论文题目：In vitro efficacy studies of HPV E6/E7 specific siRNA for the treatment of HPV driven head and neck cancer
一、论文选题的理由或意义The reason or significance of the topic selection
Head and neck cancer is a fatal disease with an increased morbidity and mortality rate. It comprises of epithelial malignancies of the upper aerodigestive tract (UADT), paranasal sinuses, nasal cavity, oral cavity, pharynx, and larynx. Occupying at sixth position among all cancers worldwide, annually approximately 550,000 people are diagnosed with head and neck cancers and 300,000 people have succumbed to death with a median age of diagnosis during the sixth decade of life. Head amp; Neck cancer is the seventh most frequent cancer and the ninth-most-frequent cause of death from cancer. It account for approximately 4% of all cancers in the US.
Human papillomavirus (HPV) infections of the high-risk group lead to the development of HPV driven head and neck cancers. Overexpression of HPV E6 and E7 oncoproteins is critical and necessary toward HPV-related diseases. Binding of E6 oncoproteins accelerates the ubiquitin-mediated degradation of TP53 tumor suppressor protein and other targets. In contrast, E7 oncoprotein specifically interacts with retinoblastoma (RB) and related pocket protein members (p107 and p130), which results in the disruption and loss of RB/E2F repressor complexes. This process liberates E2F-regulated gene transcription and allows entry into S phase of the cell cycle. TP53 status and the level of RB/E2F signaling influence the efficacy of anticancer therapies that induce DNA damage, while the loss of TP53 functions is often associated with resistance to therapy.
头颈癌是一种致命疾病，发病率和死亡率都有所增加。它包括上呼吸消化道（UADT），鼻旁窦，鼻腔，口腔，咽和喉的上皮恶性肿瘤。在全世界所有癌症中排名第六，每年约有550,000人被诊断患有头颈癌，30万人死于死亡，其中在生命的第六个十年中诊断的中位年龄。头颈癌是第七大癌症，也是癌症死亡的第九大常见原因。它占美国所有癌症的约4％。
高风险组的人乳头瘤病毒（HPV）感染导致HPV驱动的头颈癌的发展。 HPV E6和E7癌蛋白的过度表达对HPV相关疾病至关重要且必不可少。 E6癌蛋白的结合加速了泛素介导的TP53肿瘤抑制蛋白和其他靶标的降解。相反，E7癌蛋白特异性地与视网膜母细胞瘤（RB）和相关的口袋蛋白成员（p107和p130）相互作用，这导致RB / E2F阻遏物复合物的破坏和丧失。该过程释放E2F调节的基因转录并允许进入细胞周期的S期。 TP53状态和RB / E2F信号传导水平影响诱导DNA损伤的抗癌疗法的功效，而TP53功能的丧失通常与对治疗的抗性相关。
二、关于该课题的研究现状及趋势 Published articles about the research and research trends of the subject
Articles reported earlier that, HPV E6/E7 siRNA treatment on HPV positive cancer cells, which restores the TP53 and RB/E2F signaling mechanism. Also exhibits synergistic therapeutic effect towards the chemo-/radio-therapy treatment.
To confirm the synergism mechanism of how siRNA affect the head and neck cancer cell, I study into the pathway of P53. Itrsquo;s well known that PUMA plays an essential role in mediating the apoptotic responses to p53. Also PUMA-induced Bax plays an important role in apoptosis .
So far, no reports show the co-relation between PUMA mediated apopototic and E6/E7 siRNA induced P53. In addition, here, I would like to verify the WP53 mediated cancer metabolic switch induced by PUMA.
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