Effects Of Mucinl On The Regulation Of Biological Behavior Induced By Glucocorticoids In Ovarian Cancer Cell And Its Potential Mechanisms

Ovarian cancer ranks third in the incidence of gynecological malignancies, inferior only tocervical cancer and endometrial cancer., the mortality of it is higher than the sum proportion ofcervical and endometrial cancer among gynecologic cancers, and thus it turns into a serious threat tothe female health. Owning to the complexity of ovarian cancer tissue and pathological type,themechanism of cancerprogression is still unclear. In ovarian cancer, the detectable rate of theglucocorticoid receptor (GR) is up to88%, which indicate that glucocorticoids (GCs) plays animportant role in regulating the function of ovarian epithelium and may be involved in thedevelopment and progression of ovarian cancer. Our previously study showed that Dex could promotethe adhesion between cells and extracellular matrix (ECM) and inhibit cell migration and enhance cellresistance to chemotherapeutic drugs, cisplatin andpaclitaxel, thereby promoting cell survival. But sofar, mechanisms of the action of GCs is still limited, it is of great significance to find the target genesof GCs for further elucidate the effect and mechanism of GCs in ovarian cancer development andunderstanding of the neuroendocrine system in tumorigenesis.Mucin1(MUC1) is a trans-membrane glycoprotein abundantlyexpressed on the apical surface ofepithelial cells, and it is also aberrantly expressed in a variety of tumor cells. MUC1is composed oftwo subunits: and β. MUC1subunit mainly forms a protective barrier in the extracellular whileMUC1β subunit is reported to be involved in the intracellular signaling pathway. Compared withnormal ovarian epithelial cells, ovarian cancer shows higher MUC1expression which is closelyrelated toits classification and prognosis, and also, the high expression of MUC1is involved intheprocess of cancer metastasis and invasion. Our previous study showed that dexamethasone (Dex), akind of synthetic glucocorticoid, can induce morphological changes in ovarian cancer cells andenhance adhesion between cells and ECM. Dex can also inhibit cellmigration, and promotethechemotherapeutic resistance totwo kinds of chemotherapeutic drugs, cisplatin and paclitaxel (PTX).Based on the above theory, we further studied the role of MUC1in the biological behavior changes ofovarian cancer celltreated by Dex andthe potential mechanism.We verified MUC1expression in two ovarian cancer cell lines using real-time PCR and westernblot. After treated with100nM Dex, we observed that MUC1mRNA and MUC1C-terminusexpression was time-dependently up-regulated.We further used the small fragment interfering RNA (siRNA) to interfere with endogenousexpression of MUC1to study whether MUC1play a role in the effect of promoting ovarian cancercell adhesion, inhibiting migration and enhancing chemotherapy resistance by Dex.Cell adhesionassay revealed that after interference of MUC1, the capacity of ovarian cancer cell adhesion which enhancedby Dex was significantly reduced,which indicated that MUC1is partially required in theprocess of the ovarian cancer cell adhesive enhancement induced by Dex. Transwell migration assayfound that after MUC1silenced, the vertical migration of cells was slightly inhibited suggesting thatMUC1might promote cell migration which was consistent withprevious reports. Combining MUC1expression silence with Dex treatment could inhibit migration more obviously, indicating that theupregulation of MUC1wasnot involved in the process of cell migratory inhibitied by Dex. Besides,we further investigated the role of MUC1in the chemotherapy resistance enhanced by Dex in ovariancancer cells.The results showed after interference separately, there was a downward trend of theviability of cells, but when combined MUC1interference with Dex under the action ofchemotherapy drugs，cell survival had no significant change, This suggestesthat increasing of MUC1by Dexhas little effecton its enhancement role of cell chemotherapy resistance. But it requires furtherstudy.Our previous studies have shown that Dex could increase the level of Aktphosphorylationtime-dependently, and it is reported that MUC1increase the activity of the PI-3K/Aktpathway, so we examined the role of MUC1inactivation of the Akt pathway and found that MUC1indeed took part in mediating Akt phosphorylation induced by Dex.In summary, we demonstrated that in human ovarian cancer cell lines, Dex upregulated theMUC1expression and the up-regulation of MUC1was partially required in the effect of Dex onup-regulating Akt phosphoralation and the process of the ovarian cancer cell adhesive enhancementby Dex, but MUC1upregulation was not required in the process of migratory inhibition and had nosignificant effect on the enhancement of cell resistance to chemotherapy drugs induced by Dex. Theseresults further elucidate the mechanism of biological behavior regulation by Dex whichmaycontributed to a better understanding of glucocorticoids on the development and progressionin ovariancancer.