Cervical Cancer Invasion Research Articles

MiR-195-5p inhibits the cell migration and invasion of cervical carcinoma through suppressing ARL2.

MicroRNAs (miRNAs) have great effects on the progression of cervical cancer (CC). This study aimed to investigate the role of miR-195-5p in CC and to explain the regulatory mechanism between ARL2 and miR-195-5p. Quantitative Real-Time-Polymerase Chain Reaction (qRT-PCR) was used to detect miR-195-5p levels in CC tissues and cell lines. Transwell assays for cell migration and invasion were also performed. A luciferase reporter assay was used to detect the direct target of miR-195-5p. The protein levels of ARL2 were measured by Western blot analysis. In CC tissues and cell lines, miR-195-5p expression was decreased. Downregulation of miR-195-5p was associated with higher FIGO stage, deep stromal invasion, and lymph node metastasis. Moreover, over-expression of miR-195-5p inhibited cell migration and invasion in CC. Furthermore, it was observed that miR-195-5p directly targeted ARL2, which affected the suppressive effect of miR-195-5p in CC. MiR-195-5p inhibited cell migration and invasion in CC by suppressing ARL2 expression. The miR-195/ARL2 axis may provide a pathway for cell metastasis in CC.

The novel circCLK3/miR-320a/FoxM1 axis promotes cervical cancer progression

As a new class of non-coding RNA, circular RNAs (circRNAs) play crucial roles in the development and progression of various cancers. However, the detailed functions of circRNAs in cervical cancer have seldom been reported. In this study, circRNA sequence was applied to detect the differentially expressed circRNAs between cervical cancer tissues and adjacent normal tissues. The relationships between circCLK3 level with clinicopathological characteristics and prognosis were analyzed. In vitro CCK-8, cell count, cell colony, cell wound healing, transwell migration and invasion, and in vivo tumorigenesis and lung metastasis models were performed to evaluate the functions of circCLK3. The pull-down, RNA immunoprecipitation (RIP), luciferase reporter and rescue assays were employed to clarify the interaction between circCLK3 and miR-320a and the regulation of miR-320a on FoxM1. We found that the level of circCLK3 was remarkably higher in cervical cancer tissues than in adjacent normal tissues, and closely associated with tumor differentiation, FIGO stage and depth of stromal invasion. Down-regulated circCLK3 evidently inhibited cell growth and metastasis of cervical cancer in vitro and in vivo, while up-regulated circCLK3 significantly promoted cell growth and metastasis in vitro and in vivo. The pull-down, luciferase reporter and RIP assays demonstrated that circCLK3 directly bound to and sponge miR-320a. MiR-320a suppressed the expression of FoxM1 through directly binding to 3′UTR of FoxM1 mRNA. In addition, FoxM1 promoted cell proliferation, migration, and invasion of cervical cancer, while miR-320a suppressed cell proliferation, migration, and invasion through suppressing FoxM1, and circCLK3 enhanced cell proliferation, migration and invasion through sponging miR-320a and promoting FoxM1 expression. In summary, circCLK3 may serve as a novel diagnostic biomarker for disease progression and a promising molecular target for early diagnoses and treatments of cervical cancer.

HAND2-AS1 inhibits invasion and metastasis of cervical cancer cells via microRNA-330-5p-mediated LDOC1

