Loss of E-cadherin disrupts ovarian epithelial inclusion cyst formation and collective cell movement in ovarian cancer cells

Abstract

Increased inclusion cyst formation in the ovary is associated with ovarian cancer development. We employed in vitro three-dimensional (3D) organotypic models formed by normal human ovarian surface epithelial (OSE) cells and ovarian cancer cells to study the morphologies of normal and cancerous ovarian cortical inclusion cysts and the molecular changes during their transitions into stromal microenvironment. When compared with normal cysts that expressed tenascin, the cancerous cysts expressed high levels of laminin V and demonstrated polarized structures in Matrigel; and the cancer cells migrated collectively when the cyst structures were positioned in a stromal-like collagen I matrix. The molecular markers identified in the in vitro 3D models were verified in clinical samples. Network analysis of gene expression of the 3D structures indicates concurrent downregulation of transforming growth factor beta pathway genes and high levels of E-cadherin and microRNA200 (miR200) expression in the cancerous cysts and the migrating cancer cells. Transient silencing of E-cadherin expression in ovarian cancer cells disrupted cyst structures and inhibited collective cell migration. Taken together, our studies employing 3D models have shown that E-cadherin is crucial for ovarian inclusion cyst formation and collective cancer cell migration.

Cadherin-6 promotes EMT and cancer metastasis by restraining autophagy

“…[36][37][38][39] During collective cell migration, cells undergo a partial EMT, changing morphology toward a spindle-like phenotype but retaining some epithelial features including ECAD expression, which is required to allow cohesion during migration. 40,41 In our analysis ECAD was strongly and homogenously expressed in the set of PTC analyzed and its expression did not correlate with the presence of distant metastasis or with other parameters taken into consideration in this study (Supplementary Tables 2 and 3). Loss of ECAD expression has been shown to occur in the highly aggressive and poorly differentiated forms of thyroid cancer.…”

Characterization of MicroRNA-200 pathway in ovarian cancer and serous intraepithelial carcinoma of fallopian tube

“…Suppression of CDH1 expression in ovarian cancer cells disrupted inclusion cyst formation and collective movement demonstrated in the cancer 3D cultures [26]. Identification of miR-200 targets is the key to understand the function of these miRNAs in ovarian cancer.…”

“…Suppression of CDH1 expression in ovarian cancer cells disrupted inclusion cyst formation and collective movement demonstrated in the cancer 3D cultures [26]. MiR-200 family and miR-205 are the major regulators of epithelial-mesenchymal transition (EMT) and cell differentiation by suppressing the transcriptional repressors ZEB1 and ZEB2 [27] and transforming growth factor β ( TGFβ ) [28].…”

Induction of apoptosis in ovarian cancer cells by miR-493-3p directly targeting AKT2, STK38L, HMGA2, ETS1 and E2F5

“…In order to further assess the functions of miR-493 in the regulation of apoptosis in ovarian CA, the expression of miR-493 was examined in six different ovarian CA cell lines, SKOV3, OVCAR3, TOV21G, TOV112D, A2780 and A2780-cis (Cisplatin Page of 51 resistant cells). Comparing the expression of both miRNA strands to normal human ovarian surface epithelial cells (HOSE cells) [26], the expression of the 3p and 5p strand of hsa-miR-493 was reduced to at least 0.03 fold ± 0.001 fold in TOV21G cells (Fig 1 c). After induction of apoptosis by treating the cells for 48 h with the clinically relevant chemotherapeutic drugs Carboplatin, Paclitaxel [16] and Etoposide as positive controls, the expression of hsa-miR-493 increased for both strands in both cell lines SKOV3 (Fig 1 d) and OVCAR3 (Fig 1 e).…”