Therapeutic Target For Cervical Cancer Research Articles

Long non-coding RNA C5orf66-AS1 promotes cell proliferation in cervical cancer by targeting miR-637/RING1 axis

Long non-coding RNA (lncRNA) plays an important role in the development of human malignant tumours. Recently, an increasing number of lncRNAs have been identified and investigated in a variety of tumours. However, the expression pattern and biological function of lncRNAs in cervical cancer still remain largely unexplored. Differentially expressed lncRNAs in cervical cancer and para-carcinoma tissues were identified by screening using The Cancer Genome Atlas (TCGA), and candidate lncRNAs were verified by quantitative real-time PCR. We found that lncRNAC5orf66-AS1 was significantly upregulated in cervical cancer tissues and cells. Over-expression of C5orf66-AS1 promoted the proliferation of cervical cancer cells, while downregulation of C5orf66-AS1 promoted the apoptosis of cervical cancer cells. C5orf66-AS1 was identified as the sponge of miR-637 by RNA immunoprecipitation (RIP) and luciferase reporter assays. Exogenous miR-637 and RING1 interventions could reverse the proliferation ability mediated by C5orf66-AS1 in cervical cancer cells. In vivo experiments also confirmed that downregulation of C5orf66-AS1 inhibited the tumour growth. LncRNA C5orf66-AS1, as a competitive endogenous RNA (ceRNA), regulated the effect of RING1 on the proliferation, apoptosis and cell cycle of cervical cancer cells through adsorbing miR-637. Taken together, our findings provided a new theoretical and experimental basis for investigating the pathogenesis and exploring effective therapeutic targets for cervical cancer.

Potential role of cancer stem cells as biomarkers and therapeutic targets in cervical cancer.

Eradicating cancer stem cells (CSCs) that are termed as the "beating heart" of various malignant tumors, including cervical cancer, holds great importance in cancer therapeutics. CSCs not only confer chemo-radio resistance but also play an important role in tumor metastasis and thereby pose a potential barrier for the cure of cervical cancer. Cervical cancer, a common malignancy among females, is associated with high morbidity and mortality rates, and the study on CSCs residing in the niche is promising. Biomarker approach to screen the cervical CSCs has gained impetus since the past decade. Progress in identification and characterization of the stem cell biomarkers has led to many insights. For the diagnostic purpose, several biomarkers like viral (HPV16), stem cell markers, transcription factors (viz, SOX2, OCT 4, and c-Myc), and CSC surface markers (viz, ALDH1 and CD44) have been identified. The research so far has been directed to study the CSC stemness and demonstrates various gene expression signatures in cervical CSCs. Such studies hold a potential to improve diagnostic accuracy and predict therapeutic response and clinical outcome in patients. Stem cell biomarkers have been validated and their therapeutic targets are being developed as "strategies to improve therapeutic ratio in personalized medicine." This review gives a brief overview of the cervical CSC biomarkers, their current and future diagnostic, prognostic, and therapeutic potential.

Suppression of miR-22, a tumor suppressor in cervical cancer, by human papillomavirus 16 E6 via a p53/miR-22/HDAC6 pathway.

MicroRNAs (miRNAs) are small non-coding RNAs that function to down-regulate gene expression involving in various cellular processes related to carcinogenesis. Recently, miR-22 was identified as a tumor-suppressing miRNA in many human cancers. However, the regulatory mechanism and the specific function of this miRNA in cervical cancer remain unclear. In the present study, we carried out gene transfection, western blot and quantitative RT-PCR to explore the regulatory mechanism and the functional role of miR-22 in cervical cancer. We verified that miR-22 was down-regulated in cervical cancer tissues and cervical cancer cell lines relative to matched non-tumor tissues and normal human cervical keratinocyte line (HCK1T). By contrast, histone deacetylase 6 (HDAC6) was inversely correlated with miR-22 in both cervical tissues and cancer cell lines. Mechanically, HDAC6 was down-regulated by miR-22 at the post-transcriptional level, via a specific target site within the 3’UTR, identified by a luciferase reporter assay. Moreover, we also showed that the correlation between miR-22 and HDAC6 expression was regulated by an E6/p53 pathway in HCK1Ts expressing HPV16 E6. For functional study, an ectopic expression of miR-22 could inhibit cell proliferation and migration, and could induce apoptosis of cervical cancer cell lines. These findings demonstrated that miR-22 was down-regulated in cervical cancer and inversely collated with its downstream target HDAC6. MiR-22 acts as tumor suppressor by inhibiting proliferation and migration, and by inducing apoptosis of cervical cancer cell lines by targeting the 3’UTR of HDAC6. This newly identified E6/p53/miR-22/HDAC6 regulatory network might be a candidate therapeutic target for cervical cancer.

