emerin and Neoplasm-Metastasis

It is commonly recognized in the field that cancer cells exhibit changes in the size and shape of their nuclei. These features often serve as important biomarkers in the diagnosis and prognosis of cancer patients. Nuclear size can significantly impact cell migration due to its incredibly large size. Nuclear structural changes are predicted to regulate cancer cell migration. Nuclear abnormalities are common across a vast spectrum of cancer types, regardless of tissue source, mutational spectrum, and signaling dependencies. The pervasiveness of nuclear alterations suggests that changes in nuclear structure may be crucially linked to the transformation process. The factors driving these nuclear abnormalities, and the functional consequences, are not completely understood. Nuclear envelope proteins play an important role in regulating nuclear size and structure in cancer. Altered expression of nuclear lamina proteins, including emerin, is found in many cancers and this expression is correlated with better clinical outcomes. A model is emerging whereby emerin, as well as other nuclear lamina proteins, binding to the nucleoskeleton regulates the nuclear structure to impact metastasis. In this model, emerin and lamins play a central role in metastatic transformation, since decreased emerin expression during transformation causes the nuclear structural defects required for increased cell migration, intravasation, and extravasation. Herein, we discuss the cellular functions of nuclear lamina proteins, with a particular focus on emerin, and how these functions impact cancer progression and metastasis.

Topics: Animals; Humans; Membrane Proteins; Mutation; Neoplasm Metastasis; Neoplasms; Nuclear Proteins

Nuclear envelope proteins play an important role in regulating nuclear size and structure in cancer. Altered expression of nuclear lamins are found in many cancers and its expression is correlated with better clinical outcomes. The nucleus is the largest organelle in the cell with a diameter between 10 and 20 μm. Nuclear size significantly impacts cell migration. Nuclear structural changes are predicted to impact cancer metastasis by regulating cancer cell migration. Here we show emerin regulates nuclear structure in invasive breast cancer cells to impact cancer metastasis. Invasive breast cancer cells had 40% to 50% less emerin than control cells, which resulted in decreased nuclear size. Overexpression of GFP-emerin in invasive breast cancer cells rescued nuclear size and inhibited migration through 3.0 and 8.0 μm pores. Mutational analysis showed emerin binding to nucleoskeletal proteins was important for its regulation of nuclear structure, migration, and invasion. Importantly, emerin expression inhibited lung metastasis by 91% in orthotopic mouse models of breast cancer. Emerin nucleoskeleton-binding mutants failed to inhibit metastasis. These results support a model whereby emerin binding to the nucleoskeleton regulates nuclear structure to impact metastasis. In this model, emerin plays a central role in metastatic transformation, because decreased emerin expression during transformation causes the nuclear structural defects required for increased cell migration, intravasation, and extravasation. IMPLICATIONS: Modulating emerin expression and function represents new targets for therapeutic interventions of metastasis, because increased emerin expression rescued cancer metastasis.

Topics: Animals; Breast Neoplasms; Cell Cycle; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Proliferation; Cells, Cultured; Female; Green Fluorescent Proteins; Humans; Membrane Proteins; Mice, Nude; Microscopy, Confocal; Neoplasm Metastasis; Nuclear Matrix; Nuclear Proteins; Protein Binding; Transplantation, Heterologous