JARID2 regulates epithelial mesenchymal transition through the PTEN/AKT signalling pathways in ovarian endometriosis.

Recently, it has been proposed that epithelial-mesenchymal transition (EMT) plays a key role in the development of endometriosis (EMs). Although EMs is a benign disease, it has the characteristics of malignant tumors, such as invasion and migration. JARID2 (Jumonji, AT rich interaction domain) can induce EMT in cancer cells to increase their invasion and migration abilities. However, whether JARID2 has the same function in EMs is not yet known. In this study, A retrospective immunohistochemistry(IHC) was used to measure the expression of JARID2, E-cadherin, PTEN, and p-AKT in ovarian endometriosis (OE) tissues. JARID2, EMT and PTEN/AKT signaling pathway related indicators were assessed by RT-PCR and western blotting in vitro. Furthermore, functional assays were applied to evaluate the involvement of JARID2 in the invasion and migration of Ishikawa cells. Here,we conclude that JARID2 could be involved in the PTEN/AKT signalling pathway and contribute to the development of ovarian endometriosis. The expression of JARID2 was negatively correlated with PTEN, but positively correlated with p-AKT in the ectopic endometrial tissues of OE cases. JARID2 overexpression increased the expression of N-cadherin, vimentin and AKT, but inhibited the expression of E-cadherin and PTEN. Accordingly, the opposite results were obtainedwhen JARID2 was downregulated. Furthermore, JARID2 promoted the invasion and migration ability of Ishikawa cells.

LSD1 binds to HPV16 E7 and promotes the epithelial-mesenchymal transition in cervical cancer by demethylating histones at the Vimentin promoter.

Lysine-specific demethylase 1 (LSD1), which specifically demethylates histone H3 lysine 4 (H3K4) and lysine 9 (H3K9), is dysregulated in several cancers. We found that ectopic expression of LSD1 in cervical cancer cells promoted invasion and metastasis in vitro and in vivo, reduced the expression of the epithelial marker E-cadherin, and induced the expression of the mesenchymal marker, Vimentin. By contrast, LSD1 knockdown had the opposite effect and attenuated the HPV16 E7-induced epithelial-mesenchymal transition (EMT). We proposed a novel mechanism, whereby LSD1 is recruited to the Vimentin promoter and demethylates H3K4me1 and H3K4me2. Notably, HPV16 E7 enhanced the expression of LSD1, formed a complex with LSD1, and suppressed LSD1 demethylase activity by hindering the recruitment of LSD1 to the Vimentin promoter. Thus, LSD1 is a primary and positive regulator of the HPV16 E7-induced EMT and an attractive therapeutic target for alleviating HPV16 E7-induced EMT and tumor metastasis.

The indicative function of Twist2 and E-cadherin in HPV oncogene-induced epithelial-mesenchymal transition of cervical cancer cells.

High-risk human papillomavirus (HR-HPV) infections are among the most important factors for cervical carcinogenesis. However, whether patients infected with HR-HPV eventually develop a malignant tumor, largely depends on epithelial-mesenchymal transition (EMT), which plays an extraordinary role in the process of carcinogenesis and metastasis. Therefore, we evaluated the protein levels of EMT-related genes in normal cervical squamous epithelium, cervical intraepithelial neoplasia (CIN), and cervical squamous cell carcinoma (SCC) by tissue microarray and immunohistochemical staining. By comparing the expression of EMT-related proteins in 31 cases of cervical tumors and tumor adjacent tissues and exploring the relationship between HPV16 oncogenes and EMT in vitro, we found that Twist2 protein levels were significantly higher in CIN and cervical cancer than in normal cervical squamous epithelial samples (p<0.01 and p<0.001, respectively). This finding corresponded with the decreased expression of E-cadherin in cervical cancer. The difference in the expression of Twist2 and E-cadherin between 31 cases of cervical tumors and tumor adjacent tissues was statistically significant (p<0.01). HPV16 oncogenes were able to induce morphological alterations in the SiHa cell line, upregulate the expression of Twist2 and vimentin, downregulate E-cadherin in vitro, and exert an effect on invasion. Thus, joint detection of Twist2 and E-cadherin expression can help evaluate and provide greater insight into cervical carcinogenesis and progression.

Validity of 18F-fluorodeoxyglucose positron emission tomography/computed tomography for pretreatment evaluation of patients with cervical carcinoma: a retrospective pathology-matched study.