LncRNA DANCR promotes cervical cancer progression by upregulating ROCK1 via sponging miR-335-5p.

Emerging evidence highlights the key regulatory roles of long noncoding RNAs (lncRNAs) in the initiation and progression of numerous malignancies. The lncRNA identified as differentiation antagonizing nonprotein coding RNA (DANCR) is a novel lncRNA widely involved in the development of multiple human cancers. However, the function of DANCR and its potential molecular mechanism in cervical cancer remain unclear. In this study, we discovered that DANCR was significantly elevated in cervical cancer tissues and cells, and was closely correlated with poor prognosis of cervical cancer patients. In addition, knockdown of DANCR inhibited proliferation, migration, and invasion of cervical cancer cells in vitro, indicating that DANCR functioned as an oncogene in cervical cancer. Moreover, we verified that DANCR could directly bind to miR-335-5p, isolating miR-335-5p from its target gene Rho-associated coiled-coil containing protein kinase 1 (ROCK1). Functional analysis showed that DANCR regulated ROCK1 expression by competitively binding to miR-335-5p. Further cellular behavioral experiments revealed that miR-335-5p mimics and ROCK1 knockdown reversed the effects of upregulated DANCR on proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of cervical cancer cells by rescue assays. In summary, this study demonstrated that DANCR promoted cervical cancer progression by functioning as a competing endogenous RNA (ceRNA) to regulate ROCK1 expression via sponging miR-335-5p, suggesting a novel potential therapeutic target for cervical cancer.

Maternal embryonic leucine zipper kinase: A novel biomarker and a potential therapeutic target of cervical cancer.

Maternal embryo leucine zipper kinase (MELK) is highly expressed in a variety of malignant tumors and involved in cell cycle regulation, cell proliferation, apoptosis, tumor formation etc However, the biological effects of MELK in cervical cancer are still uninvestigated. This study aimed to explore the expression of MELK in cervical cancer, as well as its effects on the proliferation, apoptosis, DNA damage repair on cervical cancer cell line in vitro and to provide novel ideas for further improving the clinical efficacy of cervical cancer. Immunohistochemistry, Western blot, RT‐qPCR, CCK8, and immunofluorescence techniques were used to detect the expression of MELK in cervical cancer tissues, paracancerous tissues, and cervical cancer cell lines. Several cervical cancer cell lines were treated with MELK knockdown by siRNA and MELK selective inhibitor OTSSP167. The effects on proliferation, apoptosis, and colony formation capacity, and tumor cell DNA damage repair‐related factor were detected in cell lines. Our data showed that the high expression rate of MELK in cervical cancer patients was 56.92%. MELK expression in cervical cancer samples was significantly higher than that in paraneoplastic tissues. Highly expressed MELK correlated with the cervical histopathological grading and greatly increased with the cervical histopathological grading, from normal cervix and cervical intraepithelial neoplasia to cervical cancer. Moreover, the abnormal expression of MELK was related to cervical cancer metastasis at early stage. The knockdown of MELK with siRNA and OTSSP167 had strong inhibition effects on the proliferation, apoptosis, and colony formation of cervical cancer cells. MELK knockdown could also aggravate the DNA damage of cervical cancer cells possibly by homologous recombination repair pathway. Therefore, MELK may be a predicting marker of poor prognosis of cervical cancer and may also be a new therapeutic target for cervical cancer, providing ideas for improving the therapeutic effect of cervical cancer.

