Angiogenesis In Cervical Cancer Research Articles

Study on Signal Transduction Pathway of Migration Inhibitory Factor in Angiogenesis of Cervical Cancer

Cervical cancer is a common female malignancy worldwide that accounts for the second in women malignant tumor. Macrophage migration inhibitory factor (MIF) is an important tumor promoter that plays an important role in tumor invasion and metastasis. This study explored MIF and PD98059’s effect on cervical cancer Siha cells to analyze MIF impact on VEGF expression, so as to discuss whether MIF may influence cervical cancer angiogenesis through ERK/MAPK signaling pathway. MIF and PD98059 were adopted to treat Siha cells. Western blot were done to measure MIF, ERK1, and VEGF expression. MTT was applied to determine cell proliferation. ERK1 and VEGF were positively expressed in cells. Cell proliferation was elevated gradually at 24, 48, and 72 h in MIF group and declined in PD98059 group (P < 0.05). ERK1 and VEGF protein significantly elevated after treated by MIF for 48 hours and reduced after intervened by PD98059 for 48 h (P <0.05). ERK1 and VEGF obviously downregulated in both MIF and PD98059 treatment groups without difference between two groups (P <0.05). MIF, ERK1, and VEGF is expressed in cervical cancer SiHa cells. MIF promotes cell proliferation through regulating ERK/MAPK signaling pathway to upregulate ERK1 and VEGF expression.

Bone Marrow Mesenchymal Stem Cell (BMSC) Exosomes Inhibit Angiogenesis and Enhance Autophagy Through Decreasing miR-21 in Cervical Cancer

We aimed to explore the mechanism underlying the role of miR-21 derived from bone marrow mesenchymal stem cell exosomes (BMSC-exos) in cervical cancer (CC) and the relation between angiogenesis and autophagy. In this study, BMSC-exos were co-cultured with CC stem cells followed by analysis of miR-21 expression by RT-qPCR, autophagy after hunger-induced feeding by Acridine Orange fluorescent staining, angiogenesis by tube formation assay. Co-culture of BMSC-exos effectively reduced miR-21 expression in CC stem cells and enhanced autophagy as demonstrated by upregulated Beclin1 and LC3B with assembly of autophagosome (p < 0.05), but the autophagy restored later. Moreover, in the presence of BMSC-exos, CC stem cell angiogenesis was suppressed by 79%. In conclusion, BMSC-exos enhance autophagy and inhibit angiogenesis in CC through decreasing miR-21, which provides a novel insight into etiology of CC.

Evaluation of angiogenesis in cervical cancer using CD34 as a biomarker and its correlation with pathoanatomical features

Lung cancer is the most common cause of cancer-related death worldwide and unfortunately up to 80% of patients amongst newly diagnosed are inoperable therefore the cytological sample is often the only material available for diagnosis and assessment of molecular characteristics driving the treatment.

MiR-628–5p Inhibits Cervical Carcinoma Proliferation and Promotes Apoptosis by Targeting VEGF

BackgroundIt has been reported that the dysregulation of microRNAs (miRNAs) is implicated in the biological processes of diverse diseases, including the tumorigenesis of human cancers. MicroRNA-628–5p (miR-628–5p) is differentially expressed and plays a critical role in several cancers, but the role of miR-628–5p in cervical cancer has not been well studied. MethodsThe TCGA database and RT-qPCR were used to evaluate the expression profile of miR-628–5p in cervical cancer tissues. Transfection efficiency of synthetic miRNAs was detected using RT-qPCR. The biological effects of miR-628–5p on cervical cancer cells were assessed by the CCK-8 assay, flow cytometry, western blot analysis, and the tube formation assay. The expression levels of key proteins involved in cell apoptosis, the cell cycle and the PI3K pathway were analyzed by western blot analysis. Bioinformatic analysis and the luciferase reporter assay were performed to investigate the targeted relationship between miR-628–5p and vascular endothelial growth factor (VEGF). ResultsMiR-628–5p was downregulated and negatively correlated with Ki-67 expression in cervical cancer tissues, and its low level predicted poor survival of patients. Functional assays indicated that miR-628–5p inhibited cell proliferation and promoted cell apoptosis. Mechanically, VEGF was verified to be a downstream target of miR-628–5p. Moreover, overexpression of VEGF could reverse the effects of miR-628–5p on VEGF/PI3K/AKT signaling, cell proliferation, apoptosis, the cell cycle and angiogenesis in cervical cancer. ConclusionsMiR-628–5p inhibited cervical cancer cell proliferation and promoted apoptosis by targeting VEGF.

