Effects of metalloprotease ADAMTS12 on cervical cancer cell phenotype and its potential mechanism.

ADAMTS12 is a gene widely expressed in human tissues. We studied the expression level of ADAMTS12 in cervical cancer tissue and its relationship with clinicopathological features. We also explored the function of ADAMTS12 in cervical cancer cells and its underlying mechanisms. We found the higher expression level of ADAMTS12 in cancer tissues, which was associated with the worse overall survival rate. The immunofluorescence assay showed that the cytoplasm of cervical cancer cells is the main expression site of ADAMTS12. Overexpression of ADAMTS12 in HeLa and CaSki cells prominently promoted the cell proliferation, migration and invasion. We found that 2032 genes were correlated with ADAMTS12, which was mainly related to extracellular matrix, TGF-ß signaling pathway. The phosphorylation levels of mTOR and 4E-BP1 were upregulated in ADAMTS12-overexpressing cells. Co-Immunoprecipitation combined with protein mass spectrometry showed that TGF-ß signaling pathway-related proteins interacting with ADAMTS12 were screened from HeLa cells with ADAMTS12 overexpression. Therefore, we concluded that ADAMTS12 may affect the mTOR signaling pathway through the interacting with TGF-ß1, and then affect the biological function of cervical cancer cells.

RNA epigenetic modifications in ovarian cancer: The changes, chances, and challenges.

Ovarian cancer (OC) is the most common female cancer worldwide. Patients with OC have high mortality because of its complex and poorly understood pathogenesis. RNA epigenetic modifications, such as m6 A, m1 A, and m5 C, are closely associated with the occurrence and development of OC. RNA modifications can affect the stability of mRNA transcripts, nuclear export of RNAs, translation efficiency, and decoding accuracy. However, there are few overviews that summarize the link between m6 A RNA modification and OC. Here, we discuss the molecular and cellular functions of different RNA modifications and how their regulation contributes to the pathogenesis of OC. By improving our understanding of the role of RNA modifications in the etiology of OC, we provide new perspectives for their use in OC diagnosis and treatment. This article is categorized under: RNA Processing > RNA Editing and Modification RNA in Disease and Development > RNA in Disease.

Four Types of RNA Modification Writer-Related lncRNAs Are Effective Predictors of Prognosis and Immunotherapy Response in Serous Ovarian Carcinoma.

Serous ovarian carcinoma (SOC) is a gynecological malignancy with high mortality rates. Currently, there is a lack of reliable biomarkers for accurate SOC patient prognosis. Here, we analyzed SOC RNA-Seq data from The Cancer Genome Atlas (TCGA) to identify prognostic biomarkers. Through the pearson correlation analysis, univariate Cox regression analysis, and LASSO-penalized Cox regression analysis, we identified nine lncRNAs significantly associated with four types of RNA modification writers (m6A, m1A, APA, and A-I) and with the prognosis of SOC patients (P <0.05). Six writer-related lncRNAs were ultimately selected following multivariate Cox analysis. We established a risk prediction model based on these six lncRNAs and evaluated its prognostic value in multiple groups (training set, testing set, and entire set). Our risk prediction model could effectively predict the prognosis of SOC patients with different clinical characteristics and their responses to immunotherapy. Lastly, we validated the predictive reliability and sensitivity of the lncRNA-based model via a nomogram. This study explored the association between RNA modification writer-related lncRNAs and SOC prognosis, providing a potential complement for the clinical management of SOC patients.

Characteristics of Infiltrating Immune Cells and a Predictive Immune Model for Cervical Cancer.

