肺癌相关新基因的克隆与筛选及新的候选原癌基因OLC1的功能研究
摘要
肺癌是严重危害人类健康的恶性肿瘤之一，在中国，肺癌的发病率逐年上升，现已居恶性肿瘤发病率的首位。在过去的十余年中，我们已经对肺癌的分子遗传学改变有了一定的认识，然而，肺癌发生的确切机制仍然不清楚。
在本研究中，我们克隆了51个肺癌相关新基因，并对其进行了功能和表型筛选。通过筛选，我们发现一个基因OLC1(overexpressed in lung cancer)，能在报告基因水平激活NF-kappaB通路，外源高表达能使NIH／3T3细胞形成明显的转化集落。本研究将OLC1稳定转染NIH／3T3细胞，通过体内外实验评估其恶性转化功能。用特异性针对OLC1的小干扰RNA(small interfering RNA，siRNA)沉默OLC1的表达，并以此评价OLC1在肿瘤细胞增殖生长中的作用。为了在蛋白水平检测OLC1的表达，我们生产，纯化，并鉴定了OLC1的多克隆抗体，用免疫组织化学染色结合组织微阵列技术检测OLC1蛋白在肺癌和正常组织中的表达水平。本研究还用凝胶阻滞等方法检测OLC1对NF-kappaB通路的激活作用。
我们的研究结果显示，OLC1的稳定高表达能显著加快NIH／3T3细胞的生长速度，使其失去接触抑制，获得在软琼脂中锚定非依赖性生长的能力；体内实验表明，高表达OLC1的NIH／3T3细胞能在裸鼠身上形成纤维肉瘤，而未转染细胞和空载体转染细胞则不能形成；用特异性siRNA沉默OLC1在肺癌细胞系H520和H1299中的表达能引起生长抑制，并能在不需要其它附加凋亡诱导物的情况下引起细胞凋亡；免疫组织化学染色显示，OLC1的高表达能在大多数肺癌类型中检测到，特别是在肺癌发生的早期，如不典型增生和原位癌的阶段；我们的结果还证明OLC1能在肿瘤细胞中激活NF-kappaB通路。
综上所述，我们的研究结果提供了充分的证据，证明OLC1在肺癌的发生中扮演着重要的角色，具有原癌基因的属性，同时也提示OLC1用于肺癌早期诊断和治疗靶标的可能性。
Lung cancer is a leading cause of death worldwide. Over the past decade, much has been learned about the molecular alterations associated with lung cancer, however, the precise mechanisms underlying lung carcinogenesis remain unresolved.
In this study, fifty-one functionally unknown genes, which were potentially related to lung cancer, were cloned and further screened with functional and phenotypic methods. We found a novel gene which could both activate NF-kappaB reporter activity and induce NIH/3T3 cell transformation with the increased foci formation. We named it OLC1 (overexpressed in lung cancer). OLC1 was transfected into NIH/3T3 cells, and the oncogenic function was evaluated by both in vitro and in vivo experiments. Small interfering RNAs (siRNA) directly against OLC1 were used to determine the role of OLC1 in the tumor cell growth. Immunohistochemical analysis was used to determine the OLC1 expression level in a tissue microarray containing formalin-fixed, paraffin-embedded tissue specimens of lung cancer.
We showed that NIH/3T3 cells with enforced OLC1 overexpression grew at an accelerated rate and gained increased anchorage-independent growth capability. Nude mouse xenograft studies showed that NIH/3T3 cells overexpressing OLC1, but neither parental nor empty vector control-transfected cells produced fibrosarcomas. Silencing expression of OLC1 using siRNA resulted in inhibition of growth and increased apoptosis in both H520 and H1299 lung cancer cell lines. Using immunohistochemical staining, overexpression of OLC1 was detected in the most frequent types of lung cancers, as well as pulmonary premalignant lesions. Furthermore, overexpression of OLC1 led to constitutive activation of NF-kappaB pathway in cancer cells.