Long non-coding RNA ZEB1-AS1 promotes cell invasion and epithelial to mesenchymal transition through inducing ZEB1 expression in cervical cancer

BackgroundLong non-coding RNAs (lncRNAs) play important roles in cancer initiation and development. The purpose of the present study was to determine the functions and mechanisms of lncRNA ZEB1-AS1 in human cervical cancer (CC).MethodsA total of 106 pairs of CC tissues and adjacent normal epithelial tissues were collected from CC patients who underwent resection. Three human CC cell lines (HeLa, C33A and SiHa) and a normal cervical cell line Crl-2614 and were transfected with human ZEB1-AS1 cDNA, or empty vector as the control. Then, cells were transfected with ZEB1-AS1-specific small interfering RNA (si-ZEB1-AS1), ZEB1-specific siRNA (si-ZEB1) or negative siRNA control (si-NC). The transfection efficiency was confirmed by RT-qPCR analysis. qPCR was applied to determine the qualification of RNA. Cell proliferation was investigated by MTT assay. The apoptosis rate of cells was detected by flow cytometer. Cell invasion was detected by transwell assay. Western blot was applied to determine the expression of proteins. CC xenografts in 12 male BALB/c athymic nude mice were established. And the tumor volumes were measured by vernier caliper.ResultsWe found that ZEB1-AS1 expression was remarkably increased in human CC tissue samples and cell lines, and its expression levels were closely associated with poor prognosis of CC patients. Moreover, we found that knockdown of ZEB1-AS1 inhibited the proliferation, migration, invasion and epithelial–mesenchymal transition (EMT) of CC cells in vitro and suppressed CC xenograft tumor growth in vivo. Mechanistically, we found that knockdown of ZEB1-AS1 significantly inhibited ZEB1 expression, and knockdown of ZEB1 could rescue the effects of ZEB1-AS1 overexpression in CC cells.ConclusionIn conclusion, our findings indicated that ZEB1-AS1 serves an oncogenic role in CC, which might become a potential prognostic indicator and therapeutic target in CC.

SMAGP a novel biomarker of cervical cancer development and progression.

IntroductionCervical cancer, one of the most common malignant gynecological tumors, is a significant burden on the health of females worldwide. The purpose of this study was to investigate genes associated with lymph node metastasis in cervical cancer.MethodsWe report on the lymph node metastasis-associated gene, small cell adhesion glycoprotein (SMAGP), as a key regulator of cervical cancer development and progression. SMAGP expression levels were investigated in 70 cervical squamous cell carcinoma samples and 10 normal cervical squamous epithelium samples.ResultsImmunohistochemistry analysis revealed that SMAGP protein levels were significantly elevated in cervical cancer tissue compared with normal cervical squamous epithelium. Silencing of SMAGP induced cell cycle arrest, inhibited the cell proliferation and colony formation ability of cervical cancer cells in vitro and suppressed their tumorigenic potential in nude mice. In addition, SMAGP knockdown reduced expression of epithelial mesenchymal transition-related proteins, including vimentin, β-cadherin, MMP2, and Twist.ConclusionTogether, our findings demonstrate that SMAGP plays a critical role in cell proliferation and tumorigenesis and could be a new therapeutic target in cervical cancer.

105P - Glycolytic enzymes lactate dehydrogenase A (LDHA) and phosphofructokinase P (PFKP) are good biomarkers of survival and potential therapeutic targets in cervical cancer

105P - Glycolytic enzymes lactate dehydrogenase A (LDHA) and phosphofructokinase P (PFKP) are good biomarkers of survival and potential therapeutic targets in cervical cancer

MicroRNA-214 suppresses the growth of cervical cancer cells by targeting EZH2.

A number of studies have revealed the significance of microRNAs (miRs) in tumorigenesis. Cervical cancer (CC) is one of the most malignant cancer types and is associated with a poor overall survival rate. A previous study demonstrated a critical role of miR-214 in the development of multiple cancer types, but its role in CC remains elusive. In the current study, miR-214 was observed to be downregulated in CC tissues compared with the adjacent non-cancerous tissue. Overexpression of miR-214 reduced the proliferation of CC cells, whereas inhibiting its expression resulted in enhanced proliferation. Furthermore, Enhancer of zeste homolog 2 (EZH2) was demonstrated to be a direct target of miR-214 in CC. An MTT assay demonstrated that upregulating miR-214 expression or knocking down the expression of EZH2 impaired the proliferation of a CC cell line. Low expression of miR-214 was positively associated with tumor differentiation (P=0.037) and tumor stage (P=0.012). Notably, low expression of miR-214 predicted poor prognosis of patients with CC. Consequently, the results of the current study demonstrated that miR-214 functions as a tumor suppressor in CC and may be regarded as a potential therapeutic target in CC.

The KISS1 gene overexpression as a potential molecular marker for cervical cancer cells.

