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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS, RESULTS. Meshes: Animals, Apoptosis, Cell Line, Tumor, Cell Proliferation, Colorectal Neoplasms, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Cyclooxygenase Inhibitors, Dinoprostone, Disease Models, Animal, Genes, ras, Image Processing, Computer-Assisted, Immunohistochemistry, Isoxazoles, Ki-67 Antigen, Liver, Liver Neoplasms, Male, Mice, Mice, Inbred BALB C, Microcirculation, Mutation, Neoplasm Metastasis, Neoplasm Transplantation, Prostaglandin-Endoperoxide Synthases, Proto-Oncogene Proteins p21(ras), RNA Interference, Time Factors.
user
Is cyclooxygenase-2 a target of KRASD12 , which facilitates the outgrowth of murine C26 colorectal liver metastases? Context: Mutational activation of the KRAS oncogene and overexpression of cyclooxygenase-2 (COX-2) contribute to colorectal carcinoma (CRC) development, but the relationship between these two events is unclear. This study was designed to clarify that relationship and to assess the contribution of KRAS-dependent COX-2 to the seeding of CRC cells in the liver and to their outgrowth as liver metastases in an experimental mouse model. The effect of RNA interference-mediated KRAS knockdown on COX-2 expression and activity was tested in murine C26 CRC cells. The contribution of KRAS-dependent COX-2 to early metastatic tumor cell seeding (by intravital microscopy) and outgrowth of metastases in the liver (by bioluminescence imaging) was studied by using parecoxib, a novel and highly selective liver-activated COX-2 inhibitor. Intratumoral cell proliferation, apoptosis, and tumor-associated angiogenesis were assessed by immunohistochemistry on liver tissue sections. Stable knockdown of mutant KRAS(D12) in murine C26 CRC cells by RNA interference lead to a dramatic reduction of COX-2 synthesis and prostaglandin E2 production. Inhibition of host or tumor cell COX-2 activity had no effect on early metastatic cell seeding in the liver but greatly reduced intrahepatic tumor cell proliferation and the rate of liver metastasis outgrowth. COX-2 inhibition had no effect on early tumor vascularization or on tumor cell apoptosis.
assistant
The high levels of COX-2 enzyme and prostaglandin production in C26 CRC cells are primarily caused by the presence of endogenous mutant KRAS(D12). Furthermore, COX-2 inhibition affects the tumoral rather than the vascular compartment during the early stages of C26 liver metastasis outgrowth. Final Decision: yes