食管鳞癌候选扩增癌基因研究
摘要
食管癌的死亡率在我国恶性肿瘤中居第四位，鳞状细胞癌是我国食管癌的主要病理类型，五年生存率低于10％。为鉴定与食管癌关系密切的癌基因，本研究从基因扩增的角度出发，在实验室前期进行的食管癌细胞遗传学和分子遗传学研究以及文献报道的基础上，从扩增发生频率较高的染色体区段1q、3q、8q和11q中寻找与食管癌发生发展有关的扩增基因。
本研究首先挑选30个可能与肿瘤相关的基因，通过RT-PCR方法检测其在16对食管癌及相应的癌旁组织的表达，结果显示TXNRD3、RAB7、AMOTL2、CCNL1、EIF5A2、p63、MUC4、TMEM16A和CTTN基因在食管癌组织过表达的频率大于30％。利用这9个基因内部的UniSTS，进一步通过半定量PCR方法检测其在另外20对食管癌及配对癌旁组织中的基因组DNA含量，发现TXNRD3、RAB7、AMOTL2、CCNL1、MUC4、TMEM16A和CTTN基因在食管癌组织中扩增频率不低于20％。荧光原位杂交也证实CCNL1和CTTN基因在食管癌组织存在扩增。
定位于11q13上的cortactin(CTTN，也称为EMS1)基因编码的蛋白是促进肌动蛋白核化和支链形成的重要分子，目前对其在具体肿瘤中作用的研究还相对较少，为此我们对该基因在食管癌中的作用进行了深入的研究。食管癌组织芯片的免疫组化分析发现CTTN在食管癌中过表达率为68.8％(86／125)，过表达与淋巴结转移和肿瘤分期相关。11q13上另一重要癌基因CCND1在食管癌中过表达率为47.0％(55／117)，其表达虽与CTTN表达显著相关，但与淋巴结转移等临床参数无明显相关性。说明CTTN基因是11q13上与食管癌淋巴结转移和肿瘤分期相关的独立因素。
在食管癌细胞系EC9706的体外实验中，CTTN RNAi不影响细胞的增殖、平板集落形成、细胞周期进展和对Matrigel的粘附能力，但可抑制细胞的划痕愈合、运动穿膜、Matrigel侵袭、软琼脂集落形成和抗失巢凋亡能力。体内实验显示，CTTN表达降低可抑制裸鼠皮下瘤生长和实验性肺转移，延长实验性转移裸鼠的生存期。
针对CTTN影响EC9706细胞抗失巢凋亡能力这一现象，我们进一步探讨其分子机制。发现P13K和MEK抑制剂均可增加EC9706细胞的失巢凋亡，但CTTN只影响Akt的活化，对Erk和EGFR激活无影响，提示CTTN的抗失巢凋亡作用与P13K-Akt通路有关。我们在KYSE410食管癌细胞中也验证了CTTN的高表达有助于保护细胞抵抗失巢凋亡，并可提高Akt的活化水平。进一步在EC9706和KYSE410细胞中，Co-IP实验证实CTTN和P13K蛋白分子可被共沉淀，提示CTTN可能通过与P13K相互作用，活化P13K-Akt通路而提高食管癌细胞的抗失巢凋亡的能力。
以上结果表明，从DNA扩增片段中寻找在肿瘤过表达的基因是鉴定与特定肿瘤相关癌基因的有效方法。染色体11q13上的CTTN基因，通过发生扩增和过表达，提高食管癌细胞的运动和抗失巢凋亡能力，是促进食管癌侵袭转移的重要癌基因。
Esophageal cancer is the fourth most common malignancy in China and esophageal squamous cell carcinoma (ESCC) is the most prevalent type. Multiple genetic changes have been found in ESCC, but little is known about major oncogenes and tumor suppressor genes involved in this disease. In pursuit of candidate oncogenes in ESCC, we focused on overexpressed genes within previously identified chromosome regions with frequent amplification in ESCC in the present study.
30 cancer-related genes on chromosome 1q, 3q, 8q and 11q were examined in 16 primary esophageal tumors and matched adjacent histological normal tissues by RT-PCR. TXNRD3, RAB7, AMOTL2, CCNL1, EIF5A2, p63, MUC4, TMEM16A and CTTN presented mRNA overexpression in over 30% tumors. The genomic DNA copy number of these nine genes was then evaluated by semi-quantitative PCR of intragenic UniSTS in 20 cases of tumors and matched normal tissues. Amplification of TXNRD3, RAB7, AMOTL2, CCNL1, MUC4, TMEM16A and CTTN was found in more than 20% of cancerous tissues. CCNL1 and CTTN amplifications were confirmed in ESCC by fluorescence in situ hybridization (FISH).
