Notch1在肾细胞癌中的表达及其临床意义

发布时间：2018-06-12 01:27

  本文选题：RCC + 免疫组织化学　； 参考：《第四军医大学》2014年硕士论文

【摘要】：肾细胞癌（renal cell carcinoma，RCC）是肾脏恶性肿瘤的最常见类型。RCC对放疗和化疗均不敏感，早期RCC通过手术治疗常能取得良好的治疗效果。但是对于进展期和晚期RCC，手术治疗则效果欠佳。近年来，虽然已有多种阻断肿瘤细胞生长或血管生成的抗肿瘤药物用于晚期RCC的治疗，但其治疗效果仍不够理想，晚期RCC患者的5年生存率仍很低。 随着对肿瘤分子机制研究的不断深入，已有多条信号通路被证实参与了RCC的发生和发展过程。这些信号通路在正常肾脏细胞的恶性转化，肿瘤细胞的增殖、侵袭和转移等多种生物学过程中发挥着重要的调控作用。因此，对RCC发生发展的分子机制的研究以及针对这些信号通路的分子靶向治疗药物的研发对于晚期RCC的治疗具有重要的意义。 Notch信号通路对于胚胎发育、组织自我更新、细胞干性维持、细胞增殖和凋亡等过程均有重要的调节作用。近年来，越来越多的研究证明Notch信号通路参与了多种肿瘤生物学行为的调节，，包括肿瘤细胞的增殖、分化、凋亡及基因组稳定性等。众多研究表明Notch1在多种肿瘤中具有促进肿瘤或抑制肿瘤的效应。目前，已有多个关于Notch1及Notch信号通路与RCC的研究，但是，人们对于RCC中Notch1的作用观点并不一致，仍需进一步探讨和明确。 为了明确Notch信号通路在RCC中的作用，我们应用免疫组织化学染色和Western-blot检测了RCC临床标本中Notch1的表达,并对其与其他临床病理特征的相关性进行了分析。我们还应用Western-blot和RT-qPCR的方法检测了Notch1和Hes1在肾细胞癌786-O细胞和肾小管上皮细胞HK-2细胞中的表达。免疫组织化学染色结果显示Notch1在RCC肿瘤组织中的阳性表达率明显低于正常肾组织，其阳性率分别为23.2%和73.2%。RT-qPCR的结果显示RCC肿瘤组织中Notch1及其下游分子Hes1的mRNA水平较正常肾组织低。统计分析发现，晚期(AJCC III+IV)RCC中Notch1的表达显著低于早期(AJCC I+II)RCC，并且Fuhrman III的RCC中Notch1的表达也低于Fuhrman I+II级RCC中的水平。细胞检测结果显示，786-O细胞中Notch1和Hes1的mRNA水平均明显低于HK-2细胞。基于以上实验结果，我们认为Notch1和Notch信号通路可能参与RCC的发生和发展，Notch1的低表达和Hes1的低转录水平可能提示RCC的恶性程度较高，Notch1的表达水平和Notch信号通路的活化程度可作为RCC预后判断的一项指标。
[Abstract]:Renal cell carcinoma (RCC) is the most common type of renal malignancy. RCCs are not sensitive to radiotherapy and chemotherapy. But for advanced and advanced RCCs, surgical treatment is not effective. In recent years, although many antitumor drugs have been used to block tumor cell growth or angiogenesis in the treatment of advanced RCC, the therapeutic effect is still not satisfactory. The 5-year survival rate of advanced RCC patients is still very low. With the further study of tumor molecular mechanism, several signal pathways have been proved to be involved in the occurrence and development of RCC. These signaling pathways play an important role in many biological processes, such as malignant transformation of normal renal cells, proliferation, invasion and metastasis of tumor cells. Therefore, the study of the molecular mechanism of RCC development and the development of molecular targeted therapy drugs for these signaling pathways are of great significance for the treatment of advanced RCC. The Notch signaling pathway is of great significance for embryonic development and tissue self-renewal. Cell dryness maintenance, cell proliferation and apoptosis all play an important role in regulating the process. In recent years, more and more studies have demonstrated that Notch signaling pathway plays an important role in the regulation of tumor biological behavior, including proliferation, differentiation, apoptosis and genomic stability of tumor cells. Numerous studies have shown that Notch1 has the effect of promoting tumor or inhibiting tumor in many kinds of tumors. At present, there have been many studies on Notch1 and Notch signaling pathway and RCC. However, people do not agree on the role of Notch1 in RCC, so we need to further explore and clarify the role of Notch signaling pathway in RCC. The expression of Notch1 in RCC was detected by immunohistochemistry and Western-blot, and the correlation between Notch1 and other clinicopathological features was analyzed. Western-blot and RT-qPCR were used to detect the expression of Notch1 and Hes1 in 786-O and HK-2 cells of renal cell carcinoma. The expression of Notch1 in RCC tissues was significantly lower than that in normal renal tissues. The positive rates of Notch1 and its downstream molecule Hes1 in RCC tumor tissues were 23.2% and 73.2%, respectively. RT-qPCR showed that the mRNA levels of Notch1 and its downstream molecule Hes1 in RCC were lower than those in normal renal tissues. Statistical analysis showed that the expression of Notch1 in late stage AJCC III IVCC was significantly lower than that in early stage AJCC I IIR CCS, and the expression of Notch1 in Fuhrman III RCC was lower than that in Fuhrman I II RCC. The results showed that the mRNA levels of Notch1 and Hes1 in Hes1 cells were significantly lower than those in HK-2 cells. Based on the above experimental results, We believe that Notch1 and Notch signaling pathway may be involved in the occurrence and development of RCC. The low expression of Notch1 and the low transcription level of Hes1 may suggest that the expression of Notch1 and the activation of Notch signaling pathway may be the prognosis of RCC. A measure of judgment.
【学位授予单位】：第四军医大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R737.11

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