BackgroundCervical cancer is a serious disease with complicated pathogenesis and thus there is an urgent need to find novel targets for the treatment. Recently, long non-coding RNAs (lncRNAs) have emerged as critical factors in tumorigenesis. In this study, we aimed to investigate the mechanism of HAND2 antisense RNA 1 (HAND2-AS1) on the invasion and metastasis of cervical cancer cells.MethodsThe expression patterns of HAND2-AS1, microRNA-330-5p (miR-330-5p) and leucine zipper down-regulated in cancer 1 (LDOC1) in cervical cancer were characterized by RT-qPCR and western blot analysis. Dual luciferase reporter assay and RIP were applied to verify relationship between HAND2-AS1, miR-330-5p and LDOC1. Fluorescence in situ hybridization (FISH) was used to detect the subcellular localization of HAND2-AS1. Besides, viability, invasion and migration ability of HeLa cells were investigated by cell counting kit-8 (CCK-8) and Transwell assays respectively. Hematoxylin–eosin staining was performed for lymph node metastasis detection. In addition, the tumor growth in nude mice was evaluated.ResultsLow expression of HAND2-AS1 and LDOC1, and high expression of miR-330-5p were detected in cervical cancer tissues and cells. It was found that binding of HAND2-AS1 to miR-330-5p results in upregulation of LDOC1 expression. Also, overexpressed HAND2-AS1 and LDOC1 or down-regulated miR-330-5p inhibited expression of proliferation-associated proteins Ki-67, PCNA, migration-associated proteins N-cad and invasion-related proteins MMP-2, MMP-9 as well as lymph node metastasis. Moreover, HAND2-AS1 inhibited tumor formation and lymph node metastasis by binding to miR-330-5p in vivo.ConclusionHAND2-AS1 promotes LDOC1 expression by competitively binding to miR-330-5p and consequently inhibiting cervical cancer cell invasion and metastasis. This could facilitate development of therapeutic strategies against cervical cancer.

RACK1 promotes the invasive activities and lymph node metastasis of cervical cancer via galectin-1.

Cervical cancer remains the first leading cause of cancer-related mortality among female reproductive system malignancies worldwide, and invasion and lymph node metastasis of cervical cancer represent the major reason for its poor prognosis. In this study, we found that RACK1 facilitated tumor cell invasion and lymphatic tube formation in vitro, as well as promoted lymphangiogenesis and lymph node metastasis in vivo in a galectin-1-dependent manner. Mechanism studies revealed that RACK1 promoted the expression and secretion of galectin-1 by reducing miR-1275 levels. Additionally, RACK1 also augmented galectin-1-induced downstream MEK/ERK, FAK, and AKT signaling via integrin-β1 in cervical cancer cells. Tissue microarray confirmed that RACK1 was upregulated in squamous intraepithelial lesion and cancer, and RACK1 was positively correlated with invasion/metastasis phenotype, galectin-1 expression, and unfavorable prognosis in cervical cancer cases. Human papillomavirus E6 oncogene contributes to increased expression of RACK1 via the enhancement of its O-GlcNAcylation and protein stability. Together, our results demonstrate that RACK1 stimulates tumor invasion and lymph node metastasis of cervical cancer via galectin-1 and imply that targeting RACK1/galectin-1 axis provides promising means for cervical cancer treatment.

Estimation of the Extent of Cervical Cancer Using Multiparametric Magnetic Resonance Imaging

Objective. To increase the efficiency of diagnosis and estimation of the local extent of a tumor process in cervical cancer (CC) using all modalities of multiparametric magnetic resonance imaging (mpMRI).Subjects and methods. Examinations were made in 31 patients (mean age 45±11 years) with histologically verified minimally invasive CC, who underwent surgical treatment. The investigators used the following modalities: T2 weighted imaging (T2WI); T2WI with fat signal suppression; diffusion-weighted image (DWI) with apparent diffusion coefficient (ADC) mapping; T1WI with dynamic contrast-enhanced MRI (DCE-MRI).Results. The measured distances significantly differed from the true ones obtained from the morphological findings (p<0.05). With allowance made for the built linear regression models, the investigators generated correction formulas. The best modality of MRI in establishing the presence of parametrial invasion in CC and in measuring the actual depth of invasion was T1WI with DCE-MRI (using the images obtained 100–125 seconds after MRI contrast medium administration); the slightly worse modality was DWI with ADC mapping (with a specificity of 91%, the sensitivities of DCE-MRI and DWI with ADC mapping were 95% and 90%, respectively), and T2WI with and without fat signal suppression.Conclusion. Quantitative analysis of the extent of CC in the parametrium according to the results of complex mpMRI seems to be a possible and highly accurate method.

