eIF-4E、OPN在上皮性卵巢癌患者血清和肿瘤组织中的表达及相关性分析
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摘要
目的:卵巢肿瘤是女性生殖器常见肿瘤。卵巢恶性肿瘤是女性生殖器三大恶性肿瘤之一,至今缺乏有效的早期诊断方法,其五年存活率仍较低,徘徊在25%-30%。随着宫颈癌及子宫内膜癌诊断和治疗的进展,卵巢癌已成为严重威胁妇女生命的肿瘤。长期以来,人们一直在努力寻找可作为卵巢癌标记物的特有成分,以期达到早期诊断、追踪监测、疗效观察及判断预后等目的。通过对正常卵巢组织、良性上皮性卵巢肿瘤、交界性卵巢肿瘤及上皮性卵巢癌组织中eIF-4E、OPN的表达及血清中eIF-4E、OPN、CA125浓度的检测,探讨eIF-4E、OPN与卵巢癌之间的相关性,以期从基因水平进一步揭示卵巢肿瘤的发病机制,并通过与CA125检测的比较,探讨eIF-4E、OPN作为肿瘤标记物,与CA125联合检测,用于卵巢癌早期诊断和检测疗效、监测复发及术后随访的可能性。
方法:选择经病理证实的卵巢上皮性癌46例,卵巢交界性上皮性肿瘤16例、卵巢良性上皮性肿瘤12例,正常卵巢组织12例。1.用免疫组织化学法检测上述组织标本中eIF-4E、OPN的表达水平,并用医学图像分析系统中的病理图像免疫组化分析软件,测量气吸光度(A)值,并计算平均值进行半定量分析。2.用双抗体夹心(ELISA)法检测上述血清标本中eIF-4E、OPN的浓度,各组血清CA125浓度均由本院实验室常规测得。3.统计学方法:采用SPSS13.0统计软件处理数据,所有计量资料数据均以均数±标准差(x±s)表示,计数资料采用X2检验,不同组织学类型、临床分期及病理分级表达阳性率的比较采用X2检验和Fisher精确概率法,表达强度的比较采用多组等级秩和检验。A值及各标本血清中浓度值的比较采用单因素方差分析。均数的比较采用单因素方差分析,组间均数两两比较采用LSD-t检验。A值与血清浓度值之间的相关性采用Spearman等级相关分析,P<0.05为差异有统计学意义。
结果: 1 eIF-4E及OPN在4种不同组织中的表达:eIF-4E主要表达于卵巢肿瘤的上皮细胞胞浆中,而OPN则主要表达于卵巢肿瘤的上皮细胞胞质中。在正常卵巢组织、良性、交界性、恶性卵巢上皮性肿瘤组织中,eIF-4E的阳性表达率分别为8.3%(1/12)、16.7%(2/12)、56.3%(9/16)及84.8(39/46),OPN的阳性表达率分别为16.7(2/12)、16.7(2/12)、62.5(10/16)及89.1%(41/46)。eIF-4E在正常组织及良性肿瘤组织的阳性表达率显著低于交界性及恶性肿瘤,前两者分别与后两者比较,差异均有统计学意义(P<0.05)。而前两者之间及后两者之间分别比较,差异均无统计学意义(P>0.05);OPN在正常组织及良性肿瘤组织的阳性表达率显著低于交界性及恶性肿瘤,前两者分别与后两者比较,差异均有统计学意义(P<0.05)。而前两者之间及后两者之间分别比较,差异均无统计学意义(P>0.05)。
2 eIF-4E及OPN在卵巢癌组织中的表达:eIF-4E及OPN在浆液性囊腺癌中的阳性表达率较粘液性囊腺癌及子宫内膜样癌有增高趋势,但三者分别比较,差异均无统计学意义(P>0.05),两者的阳性表达率在临床分期及病理分级间比较,差异无统计学意义(P>0.05)。eIF-4E及OPN的表达强度均随临床分期及病理分级的升高而增强但无统计学意义(P>0.05)。
3 eIF-4E及OPN在卵巢癌中的A值:eIF-4E及OPN的A值均随临床分期的增加而升高,且Ⅲ、Ⅳ期明显高于Ⅰ、Ⅱ期,4期间相互比较,差异均有统计学意义(P<0.05)。eIF-4E及OPN在G2、G3级组织中的A值显著高于G1级,前两者分别与后者比较,差异均有统计学意义(P<0.05),前两者之间比较,差异无统计学意义(P>0.05)。
4血清eIF-4E、OPN及CA125浓度的检测结果:卵巢恶性肿瘤组及交界性肿瘤组患者血清中eIF-4E、OPN、CA125的浓度明显高于卵巢良性肿瘤组及正常对照组患者,且有统计学意义(P<0.05);而前两者之间与后两者之间分别比较,差异均无统计学意义(P>0.05)。
5不同组织学类型的卵巢癌患者血清eIF-4E、OPN、CA125的浓度:浆液性囊腺癌患者血清中CA125的浓度明显高于粘液性囊腺癌及子宫内膜样癌患者,差异有统计学意义(P<0.05)。eIF-4E、OPN的浓度在三组之间比较,差异均无统计学意义(P>0.05),但在浆液性囊腺癌组中的浓度有较粘液性囊腺癌组及子宫内膜样癌组增高的趋势。
6不同临床分期的卵巢癌患者血清eIF-4E、OPN、CA125的浓度:Ⅲ、Ⅳ期卵巢癌患者血清中CA125、eIF-4E、OPN的浓度均明显高于Ⅰ、Ⅱ期,且差异有统计学意义(P<0.05)。
7血清eIF-4E、OPN、CA125单独及联合检测卵巢癌的阳性率:eIF-4E与CA125联合检测,OPN与CA125联合检测,eIF-4E、OPN、CA125三者联合检测的阳性率均高于单独检测的阳性率,差异有统计学意义(P<0.05)。
8卵巢癌组织中eIF-4E、OPN的表达与患者血清中eIF-4E、OPN浓度的关系:两者的表达均呈正相关,r分别为0.45,0.48, (P<0.05)。
结论:eIF-4E、OPN在上皮性卵巢癌及上皮性交界性卵巢肿瘤组织中的阳性表达率及患者血清浓度显著高于在上皮性良性卵巢肿瘤及正常卵巢组织中的阳性表达率及血清浓度,且随临床分期增高而增加,III、Ⅳ期卵巢癌患者血清中eIF-4E、OPN水平明显高于Ⅰ、II期。分化越差卵巢癌中eIF-4E、OPN水平越高。卵巢癌组织中eIF-4E、OPN的表达与患者血清中eIF-4E、OPN的浓度均呈正相关。血清中eIF-4E、OPN、CA125三者联合检测可大大提高卵巢癌检测的阳性率,因此,eIF-4E、OPN参与上皮性卵巢癌发生发展过程,可作为卵巢癌的早期诊断及判断预后的标志物,并且为卵巢癌的靶向治疗提供了新的靶点。
Objective: Ovarian tumour is a common gynaecological tumour. Ovarian cancer is one of the three main gynaecological malignancies, there are no effective methods in clinic for early diagnosis. The five-year survival rate is about 25%～30%. Ovarian cancer becomes the highest mortality tumour for the well developed of diagnosis and therapy of cervical carcinoma and endometrium carcinoma. People make great efforts to search for the special biomarker of ovarian carcinoma for early diagnosis, monitorring disease, observation of curative effect and predicting prognosis. We investigatted the correlation between eIF-4E,OPN and ovarian cancer by detecting the expression of eIF-4E,OPN in ovarian cancer tissue and their serum concentration to reveal the pathogenesis of ovarian cancer on genetic level. We Explorried the possibility of eIF-4E and OPN as tumour markers combined CA125 for early diagnosis, detecting curative effect and monitoring recurrence.