Similarities between the pathologic progression of cancer and the physiologic process of placentation have been recognized for many years proposing that both present similar mechanisms and processes. Cervical cancer (CC) is one of the most frequent neoplasia among Mexican women turning it into an important health problem. The aim of this study was to determine the degree of the involvement of pregnancy related genes and in cancer progression by in-silico analysis and validated in CC samples. The data mining analysis resulted in the identification of genes expressed in term placenta, first trimester placenta and normal cervical tissues. Finally, we selected KISS1 for the involvement of pregnancy related gene and also in cancer process. In order to explore KISS1 in CC, we analyzed Copy Number Variation (CNV) and gene expression using microarray experiments. KISS1 showed 20% genomic gain in 1q32.1 on CC samples. Furthermore, microarray analysis showed KISS1 as up-regulated genes. Results were validated showing an overexpression of 85% of KISS1 in CC samples. Data suggest KISS1 as a great candidate for CC molecular markers or as a therapeutic target for CC. Also, HPV presence does not seem to alter the KISS1 expression in CC.

Clinicopathologic Significance of SATB1 and DJ-1 Proteins Expression in Cervical Carcinoma

Background: Special AT-rich sequence binding protein 1 (SATB1) and DJ-1 proteins play a crucial role in tumorigenesis and tumor progression in many human malignancies. Limited data is available in literature about their role in cervical carcinomas. Aims: The present study was designed to investigate the immunohistochemical expression of SATB1 and DJ-1 proteins in cervical carci­noma and their relationships to clinicopathologic variables. Material and Methods: Tissue sections from 100 cervical lesions distributed as 60 cases of cervical carcinoma, 30 cases of squamous intraepithelial lesion (SIL) and 10 cases with normal cervical tissue were evaluated for SATB1 and DJ-1 proteins expression by immunohistochemistry. Results: SATB1 expression was detected in 41.7% of cervical carcinomas versus 20% and 6.7% of HSIL and LSIL, respectively (p = 0.019). A significant positive correlation between SATB1 expression to lymph node metastasis (p = 0.004) and pTNM (p = 0.028) was noted. DJ-1 expression was detected in 68.3% versus 33.3% and 13.3% of HSIL and LSIL, respectively (p = 0.001). A significant positive association between DJ-1 expression and lymph node metastasis (p = 0.037) was noted. Normal cervical tissue was negative for SATB1 and DJ-1 expression. A significant positive association between SATB1 and DJ-1 immunoreactivity was detected in investigated cervical carcinomas (p = 0.027). Conclusions: SATB1 and DJ-1 are shown to be promising potential prognostic biomarkers in cervical carcinoma since their overexpression is correlated with advanced clinicopathologic variables including lymph node metastasis. SATB1 and DJ-1 can be promising therapeutic targets for cervical cancer.

Expression levels of the long noncoding RNA steroid receptor activator promote cell proliferation and invasion and predict patient prognosis in human cervical cancer.

Long noncoding RNAs (lncRNAs) are involved in developmental processes and diseases and function as critical regulators of a number of different cancer types. Previous research has revealed that lncRNAs affect cervical cancer development. Steroid receptor activator (SRA), an lncRNA, serves as a critical regulator of gynecologic cancer. However, the association between SRA expression and cervical cancer remains unclear. In the present study, the SRA expression levels in patients with cervical cancer were examined and the association between SRA expression and clinicopathological factors was determined. SRA expression was observed in cervical cancer tissues (n=100) and corresponding normal tissues (n=22) using reverse transcription-quantitative polymerase chain reaction, and its associations with clinical parameters and prognosis were analyzed. SRA expression was significantly greater in tissues from patients with cervical cancer compared with in control patients (P<0.001). Multivariate analysis revealed that high SRA expression was an independent prognostic factor of overall survival (hazard ratio=3.714, P=0.031). The present study additionally investigated the biofunctional consequences of SRA overexpression in vitro using Cell Counting kit-8, wound healing migration and Matrigel invasion assays. The results demonstrated that SRA overexpression enhanced cell proliferation, migration and invasion in vitro. Furthermore, SRA overexpression induced the epithelial-mesenchymal transition (EMT). Therefore, SRA may promote tumor aggressiveness through the upregulation of EMT-associated genes. These results indicated that SRA may represent a novel biomarker for predicting recurrence and prognosis and serve as a promising therapeutic target in cervical cancer.