LncRNA SNHG7 contributes to cell proliferation, invasion and prognosis of cervical cancer.

Long non-coding RNAs (lncRNAs) have been identified as oncogenes or tumor suppressor genes in the development of various cancers. However, the function of lncRNA SNHG7 in cervical cancer remains unclear. Therefore, the aim of this study was to investigate the potential role of lncRNA SNHG7 in cervical cancer and to explore the possible underlying mechanism. Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was used to detect the expression of lncRNA SNHG7 in 60 cervical cancer tissues and adjacent normal tissues. Cell Counting Kit-8 (CCK-8) and transwell assays were used to study the effects of lncRNA SNHG7 on the proliferation and invasion of cervical cancer cells, respectively. Furthermore, Western blot was used to detect the expression levels of proteins in the epithelial-mesenchymal transition (EMT) process. LncRNA SNHG7 expression increased significantly in cervical cancer tissues. The inhibition of lncRNA SNHG7 expression markedly inhibited cervical cell proliferation and invasion. Meanwhile, the inhibition of lncRNA SNHG7 resulted in the increased protein expression level of E-cadherin, and decreased protein expressions of N-cadherin and Vimentin. In addition, the survival time of patients with high expression of lncRNA SNHG7 was remarkably shortened. LncRNA SNHG7 contributes to cell proliferation and invasion of cervical cancer. Moreover, SNHG7 has emerged as an independent and significant factor associated with poor survival of cervical cancer patients.

Knockdown of METTL14 inhibits the growth and invasion of cervical cancer

Background: Increasing evidence has revealed that N6-methyladenosine (m6A) modification is implicated in multiple biological functions in mammals. Methyltransferase-like 14 (METTL14), an important component of m6A modification, has been reported to play important roles in the pathogenesis of acute myeloid leukaemia and hepatocellular carcinoma metastasis. However, its role in cervical cancer remains unclear. Methods: Expression of METTL14 was knocked down by shRNA-METTL14 interference in HPV-positive and HPV-negative cervical cancer cell lines SiHa and C33a. CCK8, colony formation, wound-healing, and Transwell assays were performed to evaluate the effects of METTL14 knockdown on the proliferation, migration and invasion abilities of SiHa and C33a cells. Flow cytometry analysis was utilized to detect cell cycle distribution, and the expression of related proteins was examined by western blot analysis. Results: Bioinformatics analysis demonstrated that up-regulation of METTL14 acted as an adverse prognostic factor for overall survival in cervical cancer patients. We demonstrated that down-regulation of METTL14 inhibited the proliferation, migration and invasion abilities of SiHa and C33a cells. Moreover, silencing METTL14 induced cell cycle arrest in cervical cancer cells. METTL14 knockdown suppressed the PI3K/Akt/mTOR signaling pathway by decreasing the phosphorylation of Akt and mTOR, and the expression of downstream apoptosis-related proteins was also impacted. Conclusions: In conclusion, these data suggest an important oncogenic role of METTL14 in the growth and invasion of both HPV-positive and HPV-negative cervical cancer cells.

MiR-214 down-regulates MKK3 and suppresses malignant phenotypes of cervical cancer cells

miRNA mediated genetic regulation is widely involved in carcinogenesis of cervical cancer. In this study, miR-214 was confirmed to directly regulate MKK3 via imperfect base-pairing to its 3′UTR, resulting down-regulation of its expression level. Compared to normal tissues, a down-regulated level of miR-214 was observed in cervical cancer, while MKK3 was up-regulated. Next, we demonstrated that over-expression of miR-214 or knockdown of MKK3 can inhibit the growth, proliferation, invasion and migration of cervical cancer in vitro and in vivo. Moreover, the effects of miR-214 in HeLa cells were rescued by the restoration of MKK3. In conclusion, our results laid new foundations for investigating the pathogenesis and diagnosis of cervical cancer.

