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Background: Interactions between cancer cells and their extracellular matrix play an important role in tumor growth,invasiveness and metastasis.The regulation of these interactions is unclear.Several inherent cancer cell genome aberrations and protein changes in the microenvironment of the extracellular matrix have been implicated.Fibulin1 is a multifunctional extracellular matrix protein overexpressed in ovarian cancers.Fibulin-1 gene encodes four protein isoforms (A, B, C and D) with different carboxyl termini generated by alternative mRNA splicing.Fibulin1C and D are the predominant variants in most tissues and cells studied.There is evidence to suggest that these two isoforms may have opposite role in biogenesis of ovarian cancer.Our study also demonstrates an association of overexpressed fibulin-1 with endometriosis.However, the molecular pathways modulated by fibulin-1C and D in ovarian cancer and endometriosis are not clear.Aim: To study the molecular pathways modulated by fibulin-1 C and D and to identify the isoform-specific differential gene expression profiles.Methods: The objectives have been accomplished by combined approaches of RNAi, Western Blot, GeneChip microarray and real-time RT-PCR.Result: The fibulin-lC and D have been specifically knocked down by RNAi.The knockdown effect has been confirmed at both mRNA and protein level.The use of GeneChip microarray allows us to capture the changes in the global gene expression profiles and to identify the affected pathways under different conditions of gene knockdown.The selected genes and pathways have been further verified by real-time RT-PCR.Conclusion: The networks of molecular pathways modulated by fihulin-1 isoform C and D have been determined in vitro.The study may potentially lead to discovery of more biomarkers and therapeutic targets for ovarian cancer and endometriosis.