Taken together, our studies provide strong evidence that OLC1 plays an important role in the tumorigenesis of human lung. We also indicate the importance of OLC1 as a potential early diagnostic and therapeutic target for human cancers.
在本研究中，我们克隆了51个肺癌相关新基因，并对其进行了功能和表型筛选。通过筛选，我们发现一个基因OLC1(overexpressed in lung cancer)，能在报告基因水平激活NF-kappaB通路，外源高表达能使NIH／3T3细胞形成明显的转化集落。本研究将OLC1稳定转染NIH／3T3细胞，通过体内外实验评估其恶性转化功能。用特异性针对OLC1的小干扰RNA(small interfering RNA，siRNA)沉默OLC1的表达，并以此评价OLC1在肿瘤细胞增殖生长中的作用。为了在蛋白水平检测OLC1的表达，我们生产，纯化，并鉴定了OLC1的多克隆抗体，用免疫组织化学染色结合组织微阵列技术检测OLC1蛋白在肺癌和正常组织中的表达水平。本研究还用凝胶阻滞等方法检测OLC1对NF-kappaB通路的激活作用。
我们的研究结果显示，OLC1的稳定高表达能显著加快NIH／3T3细胞的生长速度，使其失去接触抑制，获得在软琼脂中锚定非依赖性生长的能力；体内实验表明，高表达OLC1的NIH／3T3细胞能在裸鼠身上形成纤维肉瘤，而未转染细胞和空载体转染细胞则不能形成；用特异性siRNA沉默OLC1在肺癌细胞系H520和H1299中的表达能引起生长抑制，并能在不需要其它附加凋亡诱导物的情况下引起细胞凋亡；免疫组织化学染色显示，OLC1的高表达能在大多数肺癌类型中检测到，特别是在肺癌发生的早期，如不典型增生和原位癌的阶段；我们的结果还证明OLC1能在肿瘤细胞中激活NF-kappaB通路。
综上所述，我们的研究结果提供了充分的证据，证明OLC1在肺癌的发生中扮演着重要的角色，具有原癌基因的属性，同时也提示OLC1用于肺癌早期诊断和治疗靶标的可能性。
Lung cancer is a leading cause of death worldwide. Over the past decade, much has been learned about the molecular alterations associated with lung cancer, however, the precise mechanisms underlying lung carcinogenesis remain unresolved.
In this study, fifty-one functionally unknown genes, which were potentially related to lung cancer, were cloned and further screened with functional and phenotypic methods. We found a novel gene which could both activate NF-kappaB reporter activity and induce NIH/3T3 cell transformation with the increased foci formation. We named it OLC1 (overexpressed in lung cancer). OLC1 was transfected into NIH/3T3 cells, and the oncogenic function was evaluated by both in vitro and in vivo experiments. Small interfering RNAs (siRNA) directly against OLC1 were used to determine the role of OLC1 in the tumor cell growth. Immunohistochemical analysis was used to determine the OLC1 expression level in a tissue microarray containing formalin-fixed, paraffin-embedded tissue specimens of lung cancer.
We showed that NIH/3T3 cells with enforced OLC1 overexpression grew at an accelerated rate and gained increased anchorage-independent growth capability. Nude mouse xenograft studies showed that NIH/3T3 cells overexpressing OLC1, but neither parental nor empty vector control-transfected cells produced fibrosarcomas. Silencing expression of OLC1 using siRNA resulted in inhibition of growth and increased apoptosis in both H520 and H1299 lung cancer cell lines. Using immunohistochemical staining, overexpression of OLC1 was detected in the most frequent types of lung cancers, as well as pulmonary premalignant lesions. Furthermore, overexpression of OLC1 led to constitutive activation of NF-kappaB pathway in cancer cells.
Taken together, our studies provide strong evidence that OLC1 plays an important role in the tumorigenesis of human lung. We also indicate the importance of OLC1 as a potential early diagnostic and therapeutic target for human cancers.
引文
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