Long noncoding RNA ZNF667-AS1 reduces tumor invasion and metastasis in cervical cancer by counteracting microRNA-93-3p-dependent PEG3 downregulation.

Zinc finger protein 667‐antisense RNA 1 (ZNF667‐AS1), located on human chromosome 19q13.43, is a member of the C2H2 zinc finger protein family. Herein, we aimed to analyze the interactions between ZNF667‐AS1, microRNA‐93‐3p (miR‐93‐3p), and paternally expressed gene 3 (PEG3) and to explore their roles in the tumorigenesis of cervical cancer (CC). Differentially expressed long noncoding RNAs and miRNAs related to CC were determined using gene expression datasets sourced from the Gene Expression Omnibus database. Subsequently, the regulatory relationships between ZNF667‐AS1 and miR‐93‐3p and between miR‐93‐3p and PEG3 were identified using the dual‐luciferase reporter gene assay. In addition, the expression of miR‐93‐3p and ZNF667‐AS1 was up‐ or downregulated in CC cells (HeLa), in order to assess their effects on cell cycle distribution and cell invasion in vitro, and tumor growth and metastasis in vivo. MiR‐93‐3p was found to be highly expressed, while ZNF667‐AS1 and PEG3 were poorly expressed in CC. ZNF667‐AS1 could competitively bind to miR‐93‐3p, which targeted PEG3. In addition, miR‐93‐3p downregulation and ZNF667‐AS1 overexpression led to increased expression of PEG3, tissue inhibitor of metalloproteinases, and p16 and decreased expression of cyclin D1, matrix metalloproteinase‐2 and ‐9. MiR‐93‐3p inhibition and ZNF667‐AS1 elevation also inhibited cell cycle entry and cell invasion in vitro, but repressed tumor growth and metastasis in vivo. These key findings demonstrated that upregulation of ZNF667‐AS1 could suppress the progression of CC via the modulation of miR‐93‐3p‐dependent PEG3, suggesting a potential therapeutic target for the treatment of CC.

MicroRNA-449a Is Downregulated in Cervical Cancer and Inhibits Proliferation, Migration, and Invasion

Introduction: Cervical cancer is one of the most common malignant tumors among women in the world. MicroRNA-449a (miR-449a) has been identified as a tumor suppressor gene in various cancers. Our present study aimed to explore the biological role of miR-449a in cervical cancer. Methods: The expression of miR-449a in cervical cancer tissues and cell lines was detected using real-time quantitative PCR. Kaplan-Meier survival analysis and a Cox regression assay were used to identify the prognostic significance of miR-449a in cervical cancer. A CCK-8 assay and a Transwell assay were performed to determine the impact of miR-449a on the proliferation, migration, and invasion of cervical cancer cells. Results: The expression of miR-449a was decreased in both cervical cancer tissues and cell lines. The decreased expression of miR-449a was significantly associated with lymph node metastasis, differentiation, and FIGO stage, as well as with poor survival. In vitro, transfection of miR-449a mimic into cervical cancer cells inhibited cell proliferation, migration, and invasion. Conclusion: All of the results revealed that miR-449a functions as a suppressor gene and inhibits cell proliferation, migration, and invasion in cervical cancer. In addition, it may serve as a prognostic biomarker for cervical cancer.

Knockdown of METTL14 inhibits the growth and invasion of cervical cancer.