Methods: select 46 cases of ovarian epithelial carcinoma, 16 cases of borderlin ovarian epithelial tumour, 12cases of benign ovarian epithelial tumour, 12 cases of normal ovarian tissue, all confirmed by pathology. 1. Detecting the expression of eIF-4E, OPN in the above mentioned tissues by immunohistochemistry, measurring the value of absorbency (A) by pathological image analysis software of medical image analysis system, calculating average value of absorbency to make semiquantitative analysis. 2. Detecting the serum concertration of eIF-4E, OPN in the above samples, all serum concertration of CA125 are detecting by microsome chemiluminescence method in laboratory of our hospital. 3. Statistical method: all statistical analyses were performed with spss13.0 statistical software package, measurement data was expressed as mean SD values. The enumeration data were compared with the chi-square test. The positive expression rate in different pathological types, clinical staging and pathological grade were compared with the chi-square test and the fisher’s exact probability test. The comparison of the expression intensity in tissues was used Wilcoxon signed-rank test. The comparison of multiple mean was used analysis of variance after the equal check of variance, and the two-two comparison among the means was done by LSD-t method. The correlation between serum concentration and tissue A value was evaluated by spearman correlation analysis. The level of significance was set at P<0.05.
Results: 1 The expression of eIF-4E and OPN in four different tumor tissues: the eIF-4E protein was mainly expressed in plasma of ovarian tumor epithelial cells, whereas it was in cytoplasm for OPN. In normal ovary, benign, boderline and maligant ovarian lesions , the positive expression rate of eIF-4E protein was 8.3%(1/12), 16.7%(2/12), 56.3%(9/16)and 84.8(39/46), respectively; it was 16.7%(2/12), 16.7%(2/12), 62.5%(10/16) and 89.1%(41/46)for OPN protein. The positive expression rate of eIF-4E protein in normal ovary and benign ovarian lesions was lower than that in boderline and maligant ovarian lesions, the difference was remarkable between the former two and the latter two(P<0.05), but there were no significant difference in former two and in latter two(P>0.05);For OPN protein , the comparison between the former two and the latter two was the same as eIF-4E protein, but there were no significant difference in former two and in latter two(P>0.05).
2 The expression of eIF-4E and OPN in ovarian carcinoma tissues: the positive expression rate of eIF-4E and OPN protein in ovarian serous cystadenocarcinoma was higher than that in mucous cystadenocarcinoma and endometrioid adenocarcinoma, but there were no significant difference among the three groups(P>0.05). comparing the positive expression rate of eIF-4E and OPN protein in clinical stage and histopathologic grades , there were no significant difference(P>0.05); comparing the intensity of their expression, also no significant difference(P>0.05), but there was the ascending trend.
3 The A value of eIF-4E and OPN protein in ovarian carcinoma: With elevating clinical stage, the A value of eIF-4E and OPN protein were increased, in stageⅢ,Ⅳ, it was significantly higher than that in stageⅠ,Ⅱ, the difference was remarkable among the four stages(P<0.05). The A value of eIF-4E and OPN protein in G2, G3 grade was significantly higher than that in G1 grade. The difference was remarkable in the former two and the latter (P<0.05), resepectivly, there were no significant difference in former two(P>0.05).