Extracellular vesicular Wnt7b mediates HPV E6-induced cervical cancer angiogenesis by activating the \u03b2-catenin signaling pathway

BackgroundThe E6 oncoproteins of human papillomavirus (HPV) 16/18 are the critical drivers of cervical cancer (CC) progression. Extracellular vesicles (EVs) are emerging as critical mediators of cancer-tumor microenvironment (TME) communication. However, whether EVs contribute to HPV 16/18 E6-mediated impacts on CC progression remains unclear.MethodsA series of in vitro and in vivo assays were performed to elucidate the roles and mechanism of EV-Wnt7b in HPV E6-induced CC angiogenesis. The prognostic value of serum EV-Wnt7b was determined and a predictive nomogram model was established.ResultsHPV 16/18 E6 upregulated Wnt7b mRNA expression in four HPV 16/18-positive CC cell lines and their EVs. In vitro and in vivo experiments demonstrated that EV-Wnt7b mRNA was transferred to and modulated human umbilical vein endothelial cells (HUVECs) toward more proliferative and proangiogenic behaviors by impacting β-catenin signaling. Clinically, serum EV-Wnt7b levels were elevated in CC patients and significantly correlated with an aggressive phenotype. Serum EV-Wnt7b was determined to be an independent prognostic factor for CC overall survival (OS) and recurrence-free survival (RFS). Notably, we successfully established a novel predictive nomogram model using serum EV-Wnt7b, which showed good prediction of 1- and 3-year OS and RFS.ConclusionsOur results illustrate a potential crosstalk between HPV 16/18-positive CC cells and HUVECs via EVs in the TME and highlight the potential of circulating EV-Wnt7b as a novel predictive biomarker for CC prognosis.

Extracellular vesicles-encapsulated microRNA-10a-5p shed from cancer-associated fibroblast facilitates cervical squamous cell carcinoma cell angiogenesis and tumorigenicity via Hedgehog signaling pathway.

Cancer-associated fibroblast (CAF) secretes extracellular vesicle (EV)-encapsulated microRNAs (miRNAs) which have been underlined great promise for therapeutic target for diseases and cancers. Our study aimed to explore the role of EV-encapsulated miR-10a-5p from CAFs in angiogenesis in cervical cancer. Expression of miR-10a-5p in clinical samples of cervical cancer and cancer cells was detected by in situ hybridization and RT-qPCR. Results demonstrated that miR-10a-5p expression was upregulated in both cancer tissues and cells. CAFs and normal fibroblasts (NFs) from cervical cancer patient tissues were characterized under transmission electron microscopy, followed by EV isolation from CAFs. The EVs labeled with PKH67 were cultured with cervical squamous cell carcinoma (CSCC) cell line (SiHa) and HUVECs. Data indicated that CAF-EVs were internalized by cancer cells and promoted cell proliferation and tube formation. CAF-EVs then were transfected with miR-10a-5p inhibitor and then injected into nude mice. While injection of CAF-EVs promoted tumor growth and increased VEGFR and CD31 expression level, miR-10a-5p inhibitor-treated CAF-EVs resulted in decreased tumor volume and amount of vessel around tumor. Of note, dual-luciferase reporter gene assay and bioinformatic analysis indicated TBX5 as a target gene of miR-10a-5p. Moreover, EV-derived miR-10a-5p promoted angiogenesis in vivo and in vitro through activation of Hedgehog signaling via downregulation of TBX5. Taken altogether, miR-10a-5p in CAF-EVs promoted CSCC cell angiogenesis and tumorigenicity via activation of Hh signaling by inhibition of TBX5, providing insight into novel treatment based on miR-10a-5p against CSCC.

Interfering Human Papillomavirus E6/E7 Oncogenes in Cervical Cancer Cells Inhibits the Angiogenesis of Vascular Endothelial Cells via Increasing miR-377 in Cervical Cancer Cell-Derived Microvesicles.

