透明细胞癌中的表达水平与肿瘤病理分级有关,肿瘤恶性程度越高其表达率越高。
4.HIF-1α有望成为判断肾细胞癌生物学行为的重要参考指标,而且随着研究的不断深入,将可能成为抗肿瘤治疗的新靶点。
Objective and Background:
Hypoxia inducible factor-1α(HIF-1α) is a kind of transcription factor generally residing in mammalian tissues. when occupying hypoxia condition. HIF-1, which is the core regulatory factor in charge of vascularization in hypoxia condition, effects the gene regulation and transcription. HIF-1 consists of alpha subunit (HIF-1α) and beta subunit (HIF-1β). HIF-1βis a structional subunit and its expression level in cells is stable. HIF-1αis a functional subunit and not detectable in physiological condition. The level of HIF-1αin cells heightens and takes effect on some inducted conditions. In the tumorigenesis and process of growth, the changes of oncogenes or anti-oncogenes could activate the gene HIF-1. HIF-1α, which was discovered in 1992 from cellular nucleus extractive of oxygen-poor cells by Semenza, is a critical regulatory proteim of cellular response to hypoxia and extensively reside in mamma and human being cells in anoxia condition. HIF-1αis becoming a new hot spot of oncology study recently, it's overexpressed in many tumors and associated with theit biologic behavior such as invasion, metastasis and poor patient prognosis. To study the expression of hypoxia inducible factor-1α(HIF-1α) in renal cell carcinoma (RCC).
Materials and Methods:
This study included 50 cases of patients, from December,2006 to October,2007, who admitted in the General Hospital of Tianjin Medical University for the treatment of RCC. There are 28 male and 22 female. The median age was 58.2 (range 41-78). The clinical stage was assigned according to the 2002 AJCC TNM system:16 patients of stagingⅠ,19 patients of stagingⅡ,11 patients of stagingⅢand 4 patients of stagingⅣ. For pathologic grading:18 patiens of GradeⅠ,23 patients of GradeⅡand 9 patients of GradeⅢ. None of them had received chemotherapy or radiotherapy before operations.10 specimens of normal renal tissues were acquired as control. Immunohistochemical staining for HIF-1αwas carried out and SPSS 16.0 for windows was used to evaluate the association between HIF-1αexpression and development, progress, clinico-pathologic parameters.
Results:
1. The positive rate of HIF-la expression in renal cell carcinoma was 62%. While the positive rate of HIF-1αexpression in normal renal tissue was 0%. HIF-1αexpression was significant differential between RCC and normal renal tissues (χ2=12.828,P<0.01).
2. The intensive expression of HIF-1αwas related to TNM stage of RCC. The positive rate of HIF-1αexpression at each TNM stage in RCC was 43.8%、57.9％、81.8％、100.0%. HIF-1αexpression was significant differential between early RCC and advanced RCC (χ2=5.534, P<0.05).
3. The intensive expression of HIF-la was related to tumor histological classification of RCC. The positive rate of HIF-la expression at each tumor histological classification in RCC was 38.9％、69.6%、88.9%. HIF-1αexpression was significant differential in each tumor histological classification of RCC (χ2=7.401, P<0.05).
Conclusion:
1. HIF-1αwas highly expressed in RCC tissues which may predict it can play an very important role in the occurrence and development in RCC.
2. The expression of HIF-1αin renal cell carcinioma was related to TNM stage. The more expression of HIF-1α, the more TNM stage.
3. The expression of HIF-1αin renal cell carcinioma was related to tumor histological classification. The more expression of HIF-1α, the more tumor histological classification.
4. It may serve as an important indicators to evaluate the biological behaviors of RCC and become a new research direction for anti-tumor therapy.
HIF-1是一种在哺乳动物组织中广泛存在的转录因子,组织处于缺氧状态时,它发挥转录和基因调控作用,是缺氧状态下血管生成的核心调控因子。HIF-1由α亚基(HIF-1α)和β亚基(HIF-1β)组成。HIF-1β是HIF-1的结构性亚基,在细胞内的表达水平相对稳定；HIF-1α是HIF-1的功能亚基,正常生理条件下一般检测不到,在特定诱导条件下,细胞内HIF-1α水平增高并发挥调节作用。在肿瘤的发生和生长过程中,癌基因或抑癌基因改变会通过不同的信号传导途径激活HIF-1基因。缺氧诱导因子最先由Semenza于1992年在缺氧细胞的细胞核提取物中发现,是在缺氧条件下广泛存在于哺乳动物和人体内的一种转录因子,广泛参与哺乳动物细胞中缺氧诱导产生的特异应答。作为介导肿瘤细胞缺氧适应的关键性转录调控因子,HIF-1α在许多肿瘤细胞中高表达,并和肿瘤的生物学行为密切相关,已成为近年来肿瘤学研究中的一个新的热点。本实验诣在观察肾透明细胞癌组织中缺氧诱导因子-1(HIF-1α)的表达情况及意义。
材料与方法
收集2006年12月～2007年10月天津医科大学总医院肾癌患者术后新鲜冰冻保存标本50例,病理证实为肾透明细胞癌。所有病例术前均未经任何治疗,其中男28例,女性22例,年龄41-78岁,平均58.2岁。另取10例周围正常肾组织蜡块作为对照。全部标本均经10%福尔马林固定,常规石蜡包埋。肾癌细胞类型：透明细胞癌。临床分期(2002年AJCC分期方法)：Ⅰ期16例,Ⅱ期19例,Ⅲ期11例,Ⅳ期4例；组织学分期(Fuhrman法)：Ⅰ期18例,Ⅱ期23例,Ⅲ期9例。应用免疫组织化学的方法检测50例肾透明细胞癌和10例正常组织中HIF-1的表达。