4 The concentration of serum of eIF-4E, OPN and CA125: in boderline and maligant ovarian tumour patients, the concentration of serum of eIF-4E, OPN and CA125 were significantly higher than that in normal ovary and benign ovarian tumour patients(P<0.05), there were no significant difference between the former two and the latter two(P>0.05).
5 The serum concentration of eIF-4E, OPN and CA125 in different histological types: in serous cystadenocarcinoma, the serum concentration of CA125 was higher than that in mucous cystadenocarcinoma and endometrioid adenocar- cinoma, (P<0.05). Comparing the serum concentration of eIF-4E and OPN in three histological types, there were no significant difference(P>0.05), but the trend was ascending.
6 The serum concentration of eIF-4E, OPN and CA125 in different clinical stages: the serum concentration of eIF-4E, OPN and CA125 inⅢ,Ⅳstage was significantly higher than that inⅠ,Ⅱstage(P<0.05).
7 The serum positive expression rate of eIF-4E, OPN alone or combined with CA125 on the detection of ovarian carcinoma: eIF-4E or OPN combined with CA125 and using three of them, the positive expression rate in ovarian carcinoma were higher than that alone(P<0.05).
8 The ralation between the expression of eIF-4E and OPN of serum and tissue in patients with ovarian carcinoma : the expression of them was positively correlated, the correlation coefficient was 0.45, 0.48, respectively(P<0.05).
Conclusions: The positive expression rate of tissue and serum concentration of eIF-4E and OPN protein in boderline and maligant ovarian lesions are higher than that in normal ovary and benign ovarian lesions, with elevating clinical stage, the expression of their protein are increased, the level inⅢ,Ⅳstage is higher than that inⅠ,Ⅱstage. The expression of eIF-4E and OPN in ovarian carcinoma tissues were correlated with their concentration in serum. We detected the eIF-4E, OPN combined with CA125 in serum of ovarian tumour patient could improved the positive expression rate in ovarian carcinoma diagnosis. So, eIF-4E and OPN gene takes part in the development of malignant epithelial ovarian tumors. They may be regarded as the important biomarkers for early diagnosis, they can evaluate the curative effect of ovarian cancinoma and they may be become the new target for the therapy of ovarian carcinoma .
方法:选择经病理证实的卵巢上皮性癌46例,卵巢交界性上皮性肿瘤16例、卵巢良性上皮性肿瘤12例,正常卵巢组织12例。1.用免疫组织化学法检测上述组织标本中eIF-4E、OPN的表达水平,并用医学图像分析系统中的病理图像免疫组化分析软件,测量气吸光度(A)值,并计算平均值进行半定量分析。2.用双抗体夹心(ELISA)法检测上述血清标本中eIF-4E、OPN的浓度,各组血清CA125浓度均由本院实验室常规测得。3.统计学方法:采用SPSS13.0统计软件处理数据,所有计量资料数据均以均数±标准差(x±s)表示,计数资料采用X2检验,不同组织学类型、临床分期及病理分级表达阳性率的比较采用X2检验和Fisher精确概率法,表达强度的比较采用多组等级秩和检验。A值及各标本血清中浓度值的比较采用单因素方差分析。均数的比较采用单因素方差分析,组间均数两两比较采用LSD-t检验。A值与血清浓度值之间的相关性采用Spearman等级相关分析,P<0.05为差异有统计学意义。
结果: 1 eIF-4E及OPN在4种不同组织中的表达:eIF-4E主要表达于卵巢肿瘤的上皮细胞胞浆中,而OPN则主要表达于卵巢肿瘤的上皮细胞胞质中。在正常卵巢组织、良性、交界性、恶性卵巢上皮性肿瘤组织中,eIF-4E的阳性表达率分别为8.3%(1/12)、16.7%(2/12)、56.3%(9/16)及84.8(39/46),OPN的阳性表达率分别为16.7(2/12)、16.7(2/12)、62.5(10/16)及89.1%(41/46)。eIF-4E在正常组织及良性肿瘤组织的阳性表达率显著低于交界性及恶性肿瘤,前两者分别与后两者比较,差异均有统计学意义(P<0.05)。而前两者之间及后两者之间分别比较,差异均无统计学意义(P>0.05);OPN在正常组织及良性肿瘤组织的阳性表达率显著低于交界性及恶性肿瘤,前两者分别与后两者比较,差异均有统计学意义(P<0.05)。而前两者之间及后两者之间分别比较,差异均无统计学意义(P>0.05)。
2 eIF-4E及OPN在卵巢癌组织中的表达:eIF-4E及OPN在浆液性囊腺癌中的阳性表达率较粘液性囊腺癌及子宫内膜样癌有增高趋势,但三者分别比较,差异均无统计学意义(P>0.05),两者的阳性表达率在临床分期及病理分级间比较,差异无统计学意义(P>0.05)。eIF-4E及OPN的表达强度均随临床分期及病理分级的升高而增强但无统计学意义(P>0.05)。
3 eIF-4E及OPN在卵巢癌中的A值:eIF-4E及OPN的A值均随临床分期的增加而升高,且Ⅲ、Ⅳ期明显高于Ⅰ、Ⅱ期,4期间相互比较,差异均有统计学意义(P<0.05)。eIF-4E及OPN在G2、G3级组织中的A值显著高于G1级,前两者分别与后者比较,差异均有统计学意义(P<0.05),前两者之间比较,差异无统计学意义(P>0.05)。
4血清eIF-4E、OPN及CA125浓度的检测结果:卵巢恶性肿瘤组及交界性肿瘤组患者血清中eIF-4E、OPN、CA125的浓度明显高于卵巢良性肿瘤组及正常对照组患者,且有统计学意义(P<0.05);而前两者之间与后两者之间分别比较,差异均无统计学意义(P>0.05)。
5不同组织学类型的卵巢癌患者血清eIF-4E、OPN、CA125的浓度:浆液性囊腺癌患者血清中CA125的浓度明显高于粘液性囊腺癌及子宫内膜样癌患者,差异有统计学意义(P<0.05)。eIF-4E、OPN的浓度在三组之间比较,差异均无统计学意义(P>0.05),但在浆液性囊腺癌组中的浓度有较粘液性囊腺癌组及子宫内膜样癌组增高的趋势。
6不同临床分期的卵巢癌患者血清eIF-4E、OPN、CA125的浓度:Ⅲ、Ⅳ期卵巢癌患者血清中CA125、eIF-4E、OPN的浓度均明显高于Ⅰ、Ⅱ期,且差异有统计学意义(P<0.05)。
