染色体20q13扩增子中ADRM1基因在大肠癌发生发展中的功能研究
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摘要
大肠癌是全世界范围内都比较常见的恶性肿瘤。近10年来的遗传学的数据显示,人类20号染色体,特别是20q13区域的基因扩增与大肠癌的发生发展密切相关。为了进一步确认这一区段内引起上述异变的基因,我们利用我中心大肠癌病例组织库中肿瘤及正常组织的配对标本,对位于人类染色体20q13扩增子上的27个候选基因进行了半定量的RT-PCR检测。其中发现新报道的编码蛋白酶体亚基的基因ADRM1(GeneID:11047),在46.2%的临床大肠癌标本中较正常结肠壁组织表达升高,并且与大肠癌的淋巴结转移情况有统计学意义的关连(P=0.037)。
在人类大肠癌细胞系RKO中用相应的shRNA对ADRM1基因进行敲除后我们发现,通过诱导凋亡和将细胞周期阻滞于G1期这两种机制,ADRM1的缺失明显抑制了RKO细胞的贴壁生长,迁移以及分化能力。同时,此类ADRM1沉默的RKO细胞对化疗药物氟尿嘧啶(5-Fu)的耐受性也较野生型RKO细胞出现下降。
由于5-FU与ADRM1的基因干扰有协同作用,我们认为在对于ADRM1高表达的病例中,联合应用化疗药物和ADRM1靶向治疗可能可以成为一种有希望的新的治疗方法。同时,由于ADRM1与泛素-蛋白酶体系统关系密切,因此我们的发现也为蛋白酶体抑制剂的研究提供了新的位点,以期能对广谱的蛋白酶体抑制剂诱导的凋亡特异性较差这一现状有所帮助。
Colorectal cancer(CRC) is one of the most common causes of cancer-related deaths throughout the world.Karyotypic/cytogenetic data regarding CRC have been accumulated over the last 10 years,and a gain of 20q,especially the 20q13 region,was frequently reported as a common genetic aberration.The novel proteasome subunit ADRM1(GeneID:11047 ) located on the 20q13 amplicon was differentially expressed in colorectal cancer and paired normal bowel wall by semiquantitative RT-PCR based on the tissue bank generated in our center.ADRM1 mRNA were overexpressed in 46.2%colorectal cancer tissues compared to their matched normal mucosa and significantly correlated with lymph node metastasis of colorectal cancer.
Knockdown of ADRM1 by shRNA in human colon carcinoma RKO cells inhibited their anchorage-independent growth,cell migration as well as cell proliferation through inducing apoptosis and cell cycle arrest at the G1 phase.In addition,stable RNA interference of ADRM1 gene synergistic with 5-Fu treatment suppressed RKO cell growth in vitro.Collectively,these data suggested that ADRM1 is potentially oncogenic and may play an important role in colon tumorigenesis.
Regiment with combined application of ADRM1 RNA interference and chemotherapy may emerge as a novel therapeutic strategy for ADRM1 overexpressed colorectal cancer;in addition,given to the close relationship between ADRM1 and ubiquitin-proteasome system,our study provided a new target for proteasome inhibitor design.
在人类大肠癌细胞系RKO中用相应的shRNA对ADRM1基因进行敲除后我们发现,通过诱导凋亡和将细胞周期阻滞于G1期这两种机制,ADRM1的缺失明显抑制了RKO细胞的贴壁生长,迁移以及分化能力。同时,此类ADRM1沉默的RKO细胞对化疗药物氟尿嘧啶(5-Fu)的耐受性也较野生型RKO细胞出现下降。
由于5-FU与ADRM1的基因干扰有协同作用,我们认为在对于ADRM1高表达的病例中,联合应用化疗药物和ADRM1靶向治疗可能可以成为一种有希望的新的治疗方法。同时,由于ADRM1与泛素-蛋白酶体系统关系密切,因此我们的发现也为蛋白酶体抑制剂的研究提供了新的位点,以期能对广谱的蛋白酶体抑制剂诱导的凋亡特异性较差这一现状有所帮助。
Colorectal cancer(CRC) is one of the most common causes of cancer-related deaths throughout the world.Karyotypic/cytogenetic data regarding CRC have been accumulated over the last 10 years,and a gain of 20q,especially the 20q13 region,was frequently reported as a common genetic aberration.The novel proteasome subunit ADRM1(GeneID:11047 ) located on the 20q13 amplicon was differentially expressed in colorectal cancer and paired normal bowel wall by semiquantitative RT-PCR based on the tissue bank generated in our center.ADRM1 mRNA were overexpressed in 46.2%colorectal cancer tissues compared to their matched normal mucosa and significantly correlated with lymph node metastasis of colorectal cancer.
Knockdown of ADRM1 by shRNA in human colon carcinoma RKO cells inhibited their anchorage-independent growth,cell migration as well as cell proliferation through inducing apoptosis and cell cycle arrest at the G1 phase.In addition,stable RNA interference of ADRM1 gene synergistic with 5-Fu treatment suppressed RKO cell growth in vitro.Collectively,these data suggested that ADRM1 is potentially oncogenic and may play an important role in colon tumorigenesis.
Regiment with combined application of ADRM1 RNA interference and chemotherapy may emerge as a novel therapeutic strategy for ADRM1 overexpressed colorectal cancer;in addition,given to the close relationship between ADRM1 and ubiquitin-proteasome system,our study provided a new target for proteasome inhibitor design.
引文
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