BackgroundIncreasing evidence has revealed that N6-methyladenosine (m6A) modification is implicated in multiple biological functions in mammals. Methyltransferase-like 14 (METTL14), an important component of m6A modification, has been reported to play important roles in the pathogenesis of acute myeloid leukaemia and hepatocellular carcinoma metastasis. However, its role in cervical cancer remains unclear.MethodsExpression of METTL14 was knocked down by shRNA-METTL14 interference in HPV-positive and HPV-negative cervical cancer cell lines SiHa and C33a. CCK8, colony formation, wound-healing, and Transwell assays were performed to evaluate the effects of METTL14 knockdown on the proliferation, migration and invasion abilities of SiHa and C33a cells. Flow cytometry analysis was utilized to detect cell cycle distribution, and the expression of related proteins was examined by western blot analysis.ResultsBioinformatics analysis demonstrated that up-regulation of METTL14 acted as an adverse prognostic factor for overall survival in cervical cancer patients. We demonstrated that down-regulation of METTL14 inhibited the proliferation, migration and invasion abilities of SiHa and C33a cells. Moreover, silencing METTL14 induced cell cycle arrest in cervical cancer cells. METTL14 knockdown suppressed the PI3K/Akt/mTOR signaling pathway by decreasing the phosphorylation of Akt and mTOR, and the expression of downstream apoptosis-related proteins was also impacted.ConclusionsIn conclusion, these data suggest an important oncogenic role of METTL14 in the growth and invasion of both HPV-positive and HPV-negative cervical cancer cells.

The Roles of Hedgehog Signaling Pathway in Radioresistance of Cervical Cancer.

Radiotherapy is an important treatment of cervical cancer, especially for advanced cervical cancer. According to research reports, Hedgehog signaling pathway plays an essential role in the growth, invasion, metastasis, recurrence, drug resistance, and radioresistance of cervical cancer. The components of Hedgehog signaling pathway could be biomarkers, related to progression and prognosis of cervical cancer. In addition, targeted therapy for Hedgehog signaling pathway is expected to become a new strategy for the treatment of radioresistant cervical cancer. This review summarizes the research status and progress of the relationship between radiation resistance and activation of Hedgehog signaling pathway in cervical cancer.

Inhibition of human cervical cancer cell invasion by IL-37 involving runt related transcription factor 2 suppression.

IL-37 is a newly anti-inflammatory cytokine whose function is largely unknown in cancer. Our preliminary experiment found IL-37 could inhibit the invasion of human cervical cancer (CC) cells and influence the expression of RUNX family whose function was also unclear in CC. The present study aims to further investigate the effects of IL-37 on cell invasion and runt related transcription factor 2 (RUNX2) expression in CC cell lines. Firstly, plasmid overexpressing IL-37 or RUNX2 was transfected into Siha and C33A cells by Hilymax. Then, the effects of IL-37 on the mRNA expression of RUNX1, RUNX2 and RUNX3 gene were detected by quantitative real-time polymerase chain reaction. Protein expression was measured by Western blot and the grayscale scanning analysis. Finally, the effects of IL-37 or RUNX2 on cell invasion were tested by transwell assay. IL-37 inhibited the mRNA expression of RUNX1 and RUNX2, and increased that of RUNX3 in CC cells. Among the three RUNX genes, RUNX2 showed the most significant change in mRNA expression (decreased by78.5% in Siha cells and by 61.5% in C33A cells) and thus was chosen for the following study. Overexpressed IL-37 inhibited cell invasion by 36.23% in Siha cells (P<0.05) and 26.21% in C33A cells (P<0.01). Overexpression of RUNX2 promoted cell invasion. Up-regulation of IL-37 suppressed markedly the mRNA and protein expression of RUNX2. Furthermore, overexpressed RUNX2 partially restored the inhibited cell invasion by IL-37 to 86.62% in Siha cells (P<0.01) and 87.08% in C33A cells (P<0.01). IL-37 can significantly inhibit the cell invasion of Siha and C33A cells, which involves the suppression of RUNX2.

INPP1 up-regulation by miR-27a contributes to the growth, migration and invasion of human cervical cancer.