7血清eIF-4E、OPN、CA125单独及联合检测卵巢癌的阳性率:eIF-4E与CA125联合检测,OPN与CA125联合检测,eIF-4E、OPN、CA125三者联合检测的阳性率均高于单独检测的阳性率,差异有统计学意义(P<0.05)。
8卵巢癌组织中eIF-4E、OPN的表达与患者血清中eIF-4E、OPN浓度的关系:两者的表达均呈正相关,r分别为0.45,0.48, (P<0.05)。
结论:eIF-4E、OPN在上皮性卵巢癌及上皮性交界性卵巢肿瘤组织中的阳性表达率及患者血清浓度显著高于在上皮性良性卵巢肿瘤及正常卵巢组织中的阳性表达率及血清浓度,且随临床分期增高而增加,III、Ⅳ期卵巢癌患者血清中eIF-4E、OPN水平明显高于Ⅰ、II期。分化越差卵巢癌中eIF-4E、OPN水平越高。卵巢癌组织中eIF-4E、OPN的表达与患者血清中eIF-4E、OPN的浓度均呈正相关。血清中eIF-4E、OPN、CA125三者联合检测可大大提高卵巢癌检测的阳性率,因此,eIF-4E、OPN参与上皮性卵巢癌发生发展过程,可作为卵巢癌的早期诊断及判断预后的标志物,并且为卵巢癌的靶向治疗提供了新的靶点。
Objective: Ovarian tumour is a common gynaecological tumour. Ovarian cancer is one of the three main gynaecological malignancies, there are no effective methods in clinic for early diagnosis. The five-year survival rate is about 25%～30%. Ovarian cancer becomes the highest mortality tumour for the well developed of diagnosis and therapy of cervical carcinoma and endometrium carcinoma. People make great efforts to search for the special biomarker of ovarian carcinoma for early diagnosis, monitorring disease, observation of curative effect and predicting prognosis. We investigatted the correlation between eIF-4E,OPN and ovarian cancer by detecting the expression of eIF-4E,OPN in ovarian cancer tissue and their serum concentration to reveal the pathogenesis of ovarian cancer on genetic level. We Explorried the possibility of eIF-4E and OPN as tumour markers combined CA125 for early diagnosis, detecting curative effect and monitoring recurrence.
Methods: select 46 cases of ovarian epithelial carcinoma, 16 cases of borderlin ovarian epithelial tumour, 12cases of benign ovarian epithelial tumour, 12 cases of normal ovarian tissue, all confirmed by pathology. 1. Detecting the expression of eIF-4E, OPN in the above mentioned tissues by immunohistochemistry, measurring the value of absorbency (A) by pathological image analysis software of medical image analysis system, calculating average value of absorbency to make semiquantitative analysis. 2. Detecting the serum concertration of eIF-4E, OPN in the above samples, all serum concertration of CA125 are detecting by microsome chemiluminescence method in laboratory of our hospital. 3. Statistical method: all statistical analyses were performed with spss13.0 statistical software package, measurement data was expressed as mean SD values. The enumeration data were compared with the chi-square test. The positive expression rate in different pathological types, clinical staging and pathological grade were compared with the chi-square test and the fisher’s exact probability test. The comparison of the expression intensity in tissues was used Wilcoxon signed-rank test. The comparison of multiple mean was used analysis of variance after the equal check of variance, and the two-two comparison among the means was done by LSD-t method. The correlation between serum concentration and tissue A value was evaluated by spearman correlation analysis. The level of significance was set at P<0.05.
Results: 1 The expression of eIF-4E and OPN in four different tumor tissues: the eIF-4E protein was mainly expressed in plasma of ovarian tumor epithelial cells, whereas it was in cytoplasm for OPN. In normal ovary, benign, boderline and maligant ovarian lesions , the positive expression rate of eIF-4E protein was 8.3%(1/12), 16.7%(2/12), 56.3%(9/16)and 84.8(39/46), respectively; it was 16.7%(2/12), 16.7%(2/12), 62.5%(10/16) and 89.1%(41/46)for OPN protein. The positive expression rate of eIF-4E protein in normal ovary and benign ovarian lesions was lower than that in boderline and maligant ovarian lesions, the difference was remarkable between the former two and the latter two(P<0.05), but there were no significant difference in former two and in latter two(P>0.05);For OPN protein , the comparison between the former two and the latter two was the same as eIF-4E protein, but there were no significant difference in former two and in latter two(P>0.05).