BackgroundThe dysregulation of the human papillomavirus 18 E6 and E7 oncogenes plays a critical role in the angiogenesis of cervical cancer (CC), including the proliferation, migration, and tube formation of vascular endothelial cells. Interfering E6/E7 increases the number of CC cell-derived microvesicles (CC-MVs). Additionally, microRNAs (miRNAs) can modulate CC angiogenesis and can be encapsulated in MVs.ObjectiveWe aim to investigate whether E6/E7 affects CC angiogenesis via regulating miRNAs in CC-MVs.MethodsCC-MVs were isolated from a CC cell line (HeLa) which were transfected with small interfering RNAs (siRNAs) against E6/E7 or co-transfected with miR-377 mimics/inhibitors. The expression of several miRNAs in CC-MVs was detected using quantitative real-time PCR. After co-incubating CC-MVs with human umbilical vein endothelial cells (HUVECs), cell proliferation, migration, and tube formation of HUVECs were determined using cell counting kit-8, transwell, and tube formation assays, respectively.ResultsMiR-377 was increased in E6/E7-interfering CC-MVs. Overexpressing miR-377 in CC-MVs suppressed HUVEC proliferation, migration, and tube formation. LPAR2, the cell surface G protein-coupled receptor, was the downstream target of miR-377 in HUVECs. The co-transfection of E6/E7 siRNAs and miR-377 inhibitors in CCs negated the effect of E6/E7 siRNAs on the elevation of miR-377 in CC-MVs. In HUVECs, the co-transfection of E6/E7 siRNAs and miR-377 inhibitors restored the LPAR2 expression which was reduced by the E6/E7 siRNA transfection. Meanwhile, miR-377 mimic reduced LPAR2 expression and inhibited HUVEC proliferation, migration, and tube formation, while such response was negated by LPAR2 overexpression.ConclusionInterfering E6/E7 increased miR-377 in CC-MVs, and overexpressing miR-377 in CC-MVs inhibited angiogenesis of HUVECs via reducing LPAR2.

Cervical Cancer Cells-Secreted Exosomal microRNA-221-3p Promotes Invasion, Migration and Angiogenesis of Microvascular Endothelial Cells in Cervical Cancer by Down-Regulating MAPK10 Expression.

PurposeCervical cancer (CC) is recognized as a common cancer with a high risk worldwide. Exosomal microRNAs (miRNAs) have received attention for their increasing potentials in CC therapy. In this study, we identify the involvement of miR-221-3p in CC progression by affecting angiogenesis of microvascular endothelial cells (MVECs).MethodsMicroarray-based gene expression profiling was conducted to retrieve the differentially expressed genes in CC. The expression patterns of miR-221-3p were measured by RT-qPCR, while Western blot analysis and RT-qPCR were performed to determine the expression of MAPK10 in the CC tissues and cells, followed by verification of the interaction between miR-221-3p and MAPK10 using dual luciferase reporter gene assay. Then the effects of miR-221-3p and MAPK10 on cell activities were assessed through gain- and loss-of-function experiments in CC. Subsequently, the impact of exosomal miR-221-3p on MVEC proliferation, migration, invasion and angiogenesis was examined after exosomal isolation from CC cells and co-cultured with MVECs.ResultsGene expression profile showed that MAPK10 might participate in CC with a low expression. Moreover, miR-221-3p was highly expressed and MAPK10 was poorly expressed in CC tissues and cells. It was observed that miR-221-3p targeted MAPK10. Depletion of miR-221-3p blocked the cell proliferation, invasion and migration in CC by up-regulating MAPK10. Moreover, CC cells-derived exosomes carrying miR-221-3p accelerated MVEC proliferation, invasion, migration and angiogenesis in CC by regulating MAPK10.ConclusionCC cells-derived exosomes harboring miR-221-3p enhanced MVEC angiogenesis in CC by decreasing MAPK10.

Downregulation of microRNA-205 inhibits cell invasion and angiogenesis of cervical cancer through TSLC1-mediated Akt signaling pathway.

