SLUG is Enhanced by Chemotherapeutics and Functions to Promote Invasion and Metastasis by Directly Targeting MMP3 in Cervical Cancer

Abstract

BackgroundNeoadjuvant chemotherapy(NACT) is a widely used strategy in the treatment of locally advanced cancers. NACT followed by radical surgery for patients in FIGO stages IB2-IIB has proven to reduce tumor volume and numbers. Under certain conditions, however, NACT followed by radical surgery has not been found to improve overall survival, but rather to accelerate cancer growth and metastasis in current studies.MethodsIn this study, 35 paired pre/post-NACT cervical cancer tissues and 167 cervical cancer samples were examined by immunohistochemical analysis to investigate the role of SLUG in invasion and metastasis. Functional assays and a CHIP assay were performed to determine SLUG’s downstream genes and pathways. A lymph node metastatic mouse model was used to study the effects of SLUG- and MMP3-silencing on the malignant behavior of the cervical cancer cells. ResultsSLUG expression was potentially increased in cervical cancer tissues after neoadjuvant chemotherapy, which in turn positively correlated with pelvic lymph node metastasis. The expression of SLUG following neoadjuvant chemotherapy was identified as a poor survival indicator. SLUG overexpression promoted metastasis in cervical cancer in both in vitro and in vivo models, whereas SLUG silencing had the opposite effect. Mechanically, SLUG is not a prerequisite for EMT activation in cervical cancer models, but contributes to the invasiveness and metastasis of cervical cancer cells by directly tethering to the recognition sequence GCCAGGTGC in the MMP3 promoter region. ConclusionOur results provide mechanistic insight into the potential pro-cancer effect of neoadjuvant chemotherapy, and demonstrates that the SLUG-MMP3 axis could serve as a target for improving the efficacy of chemotherapy.