The primary objective of this proposal is to fully evaluate the anti-senescence activity of Trifoil Factor 1 (TFF1) in the process of pancreatic and prostate tumorigenesis in mouse models, and elucidate the signaling mechanism underlying its anti-senescent action. Cellular senescence acts as a barrier against malignant transformation, but the mechanisms associated with the overcome of senescence remain largely unknown. Thus, new information that reveals the molecular nature of such mechanisms could have a significant impact on the understanding of senescence as a critical event in the multi-step process of tumorigenesis. As a secreted protein, TFF1 functions as a tumor suppressor in the stomach by stimulating restitution of damaged tissue associated with ulceration and inflammation to reduce tumor formation. However, TFF1 is over expressed in tumor tissues from various organs, such as pancreas and prostate, where it is not normally localized, although the functional significance of this phenomenon remains poorly understood. To address this question, we investigated the function of TFF1 in the context of tumorigenesis using human pancreatic and prostate cancer cells and found that it acts to enable cells to breach the barrier of senescence induced by oncogenic Ras or reduction in tumor suppressor PTEN expression. Thus, our results indicate that in the context of pancreatic and prostate cancer, the previously defined tumor suppressor TFF1 actually promotes tumorigenesis by enabling pre-cancerous lesions to overcome the barrier of oncogene-induced senescence. To build on this unexpected discovery, we intend to fully determine the functional impact of TFF1 over expression on pancreatic and prostate tumorigenesis by employing two well-established mouse model systems in which oncogene activation-induced senescence has been thoroughly documented to act as a barrier for oncogenic transformation. In the meantime, by the identification of receptor/cell surface binding protein of TFF1 using both a candidate-approach and a RNAi-based genome-wide screen, we will test the hypothesis that TFF1 acts to suppress cellular senescence via a still undefined signaling pathway to allow clonal expansion of cells that harbor the initial genetic lesions in the early stage of tumorigenesis.
Tumorigenesis is a multi-step process with the accumulation of genetic and epigenetic lesions that drives the clonal expansion of transformed cells. However, relatively little is known about the mechanism by which oncogene activation-induced cellular senescence is breached in the early stages of the process. A better understanding of the mechanism associated with TFF1 action in the overcoming of senescence will help the development of better therapies for those cancers.
|Yuan, Lifeng; Zhai, Linhui; Qian, Lili et al. (2018) Switching off IMMP2L signaling drives senescence via simultaneous metabolic alteration and blockage of cell death. Cell Res 28:625-643|
|Chong, Mengyang; Yin, Tao; Chen, Rui et al. (2018) CD36 initiates the secretory phenotype during the establishment of cellular senescence. EMBO Rep 19:|
|Xiang, Handan; Yuan, Lifeng; Gao, Xia et al. (2017) UHRF1 is required for basal stem cell proliferation in response to airway injury. Cell Discov 3:17019|
|Alexander, Peter B; Chen, Rui; Gong, Chang et al. (2017) Distinct Receptor Tyrosine Kinase Subsets Mediate Anti-HER2 Drug Resistance in Breast Cancer. J Biol Chem 292:748-759|
|Hu, Jing; Sun, Tao; Wang, Hui et al. (2016) MiR-215 Is Induced Post-transcriptionally via HIF-Drosha Complex and Mediates Glioma-Initiating Cell Adaptation to Hypoxia by Targeting KDM1B. Cancer Cell 29:49-60|
|Markowitz, Geoffrey J; Yang, Pengyuan; Fu, Jing et al. (2016) Inflammation-Dependent IL18 Signaling Restricts Hepatocellular Carcinoma Growth by Enhancing the Accumulation and Activity of Tumor-Infiltrating Lymphocytes. Cancer Res 76:2394-405|
|Alexander, Peter B; Wang, Xiao-Fan (2015) Resistance to receptor tyrosine kinase inhibition in cancer: molecular mechanisms and therapeutic strategies. Front Med 9:134-8|
|Alexander, Peter B; Yuan, Lifeng; Yang, Pengyuan et al. (2015) EGF promotes mammalian cell growth by suppressing cellular senescence. Cell Res 25:135-8|
|Wang, Qinhong; Goldstein, Michael; Alexander, Peter et al. (2014) Rad17 recruits the MRE11-RAD50-NBS1 complex to regulate the cellular response to DNA double-strand breaks. EMBO J 33:862-77|