UBC Theses and Dissertations
The role of Activin B and TGFb1 in regulating endometrial cancer cell adhesion and migration Xiong, Siyuan
Endometrial cancer is the fourth most common female cancer and the most common gynecological malignancy. Although it comprises only ~10% of all endometrial cancers, the serous histological subtype accounts for ~40% of deaths due to its aggressive behavior and propensity to metastasize. Moreover, the number of endometrial cancer related deaths keeps rising, which can be attributed to the increased incidence of advanced-stage tumor and high risk histologies. Histopathological studies suggest that in non-endometrioid endometrial cancers (type II, mostly serous), elevated expression of activin/inhibin βB subunit is associated with reduced survival and TGFβ signalings are closely associated with the neoplastic transformation of human endometrium and the initiation of invasion of endometrial cancer. However, little is known about the specific roles and mechanisms of activin B (βB dimer) and TGFβ1 in type II endometrial cancer cell progression. We hypothesized that integrin αvβ3, E-cadherin, and PTEN play critical roles in activin B or TGFβ1 induced endometria cancer cell adhesion or migration. Type II endometrial cancer cell lines KLE, HEC-1B and HEC-50 were used as study models. Cancer cell adhesion was assessed by extracellular matrix coated 96 well adhesion assays. Cancer cell migration or invasiveness was assessed by transwell assays without or with coated matrigel following exposure to recombinant human activin B or TGFβ1. Small interfering RNA (siRNA)-mediated knockdown or vector-mediated overexpression approaches were used to investigate the molecular determinants of activin B or TGFβ1-mediated functions. In summary, our results demonstrate that SMAD-mediated integrin β3 up-regulation by activin B promotes type II endometrial cancer cell adhesion and migration while ERK1/2-SNAIL-mediated E-cadherin down-regulation by activin B plays important roles in cancer migration. Moreover, TGFβ1 induces type II endometrial cancer cell migration via ERK1/2 mediated-up-regulation of integrin αvβ3. TGFβ1 also promotes cancer cell migration by down-regulating PTEN via both SMAD-dependent and independent pathways. Our findings provide important insights into the molecular mechanisms underlying the effects of activin and TGFβ on endometrial cancer cell migration and suggest novel therapeutic targets for treating type II endometrial cancer.
Item Citations and Data
Attribution-NonCommercial-NoDerivatives 4.0 International