Cervical cancer (CC) is a common gynecological cancer and a leading cause of cancer-related deaths in women globally. Therefore, this study explores the action of microRNA-205 (miR-205) in the invasion, migration, and angiogenesis of CC through binding to tumor suppressor lung cancer 1 (TSLC1). Initially, the microarray analysis was used to select the candidate gene and the regulatory microRNA. Then, the target relationship between miR-205 and TSLC1 as well as the expression of miR-205, TSLC1, and p-Akt/total Akt in CC cells were determined. Afterwards, CC cell invasion and migration were detected after the treatment of miR-205 mimics/inhibitors and short hairpin RNA against TSLC1. After coculture of cancer cells and vascular endothelial cells, cell proliferation, tube formation, and microvessel density (MVD) were detected to determine the roles of miR-205 in angiogenesis. Finally, tumor growth in nude mice was measured in vivo. TSLC1 was determined as the candidate gene, which was found to be targeted and negatively regulated by miR-205. Then, downregulated miR-205 or forced TSLC1 expression inhibited invasion, migration, and angiogenesis in CC, corresponding to suppressed cell proliferation, tube formation, and expression of IL-8, VEGF, and bFGF, as well as the inhibited activation of the Akt signaling pathway. Furthermore, downregulation of miR-205 was found to exert an inhibitory role in tumor formation and MVD by elevating TSLC1 in CC in vivo. This study demonstrated that downregulated miR-205 inhibited cell invasion, migration, and angiogenesis in CC by inactivating the Akt signaling pathway via TSLC1 upregulation.

Long non-coding RNA cancer susceptibility candidate 2 inhibits the cell proliferation, invasion and angiogenesis of cervical cancer through the MAPK pathway.

Increasing evidence has indicated that long non-coding RNA cancer susceptibility candidate 2 (CASC2) is aberrantly expressed and acts as a key regulator in various types of cancer. However, few reports have mentioned the precise function of CASC2 in cervical cancer. In the present study, CASC2 levels in cervical cancer tissues and cell lines were measured by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). The proliferation, migration, and invasion of cervical cancer cells were detected by cell counting kit-8 (CCK-8) and transwell assays. Angiogenesis was evaluated by tube formation assays of human umbilical vein endothelial cells (HUVECs). The protein levels of the components of the mitogen-activated protein kinase (MAPK) pathway, including the c-Jun N-terminal kinase (JNK) and the extracellular-signal-regulated kinase-1 (ERK1), in cell lines of cervical cancer were detected by Western blot. CASC2 levels in human cervical cancer tissues and cell lines were significantly downregulated compared to para-cancerous tissues and the immortalized human keratinocyte line HaCaT. Compared to scramble group, CASC2 overexpression significantly inhibited the proliferation, migration, invasion, and angiogenesis of cervical cancer cells. However, the inhibition of CASC2 had the opposite effect. Moreover, the expression of p-JNK and p-ERK1 levels in the MAPK pathway was significantly decreased in pcDNA3.1-CASC2 group. Overexpression of CASC2 may inhibit the development of cervical cancer through the inactivation of the MAPK pathway and may be a potential therapeutic target for the treatment of patients with cervical cancer.

A DHX9-lncRNA-MDM2 interaction regulates cell invasion and angiogenesis of cervical cancer

Cervical cancer (CC) is the third most common carcinoma and the fourth leading cause of cancer-associated mortality in women. Here, we report that MDM2-DHX9 interaction mediates CC motility and angiogenesis in a long noncoding RNA-dependent fashion. A long noncoding RNA, named lnc-CCDST, is significantly downregulated in CC tissues, and binds to pro-oncogenic DHX9. DHX9 is upregulated in CC tissue, and promotes CC cell motility and angiogenesis. The lnc-CCDST and DHX9 interaction promotes DHX9 degradation through the ubiquitin proteasome pathway. Furthermore, DHX9 bound to E3 ubiquitin ligase MDM2, and this interaction is enhanced by lnc-CCDST. Thus, lnc-CCDST promotes DHX9 degradation by serving as a scaffold to facilitate the formation of MDM2 and DHX9 complexes. Moreover, HPV oncogenes E6 and E7 abolish the expression of lnc-CCDST resulting in the increase of DHX9. Our results have revealed a novel mechanism by which high-risk HPVs promote motility and angiogenesis of CC by inhibiting expression of lnc-CCDST to disrupt MDM2 and DHX9 interaction, and DHX9 degradation, and identified a potential therapeutic target for CC.

Effects and possible mechanism of a picosecond pulsed electric field on angiogenesis in cervical cancer in vitro.

