To Study the Role of Sp1 in Cancer Metastatic Progression( I )

Cancer is a frightening disease due to high motility and poor therapeutic efficacy. In addition to the difficulty on diagnosing early stage of cancer, enhanced metastatic potential and poor sensitivity of tumor in response to drug during tumor progression are major problems for treatment. Sp1, a transcription factor recognizing GC-rich promoter, is overexpressed in various types of cancer, and is shown to regulate expression of tumor-promoting genes which are functioning in proliferation, angiogenesis, anti-apoptosis and tumorigenesis. Some reports showed that Sp1 positively correlates with poor prognosis in gastric cancer and melanoma, suggesting that Sp1 may promote tumor progression. However, we previously indicated that Sp1 is decreased in metastatic lung cancer, and low expression of Sp1 correlates with poor prognosis. In intestinal type gastric cancer, Sp1 exhibits the similar function, which suppresses metastasis. In other types of cancer, the role of Sp1 in metastasis has not been studied, because of lack of appropriate animal models to clarify whether Sp1 manipulates tumor progression in vivo. Therefore, we attempt to employ genetically modified mouse models developing cancer spontaneously to investigate whether Sp1 plays an indispensable role in tumor development, including aberrant hyperplasia, tumor initiation, progression, and metastasis. To achieve our purpose, we design 3 specific aims for 3 years: Aim 1. To determine the expression pattern of Sp1 in cancer development, including initiation, progression and metastasis, in vivo. In particular, we will establish Scgb1a1-rtTA/TetO-Kras4bG12D (EGFRL858R)/p53+/- mice for lung cancer and Gfap-cre/Ptenflox/flox/p53+/- mice for glioblastoma. Aim 2. To investigate the influence of Sp1 knockout on cancer development, especially metastasis. Herein, we will establish conditional Sp1 knockout mice under the control of tamoxifen. After breeding, cancer mice with Sp1 knockout in lungs will be achieved by tamoxifen administration at different stages of tumor development. Aim 3. To identify impact of Sp1-regulated gene expression profile on cancer progression. Using high throughput analysis, such as next generation sequencing and cDNA microarray analysis, gene expression profile of tumor development in the presence or absence of Sp1 in vivo will be clearly identified. In addition, Sp1-regulated gene networks in different stages will be established and also confirmed in human specimens of cancer. According to networks, treatments targeting Sp1 and other oncogenic proteins will be an efficacious therapeutic strategy to cue cancer patients. Based on our findings, we will elucidate how Sp1 participates in tumor development, and provide a novel strategy targeting Sp1-regulated network to shut down tumor malignancy.