The role of infiltrating immune cells within the tumor microenvironment has received considerable attention, but their function in cervical cancer remains to be elucidated; thus, comprehensive evaluation of their predictive value is needed. Using cervical cancer samples from 406 patients, immune cell infiltration was evaluated via immunohistochemistry. CD3+, CD4+, CD8+, CD20+, CD57+, CD68+, and CD163+ cell infiltration was compared in samples from adjacent tissues and the tumor center. The associations between immune cell distributions in the tumor center, clinicopathological features, and prognosis were correlated among immune cell types. Using three immune features, an immune model was constructed based on a Cox regression analysis with the least absolute shrinkage and selection operator (lasso) penalty to derive immune risk scores. Immune cells that infiltrated the tumor center correlated with clinicopathological characteristics and prognosis. The immune risk scores were an independent prognostic indicator and were found to predict cervical cancer prognosis as well as the effects of chemoradiotherapy. We classified patients into either high- or low-risk subgroups (namely CD4+highCD163+highCD57+low and CD4+lowCD163+lowCD57+high, respectively) based on their immune scores. Significant differences were found in the 3-year overall survival of patients with high- and low-risk scores (83.0% vs. 96.6%; P < 0.001). High immune risk scores resulted in decreased overall survival for patients in stages IB1+IIA1, IB2+IIA2, and IIB-IV (P = 0.001, P = 0.008, and P = 0.044, respectively). Overall survival was significantly worse following chemoradiotherapy in high-scoring patients in stages IB1+IIA1 and IB2+IIA2 (P = 0.001 and P=0.008, respectively). Moreover, overall survival was significantly worse after radiotherapy or chemotherapy in high-scoring patients in stage IB1+IIA1 (P = 0.03). Our work reveals that the distribution of infiltrating immune cells affects their function in cervical cancer. Our tumor center-centric immune model effectively predicted survival, suggesting its potential use in identifying suitable candidates for chemoradiotherapy.

Long non-coding RNAs as a determinant of cancer drug resistance: Towards the overcoming of chemoresistance via modulation of lncRNAs.

Chemoresistance including intrinsic and acquired anticancer drug resistance continues to be a primary hindrance towards curative cancer treatment. Therefore, deciphering the underlying molecular mechanisms is of paramount importance required towards the overcoming of chemoresistance. Cumulative evidence revealed that long non-coding RNAs (lncRNAs) play a pivotal role in conferring anticancer drug resistance upon a broad spectrum of cancers. Hence, numerous lncRNAs are recognized as novel biomarkers and therapeutic targets in the diagnosis and treatment of malignancies, which urges us to comprehensively delineate the critical functions of lncRNAs in chemoresistance. In this respect, we herein succinctly elucidate the molecular mechanisms by which lncRNAs modulate their downstream targets to mediate cancer chemoresistance. Therefore, the current review may provide a significant basis for the future conquering of chemoresistance via targeting lncRNAs in cancer therapeutics.

The role of the cancer testis antigen PRAME in tumorigenesis and immunotherapy in human cancer.

Preferentially expressed antigen in melanoma (PRAME), which belongs to the cancer/testis antigen (CTA) gene family, plays a pivotal role in multiple cellular processes and immunotherapy response in human cancers. PRAME is highly expressed in different types of cancers and is involved in cell proliferation, apoptosis, differentiation and metastasis as well as the outcomes of patients with cancer. In this review article, we discuss the potential roles and physiological functions of PRAME in various types of cancers. Moreover, this review highlights immunotherapeutic strategies that target PRAME in human malignancies. Therefore, the modulation of PRAME might be useful for the treatment of patients with cancer.

Up-regulated BCAR4 contributes to proliferation and migration of cervical cancer cells.

OBJECTIVES: Recently, thousands of long non-coding RNAs (lncRNAs) involved in development and metastasis of malignant tumors have been identified. Long non-coding RNA (lncRNA) breast cancer anti-estrogen resistance 4 (BCAR4) has been proved to promote proliferation and metastasis in multiple tumors. However, the function and significance of BCAR4 in cervical cancer are still unclear. METHODS: In this study, we concentrated on the biological function and clinical significance of BCAR4 in cervical cancer. More specifically, BCAR4 expression was evaluated in cervical cancer tissues and cell lines by qRT-PCR. Moreover, the prognostic factors were assessed by Kaplan-Meier analysis and Cox proportional hazards models. Additionally, functional assays were conducted and the potential mechanism was explored. RESULTS: Our study showed that BCAR4 expression was significantly up-regulated in cervical cancer tissue and cell lines. Moreover, patients with high BCAR4 expression showed worse survival outcomes and overexpression of BCAR4 might be an independent prognostic factor in cervical cancer. Furthermore, overexpression of BCAR4 remarkably promoted the proliferation, motility of cervical cancer cells and silencing BCAR4 significantly suppressed the proliferation, migration and invasion of cervical cancer cells. Additionally, overexpression of BCAR4 promoted epithelial-mesenchymal transition (EMT) process and silencing BCAR4 suppressed EMT process in cervical cancer cells. CONCLUSIONS: The results indicated that BCAR4 might play a crucial role in cervical cancer progression and act as an underlying biomarker for the diagnosis and prognosis of cervical cancer.