Picosecond pulsed electric field (psPEF) is an athermal, minimally invasive and local ablative biomedical engineering technique used in cancer therapy. However, to the best of our knowledge, the effect of psPEF on angiogenesis in cervical cancer is unknown. Therefore, the aim of the current study was to investigate the effects and possible mechanism of psPEF on angiogenesis in cervical cancer in vitro. HeLa cell and human umbilical vein endothelial cell (HUVEC) suspensions were exposed to psPEF with an increasing gradient of electric field intensity (0, 200, 400 and 600 kV/cm). A Cell Counting kit-8 assay and flow cytometry were used to investigate the effect of psPEF on the proliferation and apoptosis of HUVECs. The invasion, migration and tube formation capabilities of HUVECs following psPEF treatment were investigated by Transwell invasion assay, scratch test and lumen formation assay, respectively. Changes in the protein and mRNA levels of angiogenesis-associated factors in HeLa cells were detected by western blot analysis and reverse transcription-quantitative polymerase chain reaction. psPEF was identified to inhibit proliferation and tube formation, and induce apoptosis and necrosis of HUVECs in a dose-dependent manner. psPEF was revealed to decrease the protein and mRNA expression levels of vascular endothelial growth factor and hypoxia-inducible factor 1α in HeLa cells. In summary, psPEF exhibited anti-angiogenic effects in cervical cancer in vitro by exerting direct effects on HUVECs and indirect effects on angiogenesis-associated factors in HeLa cells.

AKIP1 promotes angiogenesis and tumor growth by upregulating CXC-chemokines in cervical cancer cells.

Upregulation of A-kinase-interacting protein 1 (AKIP1) has been observed in breast and esophageal cancers, indicating that AKIP1 may be a potent oncogenic protein. However, the role of AKIP1 in cervical cancer still remains unknown. This study aimed to explore the role of AKIP1 in cervical cancer and to investigate the underlying mechanism of AKIP1 in tumor growth. Expression of AKIP1 in cervical cancer cells was determined by qRT-PCR and western blotting. Cell-Light EdU and colony formation assays were used to determine cell proliferation. CXCL1 and CXCL8 proteins were quantified by ELISA kits. Western blotting and qRT-PCR were used to examine the alterations in signaling-related proteins and mRNA, respectively. Endothelial cell tube formation assay was performed to evaluate the effect of AKIP1 on angiogenesis. A BALB/c nude mouse xenograft model was used to evaluate the role of AKIP1 in vivo. Cancer cell proliferation was inhibited and tumor growth and angiogenesis restrained in BALB/c nude mice by suppressing AKIP1 expression in cervical cancer cell lines. In addition, overexpression of AKIP1 in cervical cancer cells elevated the levels of CXCL1, CXCL2, and CXCL8. These three chemokines were not only involved in endothelial tube formation by binding to the endothelial receptor CXCR2, but also in cervical cancer cell proliferation and clone formation, which were induced by overexpression of AKIP1. Furthermore, we found that AKIP1-induced chemokine expression was decreased by an inhibitor of nuclear factor kappa-B kinase subunit β. These results show that AKIP1 is crucial in cervical cancer angiogenesis and growth by elevating the levels of the NF-κB-dependent chemokines CXCL1, CXCL2, and CXCL8.

Chitinase 3 like 1 (CHI3L1) promotes vasculogenic mimicry formation in cervical cancer

Vasculogenic mimicry (VM) is an alternative microvascular system which tumour cells orchestrate, independent of endothelial cell-mediated angiogenesis. VM develops tumour vascular networks that correlate with tumour growth, metastasis, and short survival time of patients with a number of cancers. However, little is known regarding VM in the vascularisation of cervical cancer. Chitinase 3 like 1 (CHI3L1) has been previously reported to display the ability to induce angiogenesis in cervical cancer. Here, we explored a pathological role of CHI3L1 in tumour cell-mediated vascularisation. Sixty-six samples of cervical cancer were collected to examine CHI3L1 expression and VM formation using immunohistochemistry and CD34-periodic acid-Schiff (PAS) dual staining. CHI3L1 expression was significantly correlated with formation of tumour cell-associated vascular channels in the absence of endothelial cells (p=0.031). Interestingly, tumour samples lacking VM were positively correlated with non-metastasis (p=0.035). Patients with VM positive tumours tended to have decreased overall survival (OS) compared to those with VM negative samples (43.9 versus 64.6 months, p=0.079). In addition, recombinant CHI3L1 enhanced cervical cancer cell lines to form tube-like structures, supporting the notion that CHI3L1 mediates VM in cervical cancer. Our present data reveal the crucial role of CHI3L1 in the formation of VM, which may contribute to tumour aggressiveness. Therefore, targeting CHI3L1 may be a valuable strategy for the reduction of cervical cancer vascularisation and metastasis.

Methyltransferase G9a promotes cervical cancer angiogenesis and decreases patient survival.

