Study of the mechanism of HPV involved tumorigenesis through Wnt signaling pathway related microRNA regulation

We observed an unexpected high prevalence of HPV16/18 infection in the female lung cancer patients when compared to male patients suffering from lung cancer. Our recent report further suggests that the HPV16/18 E6 oncoprotein is expressed in lung tumors and is related to p53 inactivation, IL-6 and Mcl-1 up-regulation, hTERT activation, and DDH inactivation, strongly suggesting that the HPV16/18 infection may be involved in lung tumor formation, at least in non-smoking Taiwanese women. These studies were conducted using tumor tissues. The mechanism of HPV involved in lung epithelial cell tumorigenesis is still unknown. And thus, finding a major molecular pathway is the key point to understand whether HPV infection induces lung cancer formation. Our preliminary results showed that the Wnt signaling pathway maybe the first step in HPV-induced lung tumorigenesis. In addition to it, the Wnt signaling-related microRNA-miR21, were significantly higher in a HPV-infected lung tumor than in non-infected tumor. Besides, patients with higher miR21 expression showed poor clinical outcome. Therefore, we hypothesize that the activation of Wnt signaling maybe the first step involved in HPV-infected lung tumorigenesis through regulation of miR21 or the other Wnt/β-catenin-related microRNA and may affect the tumor progression and clinical outcome. The following three-year-long project will be conducted to provide evidence and support this hypothesis. The following questions will be answered in this project: 1. Is the change in Wnt/β-catenin-related microRNA is associated with HPV 16-infection? 2. Is the activation of Wnt/β-catenin signaled by HPV through mircorRNA regulation? 3. Does the change of Wnt/β-catenin-related microRNA affect the transcription regulation of Wnt/β-catenin downstream gene? 4. Does the change in microRNA affect the β-catenin protein localization and downstream gene, and the cyclin D1 and c-myc, gene transcription? 5. Does the change of microRNA affect the response of lung cancer cells to chemotherapy? 6. Does the change of microRNA affect the response of lung cancer patients to chemotherapy and clinical outcome? We hope to explore the novel pathway, the effects of the clinical outcome, and the chemicotherapy response involved in lung tumorigenesis in case of nonsmokers, especially in non-smoking Taiwanese women with HPV16/18 infection.