LncRNA-TCONS_00026907 is involved in the progression and prognosis of cervical cancer through inhibiting miR-143-5p.

Our previous long noncoding RNA (lncRNA) microarray revealed that lncRNA-TCONS_00026907 is aberrantly expressed between cervical cancer tissues and adjacent tissues. This study aims to explore the potential role of TCONS_00026907 in the development of cervical cancer. The expression levels of TCONS_00026907 in cervical cancer tissues and adjacent tissues from 83 patients of cervical cancer were detected by quantitative real-time polymerase chain reaction and the survival rate was analyzed. In vitro, HeLa and SiHa cells were transfected with small hairpin RNA (shRNA)-TCONS_00026907, then cell proliferation, cycle distribution, apoptosis, migration and invasion were measured. To confirm TCONS_00026907 regulates expression of ELK1 through inhibiting miR-143-5p, overexpression of miR-143-5p and silencing of ELK1 were, respectively, performed in HeLa and SiHa cells. Results showed that TCONS_00026907 level was significantly higher in cervical cancer tissues compared to noncancerous tissues and the survival rate was lower in the high expression group. Silencing of TCONS_00026907, overexpression of miR-143-5p and silencing of ELK1 inhibited cervical cell cycle, proliferation, migration, and invasion, but promoted apoptosis, respectively. Furthermore, silencing of TCONS_00026907 suppressed the growth of cervical tumors and altered the expression of ELK1, p-ELK1, C-fos, Cyclin D1 and Bcl-2 in vivo. Our study identifies TCONS_00026907 as a potent proto-oncogene and indicates that TCONS_00026907/miR143-5p/ELK1 regulatory pathway plays an important role in cervical cancer.

Upregulation of long noncoding RNA TUG1 promotes cervical cancer cell proliferation and migration.

Long noncoding RNAs (lncRNAs), a novel class of transcripts that have critical roles in carcinogenesis and progression, have emerged as important gene expression modulators. Recent evidence indicates that lncRNA taurine-upregulated gene 1 (TUG1) functions as an oncogene in numerous types of human cancers. However, its function in the development of cervical cancer remains unknown. The aim of this research was to investigate the clinical significance and biological functions of TUG1 in cervical cancer. TUG1 was found to be significantly upregulated in cervical cancer tissues and four cervical cancer cell lines by quantitative real-time polymerase chain reaction (qRT-PCR). Elevated TUG1 expression was correlated with larger tumor size, advanced international federation of gynecology and obstetrics (FIGO) stage, poor differentiation, and lymph node metastasis. Furthermore, knockdown of TUG1 suppressed cell proliferation with activation of apoptosis, in part by regulating the expression of Bcl-2 and caspase-3. Silencing of TUG1 inhibited cell migration and invasion via the progression of epithelial-mesenchymal transition (EMT). Taken together, our findings indicate that TUG1 acts as an oncogene in cervical cancer and may represent a novel therapeutic target.

Establishment and Application of a Method for High-Risk Human Papillomavirus Genotyping in Cervical Cancer Tissue.