Research suggests that the epigenetic regulator G9a, a H3K9 histone methyltransferase, is involved in cancer invasion and metastasis. Here we show that G9a is linked to cancer angiogenesis and poor patient survival. Invasive cervical cancer has a higher G9a expression than cancer precursors or normal epithelium. Pharmacological inhibition and genetic silencing of G9a suppresses H3K9 methylation, cancer cell proliferation, angiogenesis, and cancer cell invasion/migration, but not apoptosis. Microarray and quantitative reverse transcription polymerase chain reaction analyses reveal that G9a induces a cohort of angiogenic factors that include angiogenin, interleukin-8, and C-X-C motif chemokine ligand 16. Depressing G9a by either pharmacological inhibitor or gene knock down significantly reduces angiogenic factor expression. Moreover, promoting G9a gene expression augments transcription and angiogenic function. A luciferase reporter assay suggests that knockdown of G9a inhibits transcriptional activation of interleukin-8. G9a depletion suppresses xenograft tumor growth in mouse model, which is linked to a decrease in microvessel density and proliferating cell nuclear antigen expression. Clinically, higher G9a expression correlates with poorer survival for cancer patients. For patients’ primary tumors a positive correlation between G9a expression and microvessel density also exists. In addition to increasing tumor cell proliferation, G9a promotes tumor angiogenesis and reduces the patient survival rate. G9a may possess great value for targeted therapies.

Chemotherapy-mediated miR-29b expression inhibits the invasion and angiogenesis of cervical cancer.

Radiotherapy combined with platinum-based chemotherapy is the standard-of-care of locally advanced cervical cancer (CC) patients, while nearly 50% of patients do not respond to standard chemotherapy. Thus, identification of relative molecules participated in chemotherapy might provide new insights in the treatment of CC. In this study, we found a cohort of miRNAs were dysregulated upon treatment with cisplatin, among of which miR-29b was the most upregulated one. We further detected its expression in CC tissues, and found that miR-29b was significantly suppressed in CC and its precancerous lesions, HSIL tissues, and was negatively related with tumor invasion. However, upon treatment with cisplatin, the expression of miR-29b was significantly up-regulated. The biological function assays showed that overexpression of miR-29b suppressed the invasion, EMT procedure and angiogenesis of cervical cancer cells in vitro and inhibited tumor growth and neovascularization in vivo through targeting STAT3 signal pathway. While, inhibition of miR-29b could prevent the cisplatin-induced epithelial features, cell movement and angiogenesis of CC cells, which means miR-29b/STAT3 axis participates in the chemotherapy of cisplatin in CC. Collectively, our data suggest that chemotherapy-mediated miR-29b expression participates in the initiation and progression of cervical cancer through suppressing the proliferation, EMT procedure and angiogenesis of cervical cancer cells by targeting STAT3 signal pathway.

Valproic acid inhibits the angiogenic potential of cervical cancer cells via HIF-1α/VEGF signals.

Cervical cancer is one of the most prevalent malignancies in women worldwide. Therefore, the investigation about the molecular pathogenesis and related therapy targets of cervical cancer is an emergency. The objective of the present study is to investigate the effects of valproic acid (VPA), a histone deacetylase inhibitor, on the angiogenesis of cervical cancer. The effects and mechanisms of VPA on in vitro angiogenesis and vascular endothelial growth factor (VEGF) expression of human cervical cancer HeLa and SiHa cells were investigated. Our present study reveals that 1mM VPA can significantly inhibit the in vitro angiogenic potential and VEGF expression of human cervical cancer HeLa and SiHa cells. Further, the transcription and protein levels of hypoxia inducible factor-1α (HIF-1α), and not HIF-1β, are significantly inhibited in VPA-treated cervical cancer cells. Over expression of HIF-1α can obviously reverse VPA-induced VEGF down regulation. VPA-treatment decreases the activation of Akt and ERK1/2 in both HeLa and SiHa cells in a time-dependent manner. The inhibitor of Akt (LY 294002) or ERK1/2 (PD98059) can inhibit VEGF alone and cooperatively reinforce the suppression effects of VPA on HIF-1α and VEGF expression. Collectively, our data reveal that the inhibition of PI3K/Akt and ERK1/2 signals are involved in VPA-induced HIF-1α and VEGF suppression of cervical cancer cells.

