ABSTRACT
Ovarian cancer (OC) is the gynecological malignancy type with the highest mortality rate in females. The regulatory effect of microRNAs (miRs) on their target genes serves a key role in tumor development. Therefore, in the present study, whether miR let7d5p targeting high mobility group A1 (HMGA1) regulated biological characteristics and chemosensitivity of OC cells by mediating the p53 signaling pathway was investigated. The let7d5p level was detected in OC tissues and adjacent normal tissues, followed by detection in OC cell lines SKOV3, A2780, OVCAR3 and CaOV3, and human normal ovarian epithelial cell line (IOSE80), in order to select the OC cell line for the following experiments. Subsequently, OC cells were treated with the let7d5p mimic, siHMGA1 and Tenovin1. The targeting association between let7d5p and HMGA1 was then examined, and the OC cell viability, migration, cycle and apoptosis were evaluated. Subsequently, the chemosensitivity of OC cells to cisplatin was verified. Finally, expression levels of let7d5p, HMGA1, p21, Bcell lymphoma2 (Bcl2)associated X (Bax), p27, p53 wildtype (p53wt), p53 mutated (p53mut), proliferating cell nuclear antigen (PCNA), cyclindependent kinase 2 (CDK2), matrix metallopeptidase (MMP)2, MMP9 and Bcl2 were determined. As demonstrated in the results, let7d5p expression was low in OC tissues and had an increased reduction in the OVCAR3 cell line. HMGA1 was confirmed as a target of let7d5p, and its expression was also silenced by let7d5p. let7d5p repressed OC cell viability, migration, cell cycle progression and apoptosis, while it promoted the chemosensitivity of OC cells to cisplatin by targeting HMGA1. The expression of let7d5p, p21, Bax, p27 and p53wt was increased, while that of HMGA1, p53mut, PCNA, CDK2, MMP2, MMP9 and Bcl2 was reduced following cell transfection. The results in the present study provided evidence that let7d5p may suppress proliferation, and facilitate apoptosis and cisplatin chemosensitivity of OC cells by silencing HMGA1 via the p53 signaling pathway.
Subject(s)
Down-Regulation , Drug Resistance, Neoplasm , HMGA Proteins/genetics , MicroRNAs/genetics , Ovarian Neoplasms/genetics , Signal Transduction , Adult , Cell Line, Tumor , Cisplatin/pharmacology , Drug Resistance, Neoplasm/drug effects , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , MicroRNAs/pharmacology , Middle Aged , Signal Transduction/drug effects , Tumor Suppressor Protein p53/metabolismABSTRACT
The highly refractory nature of cervical cancer to chemotherapeutic drugs and its epithelial-to-mesenchymal transition (EMT) are the key reasons contributing to the poor prognosis of this disease. Golgi Membrane Protein 1 (GOLM1), a protein involved in the trafficking of proteins through the Golgi apparatus, has been shown to be oncogenic in a variety of human cancers. Herein, we found GOLM1 was markedly up-regulated in cervical cancer and GOLM1 down-expression enhanced the anti-tumor effect of methotrexate. By performing mechanistic studies using both in vitro and in vivo models, we found that GOLM1 could target matrix metallopeptidase 13 (MMP13), a member of the MMPs, and regulate the EMT process. Moreover, altered EMT progression compromised the chemotherapy-enhancing effects of GOLM1 knock-down. Finally, we found significantly higher levels of GOLM1 and MMP13 in cervical cancer tissues compared with adjacent noncancerous tissues, and this was also associated with poor cervical cancer patients' prognosis. Taken together, our results suggest that the GOLM1/MMP13/EMT axis is an important factor involved in regulating methotrexate in cervical cancer, and highlights the potential of novel GOLM1-based clinical modalities as a therapeutic approach in cervical cancer patients.
ABSTRACT
OBJECTIVE: To detect the expression of RhoC and Ki67 in squamous carcinoma of cervix and to reveal the correlation of RhoC and Ki67 with clinic pathological parameters of cervix carcinoma. METHODS: The expressions of RhoC and Ki67 were evaluated in 26 cases of cervical intraepithelial neoplasia (CIN) and 57 cases of squamous carcinoma of cervix(SCC) by immunohistochemistry, while 14 cases of normal cervical epithelium(NCE) were taken as control. RESULTS: Immunohistochemical staining demonstrated RhoC expression in 82.46% (47/57) of SCC, 15.38% (2/13) of CIN II/III, and negative expression in NCE and CIN I. The positive rate of RhoC expression in SCC was significantly higher than that in NCE and CIN (P < 0.05). The expression of RhoC in SCC was significantly correlated with pelvic lymph node metastasis and depth of stroma infiltration, but not correlated with age, FIGO staging,histologic grade and vascular space involvement. The positive rates of Ki67 expression in NCE, CIN I, CIN II/III and SCC were 28.57%, 38.46%, 100% and 96.49% respectively. The positive rates of Ki67 expression in SCC and CIN II/III were significantly higher than those in NCE and CIN I (P < 0.05). The expression of Ki67 in SCC was not correlated with the major clinic pathological parameters. There was no obvious relationship between the expression of RhoC gene and Ki67 antigen in SCC (P > 0. 05). CONCLUSIONS: The overexpression of RhoC may play an important role in the invasion and metastasis of SCC. RhoC may be a potential marker to identify SCC patients with high risk of invasion and metastasis.