MALAT1 plays important role in MEK inhibitor, RG7420, on the proliferation and migration of endometrial cancer cell through sponging miR-129-5p/ TAK1

Abstract

Background: Endometrial cancer is one of the most common malignancies of the female genital tract. Although the overall five-year survival of EC is much higher than other genital tumor, 25% of the total patients with high risk to develop more aggressive diseases. The metastasis in EC patients is the main cause of death. The MEK inhibitor, which has significant effect on malignant molenoma, lung cancer and so on, has bright future in EC. Method: Here we treated the EC cell line HEC50 and HEC1A with different concentration of RG7420. The CCK8 was used to detecte the cell proliferation rate. Microarray analyzed the difference of LncRNAs in EC cells with or without RG7420. Luciferase reporter assay and RNA immunoprecipitation assay(RIP) were performed to verified the regulation among MALAT1, miR-129-5p and TGF-β-activated kinase 1 (TAK1). QRT-PCR and WB were used to detect the changes in mRNA and protein levels. We also performed ISH to detect the MALAT level in EC paraffin section. Results: We found the RG7420 significantly inhibited the viability and mobility of EC cell lines. Then we analyzed the profile of LncRNA in HEC50 with or without RG7420. We found after treated with IC50 of HEC50, the metastasis-associated lung adenocarcinoma transcript-1(MALAT1) decreased 6.13 times with up-regulation of tumor suppressor miR-129-5p. Our data also provided that MALAT1 may work as endogenous sponge for miR-129-5p. Here we predicted and proved TGF-β-activated kinase 1 (TAK1), encoded by MAP3K7, is the target of miR-129-5p and works as the key factor in metastasis of EC. Meanwhile we compared the MALAT1 level in EC paraffin section by in-situ hybridization. Rerospective analysis assessed the corelation between the MALAT1 level and the clinical characters of EC, MALAT1 is a poor prognostic marker of EC. Furthermore we over-expressed MALAT1 in EC cells, the function of RG7420 was reversed. Conclusion: Taken together, our data uncovered RG7420 inhibited the proliferation and migration of EC cell through MALAT1/miR-129-5p/TAK1 pathway. MALAT1 is a poor prognostic marker of EC.

The Role of Long Non-Coding RNAs (lncRNAs) in Female Oriented Cancers

“…The PCDH10–Wnt/b-catenin–MALAT1 regulatory axis has also been involved in the development and proliferation of EC, in vivo and in vitro [ 199 ]. Moreover, Y. Shen et al established that on the treatment of EC cell lines with MEK inhibitor RG7420, MALAT1 can decrease up to 6.13 times with upregulation of tumor suppressor miR-129-5p and downregulation of TAK1, leading to decreased metastasis and increased apoptosis of EC cells [ 200 ].…”