Inositol polyphosphate‐1‐phosphatase (INPP1) is an enzyme that is responsible for glycolysis and lipid metabolism. Here, we discovered that INPP1 expression was up‐regulated in CC tissues compared to that in adjacent normal tissues by RT‐qPCR. Inositol polyphosphate‐1‐phosphatase overexpression promoted and INPP1 knockdown suppressed cell viability, cellular migration/invasion and EMT in CC cells. To explore the mechanism of dysregulation, INPP1 was predicted to be a target of miR‐27a, and a pmiRGLO dual‐luciferase reporter assay showed that miR‐27a bound to the 3′ UTR of INPP1. RT‐qPCR revealed that miR‐27a was also up‐regulated and had a positive correlation with INPP1 expression in CC tissues. Furthermore, shR‐INPP1 could favour the malignant phenotype reversion induced by miR‐27a, suggesting that miR‐27a up‐regulates INPP1 to promote tumorigenic activities. Altogether, our findings show that the up‐regulation of INPP1 by miR‐27a contributes to tumorigenic activities and may provide a potential biomarker for CC.

Phenyllactic acid promotes cell migration and invasion in cervical cancer via IKK/NF-\u03baB-mediated MMP-9 activation

BackgroundPersistent infection with high-risk human papillomavirus (hrHPV) is associated with cervical cancer development. This process involves the virus-encoded E6 and E7 oncoproteins, which are maintained and expressed during all malignant transformation stages. However, HPV alone is insufficient to drive tumor progression-related behaviors such as cervical cancer cell motility. In this study, we investigated the effect of phenyllactic acid (PLA), a phenolic acid phytochemical and biomarker for discriminating various cancers, on the metastatic potential of cervical cancer cells.MethodsThe effects of PLA on HPV16/18 E6/E7 expression, migratory and invasive behavior, and matrix metalloproteinases (MMPs) expression of cervical cancers cells were measured. Specific inhibitors were used to further investigate biological function and underlying mechanism of PLA modulated cell motility.ResultsPLA significantly promoted the migration and invasion of SiHa, HeLa, and C-33A cervical cancer cells as well as upregulated matrix metalloproteinase-9 (MMP-9) expression. Moreover, PLA treatment attenuated E6/E7 expression in SiHa and HeLa cells. Further molecular analysis showed that PLA activated the nuclear factor-kappa B (NF-κB) signaling pathway and increased the nuclear translocation of both IκBα and p65. Treating cervical cancer cells with an NF-κB inhibitor potently reversed PLA-induced migratory and invasive behavior, MMP-9 upregulation, and/or E6/E7 downregulation. The PLA-induced NF-κB activation and MMP-9 upregulation were mediated by IκB kinase-β (IKK-β) phosphorylation via PKC signals. The results suggested that SiHa, HeLa, and C-33A cells might undergo a similar process to enhance their motility in response to PLA, regardless of the HPV status.ConclusionsCollectively, our study reveals a new biological function of PLA and elucidate the possible molecular role of PLA as a risk factor for triggering cervical cancer cell motility.

LncRNA RHPN1-AS1 promoted cell proliferation, invasion and migration in cervical cancer via the modulation of miR-299–3p/FGF2 axis

AimsThis study aims to determine the biological function and underlying mechanisms of lncRNA RHPN1 antisense RNA1 (RHPN1-AS1) in cervical cancer cell proliferation, invasion and migration. Main methodsGene expression was analysed by quantitative real-time PCR; protein levels were determined by western blot assay; in vitro functional assays determined the cervical cancer cell progression; in vivo tumor growth of cervical cancer cell was determined in nude mice xenograft models. Key findingsThe results showed that RHPN1-AS1 was up-regulated in cervical cancer tissues and cell lines. In vitro functional assays demonstrated that RHPN1-AS1 overexpression promoted SiHa cell proliferation, invasion and migration; while RHPN1-AS1 knockdown showed the opposite effects. In vivo study showed that RHPN1-AS1 knockdown suppressed tumor growth in the nude mice. Further investigation showed that miR-299–3p was targeted and inversely regulated by RHPN1-AS1. In addition, miR-299–3p targeted the 3’ untranslated region of fibroblast growth factor 2 (FGF2) to suppress its expression. The rescue experiments showed that the enhanced effects of RHPN1-AS1 overexpression on cell proliferation, growth, invasion and migration in SiHa cells were significantly attenuated by miR-299–3p overexpression or FGF2 inhibition. On the other hand, knockdown of miR-299–3p and overexpression of FGF2 both significantly increased cell proliferation, growth, invasion and migration in SiHa cells transfected with RHPN1-AS1 siRNA. SignificanceIn conclusion, our results revealed that RHPN1-AS1 promoted cervical cancer progression via targeting miR-299–3p/FGF2 axis. Our data suggested that RHPN1-AS1/miR-299–3p/FGF2 axis may be a promising target for cervical cancer treatment.