BACKGROUND: Persistent high-risk HPV infection is a major cause of cervical cancer and E6/E7 genes and the Li gene in the HPV genome are key targets to detect high-risk HPV. This study aims to explore the relationship between cervical lesions and E6/7 by establishing a polymerase chain reaction (PCR) to detect multiplex genes based on HPV EE7 genes. It is hoped that such methods will provide a more reliable method for clinical screening and the prevention of cervical cancer. METHODS: Based on alignment, specific primers were designed for HPV E6/E7 genes, the sequences of which came from five5 high-risk papillomaviruses that are common in China. This enabled an E6/E7 gene detection method based on multiplex PCR to be established. E6/E7 and Li gene testing were then performed on 65 cervical cancer tissue samples. The gene copy number of HPV E6/E7 genes and the Li gene were detected from different classifications by real-time fluorescence quantitative PCR. RESULTS: Out of the 65 cervical cancer tissue samples, 47 (72.31%) showed positive results in E6/E7 multiplex PCR, 21 (32.31%) showed positive results in the Ll gene PCR, and out of the 219 cervical exfoliate cell samples, 56 (25.57%) showed positive results in E6/E7 multiplex PCR, 21 (13.24%) showed positive results in the L1 gene PCR. There were significant differences (p < 0.05) between these two test results. Fluorescent quantitative PCR showed that the ratio of gene copy number of L1 genes and E6/E7 genes was below 1 (p < 0.05) in cervical cancer tissue, in which both the Li and E6/E7 genes coexist. CONCLUSIONS: The established HPV multiplex PCR assay based on the design of E6/E7 gene is a specific and sensitive method for the detection and genotype of five high-risk HPVs.

E6-associated transcription patterns in human papilloma virus 16-positive cervical tissues.

The change in transcription pattern induced by post-transcriptional RNA splicing is an important mechanism in the regulation of the early gene expression of human papilloma virus (HPV). The present study was conducted to establish a method to specifically amplify HPV-16 E6-associated transcripts. The E6-related transcripts from 63 HPV-16-positive cervical tumor tissue samples were amplified, consisting of eight cases of low-risk intraepithelial lesions, 38 cases of high-risk intraepithelial lesions and 17 cases of cervical cancer (CxCa). The appropriate amplified segments were recovered following agarose gel electrophoresis, and subjected to further sequencing and sequence alignment analysis. Six groups of E6 transcription patterns were identified from HPV-16-positive cervical tumor tissue, including five newly-discovered transcripts. Different HPV-16 E6-associated transcription patterns were detected during the development of CxCa. Over the course of the progression of the low-grade squamous intraepithelial lesions to CxCa, the specific HPV-16 E6-associated transcription patterns and the dominant transcripts were all different. As indicated by this study, the transcription pattern of the E6 early gene of HPV-16 was closely associated with the stages of cervical carcinogenesis, and may also be involved in the development of CxCa.

Expression and effect of CXCL14 in colorectal carcinoma.

Chemokines are important in the proliferation and metastasis of tumors. CXCL14 is a member of the CXCL chemokine family and exhibits various expression patterns in different types of tumor, even those tumors that occur in the same type of tissue. The expression of CXCL14 and its clinical significance in colorectal carcinoma are unclear. In the present study, the expression levels of CXCL14 in colorectal carcinoma and adjacent normal tissues were detected using reverse transcription-quantitative polymerase chain reaction and immunohistochemistry. Kaplan­Meier survival curves and the Cox regression model were applied to evaluate the clinical significance of the expression levels of CXCL14 in colorectal carcinoma compared with those in normal tissues. To investigate the effects at a cellular level, a replication­defective lentivirus overexpressing CXCL14 was constructed and transfected into HT29 colorectal carcinoma cells. The effect of CXCL14 on the proliferation of colorectal carcinoma cells and the change in cell cycle distributions were investigated using a cell counting kit­8 assay and flow cytometry, respectively. Results of the current study indicated that the expression levels of CXCL14 mRNA and protein in colorectal carcinoma were markedly reduced compared with levels in normal tissues (P<0.05). The clinical correlation analysis suggested that downregulation of CXCL14 expression in tumors was associated with lymph metastasis, tumor location, and clinicopathological stage (P<0.05). Kaplan­Meier survival analysis revealed that downregulation of CXCL14 expression was correlated with a poor prognosis (P<0.01). Overexpression of CXCL14 by lentiviral transfection produced an inhibitory effect on cell proliferation by arresting the cell cycle in the G1 stage. The data of the current study suggest that CXCL14 may be involved in the development and progression of colorectal carcinoma, and may act directly as a potential cancer suppressor gene. The level of CXCL14 expression may be a valuable adjuvant parameter in predicting the prognosis of colorectal carcinoma and may be a potential therapeutic target.