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Abstract
Epithelial ovarian carcinoma accounts for 90% of all ovarian cancer and is the most deadly gynecologic malignancy. Recent studies have suggested that fallopian tube fimbriae can be the origin of cells for high-grade serous subtype of epithelial ovarian carcinoma (HGSOC). A mouse HGSOC model with conditional Dicer-Pten double knockout (Dicer-Pten DKO) developed primary tumors, intriguingly, from the fallopian tube stroma. We examined the growth and epithelial phenotypes of the Dicer-Pten DKO mouse tumor cells contributable by each gene knockout. Unlike human ovarian epithelial cancer cells that expressed full-length E-cadherin, the Dicer-Pten DKO stromal tumor cells expressed cleaved E-cadherin fragments and metalloproteinase 2, a mixture of epithelial and mesenchymal markers. Although the Dicer-Pten DKO tumor cells lost the expression of mature microRNAs as expected, they showed high levels of tRNA fragment expression and enhanced AKT activation due to the loss of PTEN function. Introduction of a Dicer1-expressing construct into the DKO mouse tumor cells significantly reduced DNA synthesis and the cell growth rate, with concurrent diminished adhesion and ZO1 epithelial staining. Hence, it is likely that the loss of Dicer promoted mesenchymal-epithelial transition in fallopian tube stromal cells, and in conjunction with Pten loss, further promoted cell proliferation and epithelial-like tumorigenesis.
Highlights
Epithelial ovarian cancer is the deadliest of all gynecologic malignancies and is the fifth leading cause of cancer death in females in the United States [1]
We examined the epithelial phenotypes of the Dicer-Pten DKO fallopian tube tumor-derived cancer cell lines (FTdT172 and FTdT967) together with two mouse cancer cell lines originated from the ovarian surface epithelium, OVdT4306 and OVdT4088, which were derived from K-rasG12D/+Pten-/- and K-rasG12D/+ TP53-/- mice, respectively, [9]
The expression analysis showed that the Dicer-Pten DKO mouse fallopian tube tumors and cancer cells expressed a mixture of epithelial and mesenchymal markers, that were very distinct from human epithelial ovarian cancer cells
Summary
Epithelial ovarian cancer is the deadliest of all gynecologic malignancies and is the fifth leading cause of cancer death in females in the United States [1]. Dicer1-expression construct into the Dicer-Pten DKO mouse cancer cells reversed the growth and epithelial phenotypes. To investigate whether Dicer knockout caused the epithelialization of the mouse fallopian tube stromal cells and affected the growth of the Dicer-Pten DKO cancer cells, a FLAG-tagged Dicer1-expression construct was introduced into both FTdT172 and FTdT967 cells by lentiviral infection and the resulting cells were tested for FLAG-Dicer expression (Figure 4A) and cell growth and epithelial phenotypes. An adhesion assay showed that the Dicer1-lentivirus infected FTdT172 cells showed significant reduced adherence to collagen I extracellular matrix than the control cells (Figure 4D, P = 0.007). The Dicer1-lentivirus infected FTdT967 cells showed reduced, albeit not significant, cell adherence when compared with the control cells They demonstrated loss of membrane-bound expression of the tight junction-associated signaling protein ZO-1 when compared with control cells (Figure 4E). MO), and analyzed using a BD AccuriTM C6 cytometer (BD Biosciences, San Jose, CA)
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