Dysregulation of miR-375/AEG-1 Axis by Human Papillomavirus 16/18-E6/E7 Promotes Cellular Proliferation, Migration, and Invasion in Cervical Cancer.

Cervical Cancer (CC) is a highly aggressive tumor and is one of the leading causes of cancer-related deaths in women. miR-375 was shown to be significantly down-regulated in cervical cancer cells. However, the precise biological functions of miR-375 and the molecular mechanisms underlying its action in CC are largely unknown. miR-375 targets were predicted by bioinformatics target prediction tools and validated using luciferase reporter assay. Herein, we investigated the functional significance of miR-375 and its target gene in CC to identify potential new therapeutic targets. We found that miR-375 expression was significantly downregulated in CC, and astrocyte elevated gene-1 (AEG-1) was identified as a target of miR-375. Our results also showed that ectopic expression of miR-375 suppressed CC cell proliferation, migration, invasion and angiogenesis, and increased the 5-fluorouracil-induced apoptosis and cell cycle arrest in vitro. In contrast, inhibition of miR-375 expression significantly enhanced these functions. Furthermore, HPV - 16 E6/E7 and HPV - 18 E6/E7 significantly down-regulates miR-375 expression in CC. HPV 16/18-E6/E7/miR-375/AEG-1 axis plays an important role in the regulation of cell proliferation, migration, and invasion in CC. Therefore, targeting miR-375/AEG-1 mediated axis could serve as a potential therapeutic target for CC.

Downregulation of hsa_circ_0007534 restricts the proliferation and invasion of cervical cancer through regulating miR-498/BMI-1 signaling

AimsHsa_circ_0007534 has been reported to be a novel cancer-related circRNA affecting multiple cancers. However, little is known about the role of hsa_circ_0007534 in cervical cancer specifically. In the current study, we aimed to explore the expression and function of hsa_circ_0007534 in cervical cancer. Main methodsThe expression of circRNA, miRNA and mRNA was measured using real-time quantitative polymerase chain reactions. Protein expression was assessed by Western blot. Knockdown of has_circ_0007534 was achieved by siRNA-mediated gene silencing. Cell proliferation was determined using a cell counting kit-8 and colony formation assays. Cell invasion was assessed using a Transwell invasion assay. RNA interactions were measured using an RNA pull-down and dual-luciferase reporter assays. Key findingsThe expression of hsa_circ_0007534 was upregulated in cervical cancer tissues and cell lines. Depletion of hsa_circ_0007534 decreased both the proliferation and invasion of cervical cancer cells. MicroRNA-498 (miR-498) was identified as a target of the miRNA encoded by hsa_circ_0007534. Levels of miR-498 were decreased in cervical cancer tissues, a finding that was inversely correlated with hsa_circ_0007534 expression. miR-498 overexpression repressed the proliferation and invasion of cervical cancer cells. B-cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) was verified as a target gene of miR-498. BMI-1 overexpression reversed the effects of hsa_circ_0007534 depletion or miR-498 overexpression on cervical cancer cell proliferation and invasion. SignificanceOur study demonstrates that downregulation of hsa_circ_0007534 represses the proliferation and invasion of cervical cancer through regulating the miR-498/BMI-1 axis, suggesting the hsa_circ_0007534/miR-498/BMI-1 axis as a potential therapeutic target to treat cervical cancer.

