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THE SHC-DEPENDENT SIGNALS REGULATE PROLIFERATION OF COLORECTAL CANCER CELLS
V Pomerleau1, M Park2, C Saucier1
1Department of Anatomy and Cell biology, Faculty of Medicine, Université of Sherbooke; 2Molecular Oncology Group, Department of Biochemistry, Medicine and Oncology, McGill University Health Center, Montreal, Quebec
Many genetic alterations have been identified in colorectal cancer (CRC), yet the molecular events involved in the etiology and malignant progression of CRC remain poorly understood. However, compelling evidence indicates that deregulation of growth factor receptor tyrosine kinases (RTK) plays a determinant role in the initiation and malignant progression of human CRCs. Notably, members of the epidermal growth factor receptor family and the Met/Hepatocyte growth factor (HGF) RTK are deregulated in most of CRCs. To study the individual role of RTK-associated proteins in oncogenesis, we have designed variant forms of the oncogenic Met/HGF RTK that directly bind one specific signaling protein. Using these tools, we have previously shown that the sole activation of signaling pathways downstream from the adaptor proteins Shc is sufficient to induce a variety of cancer biological processes in fibroblast cell models, such as proliferation, transformation, anchorage-independent growth, angiogenic responses and experimental metastases in vivo (Saucier et al. Oncogene 2002 & PNAS 2004; Mood et al. Mol. Biol. Cell 2006). Given that all RTKs deregulated in CRC have the ability to activate Shc-dependent signals, we hypothesized that Shc regulates cancer biological behaviors fundamental to the initiation and malignant progression of CRC. The objective of this study was to instigate the identification of biological processes regulated by Shc in CRC epithelial cell models. For this, we have tested the biological consequences of oncogenic engagement of Shc by expressing the Shc-specific RTK oncoprotein in the non-tumorigenic mouse CT-36 CRC cells. Conversely, we have tested the impact of depletion of Shc in the highly tumorigenic CT-26 CRC cells by RNA interference (RNAi) strategies. Our results show that oncogenic engagement of Shc in CT-36 CRC cells is sufficient to drive epithelial-mesenchymal-like transformation and proliferation, whereas Shc RNAi decreases the proliferation of the highly tumorigenic CT-26 CRC cells. As CRC arises by the accumulation of multiple molecular changes, which may never be fully understood for each CRC tumor, the challenge in the development of new CRC therapies is to identify cellular targets that regulate biological processes fundamental for the initiation and malignant progression of many CRCs. Our studies indicate that Shc and/or Shc-dependent signals may represent therapeutic targets to reduce the proliferation of CRC epithelial cells.