Downregulation of Mad2 and BubR1 increase the malignant potential and nocodazole resistance by compromising spindle assembly checkpoint signaling pathway in cervical carcinogenesis.

Li Wang, Jian Wang, Yubiao Jin, Jun Zheng, Yongbin Yang, Xiaowei Xi

The journal of obstetrics and gynaecology research 2019 Dec

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To explore the involvement of Mad2 and BubR1 in cervical carcinogenesis. The expressions of Mad2 and BubR1 in tissues of high-grade squamous intraepithelial lesions (HSIL), low-grade squamous intraepithelial lesions (LSIL) and chronic cervicitis were analyzed immunohistochemistrily and compared with those of p16INK4A . PEGFP-Mad2 and pEGFP-BubR1 were transfected into SiHa cells to overexpress Mad2 and BubR1 and Si-RNAs to knockdown. Cell viability was measured by cell counting kit-8 (CCK-8) assay. Migration and invasion capabilities were detected by Transwell. Propidium iodide staining with flow cytometry was used for cell cycle analysis and apoptosis was detected using Annexin V/7-AAD staining after nocodazole treatment. The expression of Mad2 was significantly lower in HSIL than those in chronic cervicitis and LSIL, however, the expression of BubR1 showed no significant differences. To detect HSIL in cervical lesions, Mad2 had a sensitivity of 88.44% and a specificity of 87.23%, Mad2 was less sensitive and more specific than p16INK4a . In SiHa cells, knockdown of Mad2 and BubR1 increased cell growth, reinforced invasion capacity and migration potency, inhibited apoptosis and decreased G2-phase distribution after nocodazole treatment. Oppositely, the overexpression strategies made cells show decreased malignant behaviors, raised apoptosis and increased G2-phase distribution. Mad2 negativity was specific to identify HSIL immunohistochemistrily. Downregulation of Mad2 and BubR1 increase the malignant behavior and nocodazole resistance of SiHa cells via causing spindle assembly checkpoint defect. This mechanism may contribute to cervical carcinogenesis and resistance to microtubule-targeting drugs. © 2019 Japan Society of Obstetrics and Gynecology.

Citation

Li Wang, Jian Wang, Yubiao Jin, Jun Zheng, Yongbin Yang, Xiaowei Xi. Downregulation of Mad2 and BubR1 increase the malignant potential and nocodazole resistance by compromising spindle assembly checkpoint signaling pathway in cervical carcinogenesis. The journal of obstetrics and gynaecology research. 2019 Dec;45(12):2407-2418