17β-Oestradiol activates proteolysis and increases invasion through phosphatidylinositol 3-kinase pathway in human cervical cancer cells

ObjectiveDespite evidence that oestrogen may play an important role in the carcinogenesis of cervical cancer, its action and mechanism in cervical cancer invasion are not well defined.Study designThe invasion induced by 17β-oestradiol (E2) was measured by invasion assay. Real-time polymerase chain reaction (PCR), Western blot, enzyme-linked immunosorbent assay (ELISA) and gelatin zymography were used to study the role of E2 on metastasis-related proteases. The signal pathway was also investigated.ResultsE2 was found to significantly enhance the invasion of cervical cell lines including HeLa, CaSki and SiHa cells, but not C33A cells. Moreover, E2 10−8 M increased the expression and activation of matrix metalloproteinases (MMP-2 and MMP-9) in HeLa and CaSki cells, as shown by real-time PCR, Western blot, ELISA and gelatin zymography. The expression of tissue inhibitor of metalloproteinases (TIMP-1 and TIMP-2) was decreased significantly by E2. Pretreatment with GM6001 10 μM (total MMP inhibitor) or SB-3CT 20 μM (specific gelatinase inhibitor) blocked the pro-invasive effect of E2. E2 was found to induce invasion via the phosphatidylinositol 3-kinase (PI3K) signalling pathway.ConclusionE2 may contribute to cervical cancer metastasis through activation of proteolysis and increased invasion via the PI3K pathway.