The effects of a picosecond pulsed electric field on angiogenesis in the cervical cancer xenograft models

ObjectiveThe application of picosecond pulsed electric field (psPEF) is a new biomedical engineering technique used in cancer therapy. However, its effects on cervical cancer angiogenesis are not clear. Therefore, the aim of the present study is to investigate the effects of psPEF on angiogenesis in cervical cancer xenograft models. MethodsXenograft tumors were created by subcutaneously inoculating nude mice (athymic BALB/c nu/nu mice) with HeLa cells, then were placed closely between tweezer-type plate electrodes and subjected to psPEF with a gradually increased electric field intensity (0kV/cm, 50kV/cm, 60kV/cm, 70kV/cm). The direct effect on tumor tissue was observed by hematoxylin and eosin (H&E) staining and transmission electron microscopy (TEM). The changes of blood vessels and oxygen saturation (sO2) of tumors were monitored in vivo by photoacoustic tomography (PAT). The microvessel density (MVD), vascular endothelial growth factor (VEGF) and hypoxia-inducible transcription factors (HIF-1α and HIF-2α) were detected by immunohistochemical technique (IHC). Their protein expressions and gene transcription levels were evaluated using western blot (WB) and quantitative reverse transcription and polymerase chain reaction (RT-PCR). ResultsPsPEF induced obvious necrosis of cervical cancer tissue; with the increasing of electric field intensity, the MVD, vascular PA signal and sO2 values declined significantly. The protein expression and gene transcription levels of VEGF, HIF1α and HIF2α were significantly decreased at the same time. ConclusionPsPEF exhibited dramatic anti-tumor and anti-angiogenesis effects in cervical cancer xenograft models by exerting direct effect on cancer cells and vascular endothelial cells and indirect effect on tumor angiogenesis-related factors.

Effects of tetrahydrocurcumin on hypoxia-inducible factor-1α and vascular endothelial growth factor expression in cervical cancer cell-induced angiogenesis in nude mice.

Tetrahydrocurcumin (THC), one of the important in vivo metabolites of curcumin, inhibits tumor angiogenesis. Its effects on angiogenesis in cervical cancer- (CaSki-) implanted nude mice and its mechanisms on hypoxia-inducible factor-1α and vascular endothelial growth factor expression were investigated. Female BALB/c nude mice were divided into control (CON) and CaSki-implanted groups (CaSki group). One month after the injection with cervical cancer cells, mice were orally administered vehicle or 100, 300, and 500 mg/kg of THC daily for 30 consecutive days. The microvascular density (MVD) was evaluated using the CD31 expression. VEGF, VEGFR-2, and HIF-1α expression were also detected by immunohistochemistry. The MVD in CaSki + vehicle group was significantly increased compared to the CON + vehicle group. Interestingly, when treated with THC at all doses, the CaSki group showed a significant smaller number of the MVD. The CaSki + vehicle group also showed significantly increased VEGF, VEGFR-2, and HIF-1α expressions, but they were downregulated when mice were treated with THC at all doses. THC demonstrated an inhibitory effect against tumor angiogenesis in CaSki-implanted nude mice model. This effect is likely to be mediated by the downregulation of HIF-1-α, VEGF expression, and its receptor. THC could be developed into a promising agent for cancer therapy in the future.

Angiogenesis and antiangiogenic agents in cervical cancer.

Standard treatment of cervical cancer (CC) consists of surgery in the early stages and of chemoradiation in locally advanced disease. Metastatic CC has a poor prognosis and is usually treated with palliative platinum-based chemotherapy. Current chemotherapeutic regimens are associated with significant adverse effects and only limited activity, making identification of active and tolerable novel targeted agents a high priority. Angiogenesis is a complex process that plays a crucial role in the development of many types of cancer. The dominant role of angiogenesis in CC seems to be directly related to human papillomavirus-related inhibition of p53 and stabilization of hypoxia-inducible factor-1α. Both of these mechanisms are able to increase expression of vascular endothelial growth factor (VEGF). Activation of VEGF promotes endothelial cell proliferation and migration, favoring formation of new blood vessels and increasing permeability of existing blood vessels. Since bevacizumab, a recombinant humanized monoclonal antibody binding to all isoforms of VEGF, has been demonstrated to significantly improve survival in gynecologic cancer, some recent clinical research has explored the possibility of using novel therapies directed toward inhibition of angiogenesis in CC too. Here we review the main results from studies concerning the use of antiangiogenic drugs that are being investigated for the treatment of CC.