| Mucins (MUCs) are high-molecular-weight glycoproteins whose primary functions are to protect and lubricate the epithelial luminal surfaces of the ducts. Recent studies have uncovered unique roles of these mucins in the pathogenesis of cancer. The MUC4 mucin, a transmembrane type I glycoprotein, is overexpressed in many epithelial carcinomas, including pancreatic cancer. Numerous studies have established the association of MUC4 with the progression of pancreatic cancer and metastasis. An aberrant expression of MUC4 is reported in precancerous lesions indicating its involvement in the early disease process; however, its precise role in cellular transformation has not been explored.;To elucidate the functions of MUC4 in early phase of pancreatic cancer pathogenesis, we carried out a set of experiments to define the role of MUC4 in oncogenic transformation. MUC4 was stably expressed in NIH3T3 mouse fibroblast cells. We demonstrate that MUC4 induces tumor formation in vivo and results in enhanced cell growth, colony formation, motility and increased expression of several growth and mitochondrial energy production-associated genes. An enhanced expression of oncoprotein ErbB2/HER2, and activation of ErbB2 and Erk were observed in the NIH3T3/MUC4 cells compared to the mock (vector) transfected control cells. Further, to better comprehend the role of MUC4 in pancreatic cancer development under physiologically relevant conditions, we have conditionally expressed the MUC4 transgene in the pancreas of mice.;Recently, the MUC4 gene has been shown to be upregulated in the central zone of the pancreatic tumor compared to the peripheral zone of the tumor. Nutrient level is frequently reduced in the central zone of advanced tumors suggesting potential role of MUC4 in nutrient deprivation-induced mechanisms. We found that MUC4 attenuated nutrient deprivation-induced increases in reactive oxygen species (ROS) and pancreatic cancer cell death. Importantly, we demonstrated that MUC4 promoted autophagy as a survival response to nutrient deprivation through MUC4/HER2/ERK pathway in pancreatic cancer cells. Additionally, we also showed the role of MUC4 in the development of resistance to chemotherapeutic agents such as gemcitabine in pancreatic cancer cells.;In conclusion, our work provides experimental evidence for the multifaceted roles of MUC4 in the pathogenesis of pancreatic cancer. |