OBJECTIVE: The aim of this study was to evaluate the validity of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) for pretreatment evaluation of patients with cervical carcinoma. METHODS: Retrospective evaluation of 63 patients, diagnosed with stage IA-IIA cervical carcinoma who underwent 18F-FDG PET/CT before surgery, was performed. Sensitivity, specificity, positive predictive value, negative predictive value, likelihood ratios (LRs) of PET/CT for predicting the positive cervix, vagina, uterine body, and lymph node invasion at the surgical specimen was calculated. RESULTS: Sensitivity, specificity, positive predictive value, and negative predictive value of the positive cervix invasion in PET/CT to detect positive surgical specimen were 88.2%, 75%, 93.8%, and 60%, respectively. The LR+ ratio was 3.5, and the LR- ratio was 0.2. Sensitivity, specificity, positive predictive value, and negative predictive value of the positive vagina invasion in PET/CT to detect positive surgical specimen were 100%, 70.97%, 5.3%, and 100%, respectively. The LR+ ratio was 3.4, and the LR- ratio was 0. Sensitivity, specificity, positive predictive value, and negative predictive value of the positive uterine body invasion in PET/CT to detect positive surgical specimen were 75%, 83.1%, 23.1%, and 98%, respectively. The LR+ ratio was 4.4, and the LR- ratio was 0.3. Sensitivity, specificity, positive predictive value, and negative predictive value of the positive lymph node invasion in PET/CT to detect positive surgical specimen were 87.5%, 78.4%, 38.9%, and 97.6%, respectively. The LR+ ratio was 4.1, and the LR- ratio was 0.2. CONCLUSIONS: The cervix invasion, negative uterine body invasion, and negative lymph node invasion are effective 18F-FDG PET/CT findings.

Gankyrin is frequently overexpressed in cervical high grade disease and is associated with cervical carcinogenesis and metastasis.

Our previous studies have showed that Gankyrin expression is correlated with a malignant phenotype in endometrial carcinoma. Here, we investigated the possible role of Gankyrin in cervical disease. The increasing protein level of Gankyrin was observed in high-grade cervical intraepithelial neoplasia and carcinoma compared with benign cervical tissues and low-grade cervical intraepithelial neoplasia. In para-carcinoma tissues, it was found interestingly that there was no lymph node metastasis when nuclei Gankyrin was positively expressed, but lymph node metastasis rate was 30% (6/20) when nuclei Gankyrin was negatively expressed. In vitro, the transfection of Gankyrin resulted in markedly up-regulating of Vimentin, ß-catenin and Twist2, as well as down-regulating of E-cadherin in cervical carcinoma cells. Our results suggested that Gankyrin may be functional in cervical carcinogenesis and metastasis.

The protein levels of MCM7 and p63 in evaluating lesion severity of cervical disease.

OBJECTIVES: The objective of this study was to analyze the relationship among the protein levels of MCM7, p63, and human papillomavirus (HPV) in different cervical lesion tissues and appraise their predictive value in evaluating severity of cervical disease. METHODS: Twelve normal cervix or chronic cervicitis, 42 squamous intraepithelial lesions, and 53 cervical carcinoma tissues were enrolled, and the protein levels of MCM7, p63, and HPV were detected by immunohistochemistry. RESULTS: The positive examination rates of all the MCM7, p63, and HPV proteins increased gradually and significantly from normal cervix and chronic cervicitis tissues, low-grade squamous intraepithelial lesions, high-grade squamous intraepithelial lesions to cervical carcinomas, respectively. As to predict high-grade squamous intraepithelial lesions and carcinogenesis is concerned, the MCM7 protein had a sensitivity of 94.0%, a specificity of 56.5%, a positive predictive value of 88.8%, and a negative predictive value of 72.2%. The p63 protein had a sensitivity of 78.6%, a specificity of 81.8%, a positive predictive value of 94.3%, and a negative predictive value of 50.0%. Protein level of MCM7 was positively correlated with that of p63 in cervical tissues (r = 0.806, P < 0.01), and the p63 was also positively correlated with histopathologic type (P < 0.05). CONCLUSIONS: Protein levels of MCM7 and p63 were associated significantly with high-grade cervical lesion, and aberrant p63 protein level may distinguish different histopathologic types of cervical carcinoma. They may act as co-predictive index in both HPV-dependent and HPV-independent high-grade cervical lesion with high sensitivity and specificity.