The cortactin gene (CTTN, also as EMS1), located at 11q13, plays a pivotal role in coupling membrane dynamics to cortical actin assembly. In the present study, immunohistochemical analysis was performed on tissue microarrays and CTTN overexpression was found in 68.8% (86/125) tumors. Statistical analysis indicated that there were significant correlations between CTTN expression and lymph node metastasis and tumor stage in ESCC. CCND1 is another oncogene on 11q13 and its overexpression was detected in 47.0% (55/117) ESCC. Although a positive correlation between CCND1 and CTTN expression was observed, none of the tumor clinicopathologic features was associated with CCND1 overexpression. These results indicate that CTTN is an independent marker at 11q13 for ESCC lymphoid metastasis and tumor stage.
Functional analysis by siRNA-mediated silencing revealed that CTTN did not influence cell proliferation, cell cycle progression and adhesion to Matrigel in esophageal cancer cell line EC9706. Whereas CTTN RNAi decreased EC9706 capabilities in wound healing, haptotactic migration, Matrigel chemoinvasion colony formation in soft agar and anoikis resistance. In vivo assay showed that inhibition of CTTN expression also decreased tumor growth and lung metastasis of EC9706 cells.
To explore the molecular mechanism by which CTTN protected cells from anoikis, we examined the potential effect of CTTN on the activation of several known pathway associated with anoikis. Both PI3K and MEK inhibitors abrogated the survival protection of CTTN in EC9706, while only phosphorylated Akt was down-regulated in CTTN RNAi cells. No difference in Erk activation or EGFR expression was observed after CTTN suppression, suggesting that PI3K-Akt, not MEK-Erk or EGFR signaling, contributed to CTTN-related survival in detached EC9706. CTTN also protected KYSE410 esophageal cancer cells from anoikis when overexpressed. Akt activation was observed in these cells after CTTN transfection as well. In EC9706 and KYSE410 cells, CTTN and PI3K could be co-immunoprecipitated by either of the antibodies. These data imply that CTTN may interact with PI3K and activate it to serve a protective function in anoikis resistance.
In conclusion, analysis of amplified genes may be helpful to the identification of oncogenes associated with malignant tumors. The CTTN gene in the 11q13 amplicon, through DNA copy number increase and protein overexpression, plays an oncogenic role in ESCC metastasis by promoting cell migration and anoikis resistance.
本研究首先挑选30个可能与肿瘤相关的基因，通过RT-PCR方法检测其在16对食管癌及相应的癌旁组织的表达，结果显示TXNRD3、RAB7、AMOTL2、CCNL1、EIF5A2、p63、MUC4、TMEM16A和CTTN基因在食管癌组织过表达的频率大于30％。利用这9个基因内部的UniSTS，进一步通过半定量PCR方法检测其在另外20对食管癌及配对癌旁组织中的基因组DNA含量，发现TXNRD3、RAB7、AMOTL2、CCNL1、MUC4、TMEM16A和CTTN基因在食管癌组织中扩增频率不低于20％。荧光原位杂交也证实CCNL1和CTTN基因在食管癌组织存在扩增。
定位于11q13上的cortactin(CTTN，也称为EMS1)基因编码的蛋白是促进肌动蛋白核化和支链形成的重要分子，目前对其在具体肿瘤中作用的研究还相对较少，为此我们对该基因在食管癌中的作用进行了深入的研究。食管癌组织芯片的免疫组化分析发现CTTN在食管癌中过表达率为68.8％(86／125)，过表达与淋巴结转移和肿瘤分期相关。11q13上另一重要癌基因CCND1在食管癌中过表达率为47.0％(55／117)，其表达虽与CTTN表达显著相关，但与淋巴结转移等临床参数无明显相关性。说明CTTN基因是11q13上与食管癌淋巴结转移和肿瘤分期相关的独立因素。
在食管癌细胞系EC9706的体外实验中，CTTN RNAi不影响细胞的增殖、平板集落形成、细胞周期进展和对Matrigel的粘附能力，但可抑制细胞的划痕愈合、运动穿膜、Matrigel侵袭、软琼脂集落形成和抗失巢凋亡能力。体内实验显示，CTTN表达降低可抑制裸鼠皮下瘤生长和实验性肺转移，延长实验性转移裸鼠的生存期。
针对CTTN影响EC9706细胞抗失巢凋亡能力这一现象，我们进一步探讨其分子机制。发现P13K和MEK抑制剂均可增加EC9706细胞的失巢凋亡，但CTTN只影响Akt的活化，对Erk和EGFR激活无影响，提示CTTN的抗失巢凋亡作用与P13K-Akt通路有关。我们在KYSE410食管癌细胞中也验证了CTTN的高表达有助于保护细胞抵抗失巢凋亡，并可提高Akt的活化水平。进一步在EC9706和KYSE410细胞中，Co-IP实验证实CTTN和P13K蛋白分子可被共沉淀，提示CTTN可能通过与P13K相互作用，活化P13K-Akt通路而提高食管癌细胞的抗失巢凋亡的能力。
以上结果表明，从DNA扩增片段中寻找在肿瘤过表达的基因是鉴定与特定肿瘤相关癌基因的有效方法。染色体11q13上的CTTN基因，通过发生扩增和过表达，提高食管癌细胞的运动和抗失巢凋亡能力，是促进食管癌侵袭转移的重要癌基因。
