Abstract
BackgroundDespite our substantial understanding of molecular mechanisms and gene mutations involved in cancer, the technical approaches for diagnosis and prognosis of cancer are limited. In routine clinical diagnosis of cancer, the procedure is very basic: nuclear morphology is used as a common assessment of the degree of malignancy, and hence acts as a prognostic and predictive indicator of the disease. Furthermore, though the atypical nuclear morphology of cancer cells is believed to be a consequence of oncogenic signaling, the molecular basis remains unclear. Another common characteristic of human cancer is aneuploidy, but the causes and its role in carcinogenesis are not well established.MethodsWe investigated the expression of the nuclear envelope proteins lamin A/C in ovarian cancer by immunohistochemistry and studied the consequence of lamin A/C suppression using siRNA in primary human ovarian surface epithelial cells in culture. We used immunofluorescence microscopy to analyze nuclear morphology, flow cytometry to analyze cellular DNA content, and fluorescence in situ hybridization to examine cell ploidy of the lamin A/C-suppressed cells.ResultsWe found that nuclear lamina proteins lamin A/C are often absent (47%) in ovarian cancer cells and tissues. Even in lamin A/C-positive ovarian cancer, the expression is heterogeneous within the population of tumor cells. In most cancer cell lines, a significant fraction of the lamin A/C-negative population was observed to intermix with the lamin A/C-positive cells. Down regulation of lamin A/C in non-cancerous primary ovarian surface epithelial cells led to morphological deformation and development of aneuploidy. The aneuploid cells became growth retarded due to a p53-dependent induction of the cell cycle inhibitor p21.ConclusionsWe conclude that the loss of nuclear envelope structural proteins, such as lamin A/C, may underlie two of the hallmarks of cancer - aberrations in nuclear morphology and aneuploidy.
Highlights
Despite our substantial understanding of molecular mechanisms and gene mutations involved in cancer, the technical approaches for diagnosis and prognosis of cancer are limited
Molecular changes in the nuclear matrix and/or nuclear envelope have been postulated, and deformation of nuclear morphology was shown to associate with oncogenic signaling [7,8,9], but no definite conclusions have been reached regarding the molecular basis of nuclear deformation in malignant cells [1,10]
Lamin A/C expression is frequently lost in ovarian cancer cells and tissues Since the nuclear envelope structural protein emerin was found lost in a fraction (38%) of ovarian cancer [39], we examined if the expression of other nuclear envelope proteins might account for nuclear morphological deformation of emerin-expressing ovarian cancer cells
Summary
Despite our substantial understanding of molecular mechanisms and gene mutations involved in cancer, the technical approaches for diagnosis and prognosis of cancer are limited. In routine clinical diagnosis of cancer, the procedure is very basic: nuclear morphology is used as a common assessment of the degree of malignancy, and acts as a prognostic and predictive indicator of the disease. Though the atypical nuclear morphology of cancer cells is believed to be a consequence of oncogenic signaling, the molecular basis remains unclear. Another common characteristic of human cancer is aneuploidy, but the causes and its role in carcinogenesis are not well established. A deformed and enlarged nuclear morphology is a common characteristic of cancer cells, and the “roundness” of the nucleus is a good indicator to distinguish benign, low grade, and malignant cells [1,2]. Molecular changes in the nuclear matrix and/or nuclear envelope have been postulated, and deformation of nuclear morphology was shown to associate with oncogenic signaling [7,8,9], but no definite conclusions have been reached regarding the molecular basis of nuclear deformation in malignant cells [1,10]
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