REX1 promotes EMT-induced cell metastasis by activating the JAK2/STAT3-signaling pathway by targeting SOCS1 in cervical cancer

ZFP42 zinc finger protein (REX1), a pluripotency marker in mouse pluripotent stem cells, has been identified as a tumor suppressor in several human cancers. However, the function of REX1 in cervical cancer remains unknown. Both IHC and western blot assays demonstrated that the expression of REX1 protein in cervical cancer tissue was much higher than that in normal cervical tissue. A xenograft assay showed that REX1 overexpression in SiHa and HeLa cells facilitated distant metastasis but did not significantly affect tumor formation in vivo. In addition, in vitro cell migration and invasion capabilities were also promoted by REX1. Mechanistically, REX1 overexpression induced epithelial-to-mesenchymal transition (EMT) by upregulating VIMENTIN and downregulating E-CADHERIN. Furthermore, the JAK2/STAT3-signaling pathway was activated in REX1-overexpressing cells, which also exhibited increased levels of p-STAT3 and p-JAK2, as well as downregulated expression of SOCS1, which is an inhibitor of the JAK2/STAT3-signaling pathway, at both the transcriptional and translational levels. A dual-luciferase reporter assay and qChIP assays confirmed that REX1 trans-suppressed the expression of SOCS1 by binding to two specific regions of the SOCS1 promoter. Therefore, all our data suggest that REX1 overexpression could play a crucial role in the metastasis and invasion of cervical cancer by upregulating the activity of the JAK2/STAT3 pathway by trans-suppressing SOCS1 expression.

Hybrid PET/MRI in major cancers: a scoping review.

PET/MRI was introduced for clinical use in 2011 and is now an established modality for the imaging of brain and certain pelvic cancers, whereas clinical use for the imaging of other forms of cancer is not yet widespread. We therefore systematically investigated what has been published on the use of PET/MRI compared to PET/CT in the imaging of cancers outside the brain, focusing on clinical areas of application related to diagnosis, staging and restaging. A systematic search of PubMed/MEDLINE, Embase and the Cochrane Library was performed. Studies evaluating the diagnostic performance of simultaneous PET/MRI in cancer patients were chosen. A total of 3,138 publications were identified and 116 published during the period 2012-2018 were included and were grouped according to the major cancer forms: 13 head and neck (HNC), 9 breast (BC), 21 prostate (PC), 14 gynaecological, 13 gastrointestinal (GIC), and 46 various cancers. Data from studies comparing PET/MRI and PET/CT for staging/restaging suggested the superiority of 18F-FDG PET/MRI for the detection of tumour extension and retropharyngeal lymph node metastases in nasopharyngeal cancer, and for the detection of liver metastases and possibly bone marrow metastases in high-risk BC. FDG PET/MRI tended to be inferior for the detection of lung metastases in HNC and BC. 68Ga-PSMA-11 PET/MRI was superior to PET/CT for the detection of local PC recurrence. FDG PET/MRI was superior to FDG PET/CT for the detection of local tumour invasion in cervical cancer and had higher accuracy for the detection of liver metastases in colorectal cancer. The scoping review methodology resulted in the identification of a huge number of records, of which less than 5% were suitable for inclusion and only a limited number allowed conclusions on the advantages/disadvantages of PET/MRI compared to PET/CT in the oncological setting. There was evidence to support the use of FDG PET/MRI in staging of nasopharyngeal cancer and high-risk BC. Preliminary data indicate the superiority of PET/MRI for the detection of local recurrence in PC, local tumour invasion in cervical cancer, and liver metastases in colorectal cancer. These conclusions are based on small datasets and need to be further explored.