2 The expression of eIF-4E and OPN in ovarian carcinoma tissues: the positive expression rate of eIF-4E and OPN protein in ovarian serous cystadenocarcinoma was higher than that in mucous cystadenocarcinoma and endometrioid adenocarcinoma, but there were no significant difference among the three groups(P>0.05). comparing the positive expression rate of eIF-4E and OPN protein in clinical stage and histopathologic grades , there were no significant difference(P>0.05); comparing the intensity of their expression, also no significant difference(P>0.05), but there was the ascending trend.
3 The A value of eIF-4E and OPN protein in ovarian carcinoma: With elevating clinical stage, the A value of eIF-4E and OPN protein were increased, in stageⅢ,Ⅳ, it was significantly higher than that in stageⅠ,Ⅱ, the difference was remarkable among the four stages(P<0.05). The A value of eIF-4E and OPN protein in G2, G3 grade was significantly higher than that in G1 grade. The difference was remarkable in the former two and the latter (P<0.05), resepectivly, there were no significant difference in former two(P>0.05).
4 The concentration of serum of eIF-4E, OPN and CA125: in boderline and maligant ovarian tumour patients, the concentration of serum of eIF-4E, OPN and CA125 were significantly higher than that in normal ovary and benign ovarian tumour patients(P<0.05), there were no significant difference between the former two and the latter two(P>0.05).
5 The serum concentration of eIF-4E, OPN and CA125 in different histological types: in serous cystadenocarcinoma, the serum concentration of CA125 was higher than that in mucous cystadenocarcinoma and endometrioid adenocar- cinoma, (P<0.05). Comparing the serum concentration of eIF-4E and OPN in three histological types, there were no significant difference(P>0.05), but the trend was ascending.
6 The serum concentration of eIF-4E, OPN and CA125 in different clinical stages: the serum concentration of eIF-4E, OPN and CA125 inⅢ,Ⅳstage was significantly higher than that inⅠ,Ⅱstage(P<0.05).
7 The serum positive expression rate of eIF-4E, OPN alone or combined with CA125 on the detection of ovarian carcinoma: eIF-4E or OPN combined with CA125 and using three of them, the positive expression rate in ovarian carcinoma were higher than that alone(P<0.05).
8 The ralation between the expression of eIF-4E and OPN of serum and tissue in patients with ovarian carcinoma : the expression of them was positively correlated, the correlation coefficient was 0.45, 0.48, respectively(P<0.05).
Conclusions: The positive expression rate of tissue and serum concentration of eIF-4E and OPN protein in boderline and maligant ovarian lesions are higher than that in normal ovary and benign ovarian lesions, with elevating clinical stage, the expression of their protein are increased, the level inⅢ,Ⅳstage is higher than that inⅠ,Ⅱstage. The expression of eIF-4E and OPN in ovarian carcinoma tissues were correlated with their concentration in serum. We detected the eIF-4E, OPN combined with CA125 in serum of ovarian tumour patient could improved the positive expression rate in ovarian carcinoma diagnosis. So, eIF-4E and OPN gene takes part in the development of malignant epithelial ovarian tumors. They may be regarded as the important biomarkers for early diagnosis, they can evaluate the curative effect of ovarian cancinoma and they may be become the new target for the therapy of ovarian carcinoma .
引文
1 De Benedetti A, Graff JR. eIF-4E expression and its role in malignanries [J]. Oncogene, 2004, 23(18): 3189-3199
2 Mamane Y,Petroulakis E,Rong L, et al. eIF-4E translation to tranformation [J]. Oncogene, 2004, 23(18): 3172-3179
3 Wendel HG, Silva RL,Malina A, Mills JR, et al. Diss-ecting eIF4E action in tumorigenesis [J]. Genes Dev, 2007, 21(24): 3232-3327
4 Rhoads RE. Regulation of eukaryotic protein sythesis by initiation factors [J]. J Biol Chem, 1993, 268(5): 3017-3021
5 Wang X, Yue P, Chan CB, et al. Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinas-edependent and Mnk-mediated eukaryotic translatio-n initiation factor 4E phosphorylation [J]. Mol Cell Biol, 2007, 27(21): 7405-7413
6 Chung J, Bachelder RE, Lipscomb EA, et al. Integrin regulation of eIF-4E activity and VEGF translation: a survival mechanism for carcinoma cell [J]. J Cell Biol, 2002, 158(1): 165-174
7 Graff JR, Zimmer SG. Translational control and metastatic progression: Enhanced activity of mRNA cap-binding protein eIF-4E selectively enhances translation of metastasis-relate dmRNAs [J]. Clin ExpMetastasis, 2003, 20(3): 265-273
8 Rosenwald IB. The role of translation in neoplastic trasformation from a pathologist’s point of view [J]. Oncogene, 2004, 23(18): 3230-3247