Esophageal cancer is the fourth most common malignancy in China and esophageal squamous cell carcinoma (ESCC) is the most prevalent type. Multiple genetic changes have been found in ESCC, but little is known about major oncogenes and tumor suppressor genes involved in this disease. In pursuit of candidate oncogenes in ESCC, we focused on overexpressed genes within previously identified chromosome regions with frequent amplification in ESCC in the present study.
30 cancer-related genes on chromosome 1q, 3q, 8q and 11q were examined in 16 primary esophageal tumors and matched adjacent histological normal tissues by RT-PCR. TXNRD3, RAB7, AMOTL2, CCNL1, EIF5A2, p63, MUC4, TMEM16A and CTTN presented mRNA overexpression in over 30% tumors. The genomic DNA copy number of these nine genes was then evaluated by semi-quantitative PCR of intragenic UniSTS in 20 cases of tumors and matched normal tissues. Amplification of TXNRD3, RAB7, AMOTL2, CCNL1, MUC4, TMEM16A and CTTN was found in more than 20% of cancerous tissues. CCNL1 and CTTN amplifications were confirmed in ESCC by fluorescence in situ hybridization (FISH).
The cortactin gene (CTTN, also as EMS1), located at 11q13, plays a pivotal role in coupling membrane dynamics to cortical actin assembly. In the present study, immunohistochemical analysis was performed on tissue microarrays and CTTN overexpression was found in 68.8% (86/125) tumors. Statistical analysis indicated that there were significant correlations between CTTN expression and lymph node metastasis and tumor stage in ESCC. CCND1 is another oncogene on 11q13 and its overexpression was detected in 47.0% (55/117) ESCC. Although a positive correlation between CCND1 and CTTN expression was observed, none of the tumor clinicopathologic features was associated with CCND1 overexpression. These results indicate that CTTN is an independent marker at 11q13 for ESCC lymphoid metastasis and tumor stage.
Functional analysis by siRNA-mediated silencing revealed that CTTN did not influence cell proliferation, cell cycle progression and adhesion to Matrigel in esophageal cancer cell line EC9706. Whereas CTTN RNAi decreased EC9706 capabilities in wound healing, haptotactic migration, Matrigel chemoinvasion colony formation in soft agar and anoikis resistance. In vivo assay showed that inhibition of CTTN expression also decreased tumor growth and lung metastasis of EC9706 cells.
To explore the molecular mechanism by which CTTN protected cells from anoikis, we examined the potential effect of CTTN on the activation of several known pathway associated with anoikis. Both PI3K and MEK inhibitors abrogated the survival protection of CTTN in EC9706, while only phosphorylated Akt was down-regulated in CTTN RNAi cells. No difference in Erk activation or EGFR expression was observed after CTTN suppression, suggesting that PI3K-Akt, not MEK-Erk or EGFR signaling, contributed to CTTN-related survival in detached EC9706. CTTN also protected KYSE410 esophageal cancer cells from anoikis when overexpressed. Akt activation was observed in these cells after CTTN transfection as well. In EC9706 and KYSE410 cells, CTTN and PI3K could be co-immunoprecipitated by either of the antibodies. These data imply that CTTN may interact with PI3K and activate it to serve a protective function in anoikis resistance.
In conclusion, analysis of amplified genes may be helpful to the identification of oncogenes associated with malignant tumors. The CTTN gene in the 11q13 amplicon, through DNA copy number increase and protein overexpression, plays an oncogenic role in ESCC metastasis by promoting cell migration and anoikis resistance.
引文
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