Gfi-1 promotes proliferation of human cervical carcinoma via targeting of FBW7 ubiquitin ligase expression.

BackgroundThe independent growth factor 1 (Gfi-1) is a transcription factor essential for several diverse hematopoietic functions and developments. However, the role and molecular mechanism of Gfi-1 in the development and progression of cervical cancer remains unclear.PurposeThe present study investigates the relation of expression of Gfi-1 with prognoses in patients with cervical cancer.MethodsWe used Western blot and reverse transcription polymerase chain reaction (RT-PCR) and the inhibition of proliferation and metastasis of cervical cancer cells in vitro.ResultsThis study confirms that the expression of Gfi-1 in cervical cancer tissues was higher than that in adjacent normal tissues. The level of Gfi-1 mRNA in human cervical cancer tissues was significantly higher than that in normal tissues adjacent to cancer. Furthermore, overexpression of Gfi-1 promoted cell proliferation, colony formation, and migration of cervical cancer cells. The increased expression of Gfi-1 promotes the proliferation of cervical cancer cells targeting the tumor suppressor F-box and WD repeat domain containing 7 (FBW7). Clinically, our data suggest that overexpression of Gfi-1 is associated with poor prognosis in patients with cervical cancer. In a tumor xenograft model, knockdown of Gfi-1 inhibited the tumor growth of Hela cells in vivo.ConclusionOur results reveal that Gfi-1 plays an important role in cervical cancer and Gfi-1/FBW7 axis serves as a potential therapeutic target for cervical cancer.

Potential biomarkers and therapeutic targets in cervical cancer: Insights from the meta-analysis of transcriptomics data within network biomedicine perspective.

The malignant neoplasm of the cervix, cervical cancer, has effects on the reproductive tract. Although infection with oncogenic human papillomavirus is essential for cervical cancer development, it alone is insufficient to explain the development of cervical cancer. Therefore, other risk factors such as host genetic factors should be identified, and their importance in cervical cancer induction should be determined. Although gene expression profiling studies in the last decade have made significant molecular findings about cervical cancer, adequate screening and effective treatment strategies have yet to be achieved. In the current study, meta-analysis was performed on cervical cancer-associated transcriptome data and reporter biomolecules were identified at RNA (mRNA, miRNA), protein (receptor, transcription factor, etc.), and metabolite levels by the integration of gene expression profiles with genome-scale biomolecular networks. This approach revealed already-known biomarkers, tumor suppressors and oncogenes in cervical cancer as well as various receptors (e.g. ephrin receptors EPHA4, EPHA5, and EPHB2; endothelin receptors EDNRA and EDNRB; nuclear receptors NCOA3, NR2C1, and NR2C2), miRNAs (e.g., miR-192-5p, miR-193b-3p, and miR-215-5p), transcription factors (particularly E2F4, ETS1, and CUTL1), other proteins (e.g., KAT2B, PARP1, CDK1, GSK3B, WNK1, and CRYAB), and metabolites (particularly, arachidonic acids) as novel biomarker candidates and potential therapeutic targets. The differential expression profiles of all reporter biomolecules were cross-validated in independent RNA-Seq and miRNA-Seq datasets, and the prognostic power of several reporter biomolecules, including KAT2B, PCNA, CD86, miR-192-5p and miR-215-5p was also demonstrated. In this study, we reported valuable data for further experimental and clinical efforts, because the proposed biomolecules have significant potential as systems biomarkers for screening or therapeutic purposes in cervical carcinoma.

The association of semaphorin 5A with lymph node metastasis and adverse prognosis in cervical cancer

BackgroundSemaphorin 5A has been linked to tumor growth, invasion, and metastasis in pancreatic cancer. However, the role of semaphorin 5A in cervical cancer is not known. Our aim is to investigate the prognostic value of semaphorin 5A and its potential role in lymphangiogenesis and invasion in cervical cancer.MethodsIn this study, pathological features and clinical data of 232 cervical cancer patients were retrospectively reviewed. Semaphorin 5A protein and mRNA expression was detected by immunohistochemistry and quantitative real-time reverse transcription-polymerase chain reaction, respectively. In vitro, we determined the role and mechanistic pathways of semaphorin 5A in tumor progression in cervical carcinoma cell lines.ResultsSemaphorin 5A expression was significantly higher in stage IIb tumors than in stage Ia, Ib, and IIa tumors. High semaphorin 5A expression was significantly associated with pelvic lymph node metastasis, lymphovascular permeation, and poor survival. Semaphorin 5A induced lymphangiogenesis through a plexin-B/Met/vascular endothelial growth factor-C pathway. Semaphorin 5A also increased cervical cancer cell invasion by stimulating the expression and activity of matrix metalloproteinase-2 and matrix metalloproteinase-9 via PI3K/AKT and plexin-B3.ConclusionOur findings indicate that semaphorin 5A may represent a poor prognostic biomarker and anti-metastasis therapeutic target in cervical cancer.