9 Rinker SCW, Graff JR, De Benedetti, et al. Decreasing the level of translation initiation factor 4E with antisense RNA caused reveral of rasmedliated transformation and tumorigenesis of cloned rat embryo fibroblasts [J]. Int J Cancer, 1993, 55(5): 841-84
10 De Benedetti A, Graff JR. eIF4E expression and itsrol inmalignancies and metastases [J]. Oncogene, 2004, 23(18): 3189-3199
11 Wang S, Lloyd RV, Hutzler MJ, et al. Expression of eukaryotic translation initiation factors 4E and alpha correlates with the progression of thyroid carcinoma [J]. Thyroid, 2001, 11(12): 1101-1107
12 Zimmer SG, De Benedetti A, Graff JR. Translational control ofmalignancy: the mRNA cap-binding protein, eIF-4E, as a central regulator of tumor formation, growth, invasion and metastasis [J]. Anticancer Res, 2000, 20(3): 1343-1351
13 Salehi Z, Mashayekhif F, Shahosseini F. Significance of eIF4E expression in skin squamous cell carcinoma [J]. Cell Biol Int, 2007, 31(11): 1400-1404
14 Fedarko NS, Jain A, Karaadag A, et al. Elevated serum bone sialoprotein and osteopontin in colon, breast, prostate, and lung cancer [J]. Clin Cancer Res, 2001, 7(12): 4060-4066
15 Lin YH, Yang-Yen HF. The osteopontin-CD44 survival signal involves activation of the phosphatidylinositol 3-kinase/Akt signaling pathway [J]. J Biol Chem, 2001, 276(49): 46024-46030
16 Zohar R, Suzuki N, Suzuki K, et al. Intracellular osteopontin is an integral component of the CD44-ERM complex involved in cell migration [J]. J Cell Physiol, 2000, 184(1): 118-130
17 Castellone MD, Celetti A, Guarino V, et al. Autocrine stimulation by osteopontin plays a pivotal role in the expression of the mitogenic and invasive phenotype of RET/PTC-transformed thyroid cells [J]. Oncogene, 2004,23(12): 2188-2189
18 Ue T, YokozakiH, KitadaiY, et al. Co-expression of osteopontin and CD44v9 in gastric cancer [J]. Int JCancer,1998, 79(2): 127-132
19 Reiniger IW, Wolf A, Welge-Lussen U. Osteopontin as a serologic marker for metastatic uveal melanoma: results of a pilot study [J]. Am J Ophthalmol, 2007, 143 (4): 705-707
20 Eto M, Kodama S,Nomy N, et al. Clinical significance of elevated osteopontin levels in head and neck cancer patients[J]. Auris Nasus Larynx, 2007, 34(3): 343-346
21 Saeki Y, Mima T, Ishii T, et al Enhanced production of osteopontin inmultiplemyeloma: clinical and pathogen-ic implications [J]. Br J Haematol, 2003, 123(2): 263-270
22 Wu CY, Wu MS, Chiang EP, et al. Elevated plasma osteopontin associated with gastric cancer development, invasion and survival [J].Gut, 2007, 56(6): 782-789
23 Coppola D, SzaboM, Boulware D, et al. Correlation of osteopontin protein expression and pathological stage across awide variety of tumor histologies [J]. Clin CancerRes, 2004, 10(1): 184-190
24 Chang YS, Kim HJ, Chang J. Elevated circulating level of osteopontin is associated with advanced disease state of non-small cell lung cancer [J]. Lung Cancer, 2007, 57(3): 373-380
25 Rohde F, Rimkus C, FriederichsJ. Expression of osteopontin, a target gene of de-regulated Wnt signaling, pre-dicts survival in colon cancer [J]. Int J Cancer, 2007, 121(8):1717-1723
26 Ramankulov A, Lein M, Kristiansen G. Elevated plasma osteopontin as marker for distant metastases and poor survival in patients with renal cell carcinoma[J]. J Cancer Res Clin Oncol, 2007, 133(9): 643-652
27 Coppola D, SzaboM, Boulware D, et al. Correlation of osteopontin protein expression and pathological stage across awide variety of tumor histologies [J]. Clin CancerRes, 2004, 10(1): 184-190
28 Fedarko NS, Jain A, Karadag A, et al. Elevated serum bone sialoprotein and osteopontin in colon, breast, prostate and lung cancer [J]. Clin Cancer Res, 2001, 7(12): 4060-4066
1 Joshi B, Cameron A, Jagus R. Characterization of mammalian eIF4E family members [J]. Eur J Biochem, 2004, 271(11): 2189-2203
2 Strudwick S, Borden KL. The emerging role of translation factor eIF4E in the nucleus [J]. Differentiation, 2002, 70(1): 10-22
3 Clemens MJ. Targets and mechanisms for the regulation of translation in malignant transformation [J]. Oncogene, 2004, 23(18): 3180-3188
4 Wendel HG, Silva RL, Malina A, Mills JR, et al. Dissecting eIF4E action in tumorigenesis[J]. Genes Dev, 2007, 21(24): 3232-3327
5 Ivan Topisirovic ML, Alex Kentsis, Jacqueline M, et al. Eukaryotic translation initiation factor 4E activity is modulated by HOXA9 at multiple levels [J]. Molecular and Cellular Biology, 2005, 25(3): 1100-1112
6 Wang X, Yue P, Chan CB, et al. Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-k-inase-dependent and Mnk-mediated eukaryotic translati-on initiation factor 4E phosphorylation[J]. Mol Cell Biol,2007, 27(21): 7405-7413
7 Scheper GC, Proud GC. Dose phosphotylation of the cap-binding protein eIF4E play a role in translation initiation[J]. Eur J BioLChem, 2002, 269(22): 5350-5359