结果
1.肾透明细胞癌中HIF-1α的表达水平明显低于正常肾组织中的表达水平,其阳性表达率分别为为62%和0%,两者之间比较有统计学差异(χ2值=12.828,P<0.01)。
2.HIF-1α的阳性表达水平与肾透明细胞癌临床分期有关。在肾透明细胞癌临床分期(Ⅰ～Ⅳ期)中,HIF-1α的阳性率分别为43.8%、57.9%、81.8%和100.0%。其中早期肾癌(Ⅰ+Ⅱ期)与晚期肾癌(Ⅲ+Ⅳ期)阳性率分别为51.4%和86.7%,二者比较有统计学差异(χ2值=5.534,P<0.05)。
3.HIF-1α的阳性表达水平与肾透明细胞癌病理分级有关。HIF-1α在肾透明细胞癌病理分级(Ⅰ～Ⅲ级)中的阳性表达率分别为38.9%、69.6%和88.9%,各分级之比较有统计学差异(χ2值=7.401,P<0.05)。
结论
1.HIF-1α在肾透明细胞癌中高度表达,说明HIF-1α可能在肾透明细胞癌发生发展的过程中起到了重要作用。
2.HIF-1α在肾透明细胞癌中的表达水平与肿瘤临床分期有关,肿瘤分期越晚HIF-1α越高表达。
3.HIF-1α在肾透明细胞癌中的表达水平与肿瘤病理分级有关,肿瘤恶性程度越高其表达率越高。
4.HIF-1α有望成为判断肾细胞癌生物学行为的重要参考指标,而且随着研究的不断深入,将可能成为抗肿瘤治疗的新靶点。
Objective and Background:
Hypoxia inducible factor-1α(HIF-1α) is a kind of transcription factor generally residing in mammalian tissues. when occupying hypoxia condition. HIF-1, which is the core regulatory factor in charge of vascularization in hypoxia condition, effects the gene regulation and transcription. HIF-1 consists of alpha subunit (HIF-1α) and beta subunit (HIF-1β). HIF-1βis a structional subunit and its expression level in cells is stable. HIF-1αis a functional subunit and not detectable in physiological condition. The level of HIF-1αin cells heightens and takes effect on some inducted conditions. In the tumorigenesis and process of growth, the changes of oncogenes or anti-oncogenes could activate the gene HIF-1. HIF-1α, which was discovered in 1992 from cellular nucleus extractive of oxygen-poor cells by Semenza, is a critical regulatory proteim of cellular response to hypoxia and extensively reside in mamma and human being cells in anoxia condition. HIF-1αis becoming a new hot spot of oncology study recently, it's overexpressed in many tumors and associated with theit biologic behavior such as invasion, metastasis and poor patient prognosis. To study the expression of hypoxia inducible factor-1α(HIF-1α) in renal cell carcinoma (RCC).
Materials and Methods:
This study included 50 cases of patients, from December,2006 to October,2007, who admitted in the General Hospital of Tianjin Medical University for the treatment of RCC. There are 28 male and 22 female. The median age was 58.2 (range 41-78). The clinical stage was assigned according to the 2002 AJCC TNM system:16 patients of stagingⅠ,19 patients of stagingⅡ,11 patients of stagingⅢand 4 patients of stagingⅣ. For pathologic grading:18 patiens of GradeⅠ,23 patients of GradeⅡand 9 patients of GradeⅢ. None of them had received chemotherapy or radiotherapy before operations.10 specimens of normal renal tissues were acquired as control. Immunohistochemical staining for HIF-1αwas carried out and SPSS 16.0 for windows was used to evaluate the association between HIF-1αexpression and development, progress, clinico-pathologic parameters.
Results:
1. The positive rate of HIF-la expression in renal cell carcinoma was 62%. While the positive rate of HIF-1αexpression in normal renal tissue was 0%. HIF-1αexpression was significant differential between RCC and normal renal tissues (χ2=12.828,P<0.01).
2. The intensive expression of HIF-1αwas related to TNM stage of RCC. The positive rate of HIF-1αexpression at each TNM stage in RCC was 43.8%、57.9％、81.8％、100.0%. HIF-1αexpression was significant differential between early RCC and advanced RCC (χ2=5.534, P<0.05).
3. The intensive expression of HIF-la was related to tumor histological classification of RCC. The positive rate of HIF-la expression at each tumor histological classification in RCC was 38.9％、69.6%、88.9%. HIF-1αexpression was significant differential in each tumor histological classification of RCC (χ2=7.401, P<0.05).
Conclusion:
1. HIF-1αwas highly expressed in RCC tissues which may predict it can play an very important role in the occurrence and development in RCC.
2. The expression of HIF-1αin renal cell carcinioma was related to TNM stage. The more expression of HIF-1α, the more TNM stage.
3. The expression of HIF-1αin renal cell carcinioma was related to tumor histological classification. The more expression of HIF-1α, the more tumor histological classification.
4. It may serve as an important indicators to evaluate the biological behaviors of RCC and become a new research direction for anti-tumor therapy.
引文
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