MicroRNA‑485 targets MACC1 and inhibits cervical cancer cell proliferation and invasion.

A large body of evidence has indicated that microRNAs (miRNAs/miRs) have essential roles in the development and progression of cervical cancer. Thus, miRNAs with dysregulated expression are potential biomarkers for cervical cancer diagnosis and prognosis. In the present study, expression levels of miR‑485 were detected in cervical cancer tissues and cell lines. The effects of miR‑485 overexpression on the proliferation and invasion of cervical cancer cells were determined with Cell Counting kit‑8 and Transwell invasion assays. The mechanisms underlying the action of miR‑485 in cervical cancer were investigated using bioinformatics analysis, a luciferase reporter assay, reverse transcription‑quantitative polymerase chain reaction and western blot analysis. In addition, the association between miR‑485 and metastasis associated in colon cancer‑1 (MACC1) in cervical cancer tissues was examined. The present study demonstrated that miR‑485 expression was significantly downregulated in cervical cancer tissues and cell lines. Reduced miR‑485 expression in patients with cervical cancer was correlated with International Federation of Gynecology and Obstetrics stage and lymph node metastasis. Furthermore, restored expression of miR‑485 significantly reduced cervical cancer cell proliferation and invasion. MACC1 was identified as a direct target gene of miR‑485 in cervical cancer. MACC1 expression was significantly upregulated in cervical cancer specimens and was inversely correlated with miR‑485 expression. Additionally, the restored expression of MACC1 eliminated the suppressive effects of miR‑485 overexpression on the proliferation and invasion of cervical cancer cells. Notably, the upregulation of miR‑485 suppressed the MET proto‑oncogene, receptor tyrosine kinase (Met)/RAC‑α serine/threonine‑protein kinase (AKT) signaling pathway. These results demonstrated that miR‑485 may perform its tumor suppressive function in cervical cancer by directly targeting MACC1 and inhibiting the Met/AKT signaling pathway. Therefore, the miR‑485/MACC1 axis may be a novel and effective therapeutic target in cervical cancer.

Comprehensive Genomic Variation Profiling of Cervical Intraepithelial Neoplasia and Cervical Cancer Identifies Potential Targets for Cervical Cancer Early Warning

To better understand the pathogenesis of cervical cancer (CC), we systematically analyzed the genomic variation and human papillomavirus (HPV) integration profiles of cervical intraepithelial neoplasia (CIN) and CC. We performed whole-genome sequencing (WGS) or whole-exome sequencing (WES) of 102 tumor-normal pairs and human papillomavirus (HPV) probe capture sequencing (HPCS) of 45 CCs, 44 cervical intraepithelial neoplasia (CIN) samples, and 25 normal cervical samples, and constructed strict integrated workflow of genomic analysis. Mutational analysis identified eight significantly mutated genes in CC including four genes (FAT1, MLL3, MLL2, and FADD), which have not previously been reported in CC. Targetable alterations were identified in 55.9% of patients. In addition, HPV integration breakpoints occurred in 97.8% of the CC samples, 70.5% of the CIN samples and 42.8% of the normal cervical samples with HPV infection. Integrations of high-risk HPV strains in CCs, including HPV16, 18, 33 and 58, also occurred in the CIN samples. Moreover, gene mutations were detected in 52% of the CIN specimens, and 54.8% of these mutations occurred in genes that also mutated in CCs. Our results lay the foundation for a deep understanding of the molecular mechanisms and finding new diagnostic and therapeutic targets of CC. Funding Statement: This work was supported by grants from the National High Technology Research and Development Program of China (2012AA02A205), the Chinese National Key Program on Basic Research (2014CB965002), the National Natural Science Foundation of China (81272306 and 81472639), and the Shanghai Commission for Science and Technology (15431902900 and 15JC1403000). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: Chinese CC patients were recruited under the approval of the Research Ethics Committee of Southwestern Hospital (No. 2014-016) and this project and protocols were conducted according to the Declaration of Helsinki. Informed consents were provided.