8 Graff GR, Kanicek BW, Vincent TM, et al. Therapeutic suppression of translation initiation factor eIF4E expression reduces tumor growth without toxicity [J]. Clin Invest, 2007, 117(9): 2638-2648
9 Topisirovic IB, Culjkovic N, Cohen JM, et al. The proline-rich homeodomain protein, PRH, is a tissue specific inhibitor of eIF4E-dependent cyclin D1 mRNA transport and growth [J]. EMBO J, 2003, 22(3): 689-703
10 Cohen N, MSharma, AKentsis, et al. PML RING suppresses oncogenic transformation by reducing the affinity of eIF4E for mRNA [J]. EMBO J, 2001, 20(16): 4547-4559
11 Rosenwald IB. The role of translation in neoplastic transformation from a pathologist’s point of view [J]. Oncogene, 2004, 23(18): 3230-3247
12 Chandy B, Abreo F, Nassar R, et al. expression of the proto-oncogene eIF-4E in inflammation of the oral cavi-ty.Otolaryngol Head Neck Surg, 2002, 126(3):290-295
13 Haydon MS, Googe JD, Sorrells DS, et al. Progressionof eIF4e gene amplification and overexpression in benign and malignant tumors of the head and neck [J]. Cancer, 2000, 88(12): 2803-2810
14 Nathan CA, Sanders K, Abreo FW, et al. Correlation of p53 and the protooncogene eIF4E in larynx cancer: prognostic implications [J].Cancer Res, 2000, 60 (13): 3599-3604
15 Liang Z, Lei T, Lu Ying Z, et al. The expression of proto-oncogene elF4E in laryngeal squamous cell carcinoma [J]. Laryngoscope, 2003, 113(7): 1238-1243
16 Norton KS, Icclusky D, Sen S. TLKIB is elevated with eIF4E overexpression in breast cancer [J]. J Surg Res, 2004, 116(1): 98-103
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47 Eto M, Kodama S, Nomy N, et al. Clinical significance of elevated osteopontin levels in head and neck cancer patients[J]. Auris Nasus Larynx, 2007, 34(3): 343-346
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50 Ramankulov A, Lein M, Kristiansen G. Elevated plasma osteopontin as marker for distant metastases and poor survival in patients with renal cell carcinoma[J]. Cancer Res Clin Oncol, 2007, 133(9): 643-652
51 Rohde F, Rimkus C, FriederichsJ. Expression of osteopontin, a target gene of de-regulated Wnt signaling, predicts survival in colon cancer[J]. Int J Cancer, 2007, 121(8): 1717-1723
52 Hirama M, Takahashi F, Takahashi K, et al. Osteopontin overproduced by tumor cells acts as a potent angiogenic factor contributing to tumor growth[J]. Cancer Lett, 2003, 198(1): 107-117
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2 Mamane Y,Petroulakis E,Rong L, et al. eIF-4E translation to tranformation [J]. Oncogene, 2004, 23(18): 3172-3179
3 Wendel HG, Silva RL,Malina A, Mills JR, et al. Diss-ecting eIF4E action in tumorigenesis [J]. Genes Dev, 2007, 21(24): 3232-3327
4 Rhoads RE. Regulation of eukaryotic protein sythesis by initiation factors [J]. J Biol Chem, 1993, 268(5): 3017-3021
5 Wang X, Yue P, Chan CB, et al. Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinas-edependent and Mnk-mediated eukaryotic translatio-n initiation factor 4E phosphorylation [J]. Mol Cell Biol, 2007, 27(21): 7405-7413
6 Chung J, Bachelder RE, Lipscomb EA, et al. Integrin regulation of eIF-4E activity and VEGF translation: a survival mechanism for carcinoma cell [J]. J Cell Biol, 2002, 158(1): 165-174
7 Graff JR, Zimmer SG. Translational control and metastatic progression: Enhanced activity of mRNA cap-binding protein eIF-4E selectively enhances translation of metastasis-relate dmRNAs [J]. Clin ExpMetastasis, 2003, 20(3): 265-273
8 Rosenwald IB. The role of translation in neoplastic trasformation from a pathologist’s point of view [J]. Oncogene, 2004, 23(18): 3230-3247
9 Rinker SCW, Graff JR, De Benedetti, et al. Decreasing the level of translation initiation factor 4E with antisense RNA caused reveral of rasmedliated transformation and tumorigenesis of cloned rat embryo fibroblasts [J]. Int J Cancer, 1993, 55(5): 841-84
10 De Benedetti A, Graff JR. eIF4E expression and itsrol inmalignancies and metastases [J]. Oncogene, 2004, 23(18): 3189-3199
11 Wang S, Lloyd RV, Hutzler MJ, et al. Expression of eukaryotic translation initiation factors 4E and alpha correlates with the progression of thyroid carcinoma [J]. Thyroid, 2001, 11(12): 1101-1107
12 Zimmer SG, De Benedetti A, Graff JR. Translational control ofmalignancy: the mRNA cap-binding protein, eIF-4E, as a central regulator of tumor formation, growth, invasion and metastasis [J]. Anticancer Res, 2000, 20(3): 1343-1351
13 Salehi Z, Mashayekhif F, Shahosseini F. Significance of eIF4E expression in skin squamous cell carcinoma [J]. Cell Biol Int, 2007, 31(11): 1400-1404
14 Fedarko NS, Jain A, Karaadag A, et al. Elevated serum bone sialoprotein and osteopontin in colon, breast, prostate, and lung cancer [J]. Clin Cancer Res, 2001, 7(12): 4060-4066
15 Lin YH, Yang-Yen HF. The osteopontin-CD44 survival signal involves activation of the phosphatidylinositol 3-kinase/Akt signaling pathway [J]. J Biol Chem, 2001, 276(49): 46024-46030
16 Zohar R, Suzuki N, Suzuki K, et al. Intracellular osteopontin is an integral component of the CD44-ERM complex involved in cell migration [J]. J Cell Physiol, 2000, 184(1): 118-130
17 Castellone MD, Celetti A, Guarino V, et al. Autocrine stimulation by osteopontin plays a pivotal role in the expression of the mitogenic and invasive phenotype of RET/PTC-transformed thyroid cells [J]. Oncogene, 2004,23(12): 2188-2189
18 Ue T, YokozakiH, KitadaiY, et al. Co-expression of osteopontin and CD44v9 in gastric cancer [J]. Int JCancer,1998, 79(2): 127-132
19 Reiniger IW, Wolf A, Welge-Lussen U. Osteopontin as a serologic marker for metastatic uveal melanoma: results of a pilot study [J]. Am J Ophthalmol, 2007, 143 (4): 705-707
20 Eto M, Kodama S,Nomy N, et al. Clinical significance of elevated osteopontin levels in head and neck cancer patients[J]. Auris Nasus Larynx, 2007, 34(3): 343-346
21 Saeki Y, Mima T, Ishii T, et al Enhanced production of osteopontin inmultiplemyeloma: clinical and pathogen-ic implications [J]. Br J Haematol, 2003, 123(2): 263-270
22 Wu CY, Wu MS, Chiang EP, et al. Elevated plasma osteopontin associated with gastric cancer development, invasion and survival [J].Gut, 2007, 56(6): 782-789
23 Coppola D, SzaboM, Boulware D, et al. Correlation of osteopontin protein expression and pathological stage across awide variety of tumor histologies [J]. Clin CancerRes, 2004, 10(1): 184-190
24 Chang YS, Kim HJ, Chang J. Elevated circulating level of osteopontin is associated with advanced disease state of non-small cell lung cancer [J]. Lung Cancer, 2007, 57(3): 373-380
25 Rohde F, Rimkus C, FriederichsJ. Expression of osteopontin, a target gene of de-regulated Wnt signaling, pre-dicts survival in colon cancer [J]. Int J Cancer, 2007, 121(8):1717-1723
26 Ramankulov A, Lein M, Kristiansen G. Elevated plasma osteopontin as marker for distant metastases and poor survival in patients with renal cell carcinoma[J]. J Cancer Res Clin Oncol, 2007, 133(9): 643-652
27 Coppola D, SzaboM, Boulware D, et al. Correlation of osteopontin protein expression and pathological stage across awide variety of tumor histologies [J]. Clin CancerRes, 2004, 10(1): 184-190
28 Fedarko NS, Jain A, Karadag A, et al. Elevated serum bone sialoprotein and osteopontin in colon, breast, prostate and lung cancer [J]. Clin Cancer Res, 2001, 7(12): 4060-4066
1 Joshi B, Cameron A, Jagus R. Characterization of mammalian eIF4E family members [J]. Eur J Biochem, 2004, 271(11): 2189-2203
2 Strudwick S, Borden KL. The emerging role of translation factor eIF4E in the nucleus [J]. Differentiation, 2002, 70(1): 10-22
3 Clemens MJ. Targets and mechanisms for the regulation of translation in malignant transformation [J]. Oncogene, 2004, 23(18): 3180-3188
4 Wendel HG, Silva RL, Malina A, Mills JR, et al. Dissecting eIF4E action in tumorigenesis[J]. Genes Dev, 2007, 21(24): 3232-3327
5 Ivan Topisirovic ML, Alex Kentsis, Jacqueline M, et al. Eukaryotic translation initiation factor 4E activity is modulated by HOXA9 at multiple levels [J]. Molecular and Cellular Biology, 2005, 25(3): 1100-1112
6 Wang X, Yue P, Chan CB, et al. Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-k-inase-dependent and Mnk-mediated eukaryotic translati-on initiation factor 4E phosphorylation[J]. Mol Cell Biol,2007, 27(21): 7405-7413
7 Scheper GC, Proud GC. Dose phosphotylation of the cap-binding protein eIF4E play a role in translation initiation[J]. Eur J BioLChem, 2002, 269(22): 5350-5359
8 Graff GR, Kanicek BW, Vincent TM, et al. Therapeutic suppression of translation initiation factor eIF4E expression reduces tumor growth without toxicity [J]. Clin Invest, 2007, 117(9): 2638-2648
9 Topisirovic IB, Culjkovic N, Cohen JM, et al. The proline-rich homeodomain protein, PRH, is a tissue specific inhibitor of eIF4E-dependent cyclin D1 mRNA transport and growth [J]. EMBO J, 2003, 22(3): 689-703
10 Cohen N, MSharma, AKentsis, et al. PML RING suppresses oncogenic transformation by reducing the affinity of eIF4E for mRNA [J]. EMBO J, 2001, 20(16): 4547-4559
11 Rosenwald IB. The role of translation in neoplastic transformation from a pathologist’s point of view [J]. Oncogene, 2004, 23(18): 3230-3247
12 Chandy B, Abreo F, Nassar R, et al. expression of the proto-oncogene eIF-4E in inflammation of the oral cavi-ty.Otolaryngol Head Neck Surg, 2002, 126(3):290-295
13 Haydon MS, Googe JD, Sorrells DS, et al. Progressionof eIF4e gene amplification and overexpression in benign and malignant tumors of the head and neck [J]. Cancer, 2000, 88(12): 2803-2810
14 Nathan CA, Sanders K, Abreo FW, et al. Correlation of p53 and the protooncogene eIF4E in larynx cancer: prognostic implications [J].Cancer Res, 2000, 60 (13): 3599-3604
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