Long noncoding RNA UFC1 is activated by E2F1 and exerts oncogenic properties by functioning as a ceRNA of FOXP3.

Cervical cancer is one of the most common gynecologic cancers around the world. Long noncoding RNAs (lncRNAs) are considered to be important regulators of some biological processes. Recently, it has been reported that linc‐UFC1 is a putative oncogene in some cancers. However, the functional roles of linc‐UFC1 have not been investigated in cervical cancer. Here, it was demonstrated that linc‐UFC1 expression was significantly increased in cervical cancer tissues, and its overexpression was associated with the poor survival of patients with cervical cancer. Loss‐of‐function assays indicated that linc‐UFC1 exerted as an oncogene because it promoted the growth and metastasis of cervical cancer cells in vitro and in vivo. Mechanistic investigations revealed that linc‐UFC1 upregulated FOXP3 expression through competitively binding miR‐34a. Finally, luciferase reporter and chromatin immunoprecipitation (ChIP) assays provided evidence that E2F1 could directly bind to the linc‐UFC1 promoter region and enhance its transcription. Taken together, our findings indicate that the linc‐UFC1 expression signature may serve as a novel biomarker for the diagnosis and prognosis of cervical cancer, and it is also highlighted that the E2F1‐linc‐UFC1/miR‐34a/FOXP3 axis may be a potentially therapeutic target of cervical cancer.

Abstract B28: Development of estrogen-dependent and estrogen receptor-negative cervical cancer in HPV transgenic mice

Abstract Estradiol (E2) and human papillomavirus (HPV) cooperate to cause cervical cancer. The role of estrogen receptor α (ERα) in cervical cancer has been underappreciated. Chronic treatment with E2 promotes the development of cervical cancer in K14E7 transgenic mice expressing HPV16 E7 oncoprotein. In the present study, we bred K14E7 to mice with conditional ablation of Esr1 (ERα-coding gene) in the cervical epithelial cells (Wnt7aCre/Esr1f/f; Esr1ed/ed). We found that E2 promoted the development of ERα cervical cancer in K14E7/Esr1ed/ed mice. In addition, proliferation and apoptotic indices of ERα cancer in K14E7/Esr1ed/ed mice were similar to those of ERα+ cancer in K14E7/Esr1f/f mice. We also found that E2 increased the epithelium thickness and epithelial cell proliferation in the cervix of Esr1ed/ed mice. Our published results have demonstrated that deletion of Esr1 in the cervical stroma promotes the regression of cervical precancer lesions in K14E7 mice. In patients, ERα is expressed in the cancer stroma but not cancer epithelial cells. These observations support that stromal ERα, rather than epithelial ERα, mainly mediates oncogenic E2 signaling for cervical cancer. They also suggest that stromal ERα might be an effective therapeutic target for cervical cancer. Note: This abstract was not presented at the conference. Citation Format: Jieun Son, Sang-Hyuk Chung. Development of estrogen-dependent and estrogen receptor-negative cervical cancer in HPV transgenic mice [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B28.

Aberrant expression of miR-153 is associated with the poor prognosis of cervical cancer.

Previous studies have demonstrated that microRNAs (miRNAs) are frequently dysregulated in tumors and are associated with the initiation and progression of various types of cancer. miR-153 has been previously shown to have an anti-tumor effect in the majority of cancer types. However, to date, the expression status and function of miR-153 in cervical cancer (CC) remains unclear. In the present study, the expression of miR-153 in CC tissues and cell lines was examined, revealing that the expression of miR-153 was markedly downregulated in the CC tissues and cell lines investigated, when compared with matched noncancerous tissues and normal cervical epithelial cell line. Furthermore, ectopic expression of miR-153 by miR-153 mimic inhibited cell proliferation; however, transfection with the miR-153 inhibitor promoted the cell proliferation in CC cell lines. Finally, the results showed that the downregulation of miR-153 was associated with poor 5-year over survival in CC patients and it could be regarded as an independent biomarker to predict the prognosis of CC patients. Collectively, these results indicated that miR-153 may function as a tumor suppressor in CC, and it may be a potential novel therapeutic target for CC.