Cervical Cancer Growth Research Articles

Umbilical cord-derived secretome induces apoptosis and reduces proliferation in cancer cells

Umbilical cord mesenchymal stem cells (UCMSCs) have the best ability to travel to the tumor site and they serve as a tool to fight cancer. This study showed that secretome from UCMSCs (UCMSCs-Sec) could inhibit the growth of prostate cancer (PC-3) and cervical cancer (HeLa) cells, and induce apoptosis in the cells. The UCMSCs-Sec treatment was given to PC-3 and HeLa cells. After 7 days, cell viability assay was performed to evaluate cell viability, and ELISA for vascular endothelial growth factor (VEGF) was performed to evaluate neovascularization. RT-PCR was also done to measure the expression of ki67, caspase-3, PCNA, BAX and GAPDH genes. The levels of secreted antioxidative enzymes, including superoxide dismutase, ascorbate peroxidase, catalase, and glutathione, were estimated in the treated and untreated groups. Decreased cellular viabilty revealed increased apoptosis in HeLa and PC-3 cells treated with UCMSCs-Sec. Gene expression analysis showed that apoptotic genes (BAX and caspase-3) were upregulated, proliferative genes including ki67 and PCNA were reduced, while GAPDH remained unchanged as it is a house-keeping gene. The UCMSCs-Sec treatment was also found to reduce neovascularization in the cancer cells. Furthermore, relative levels of secreted antioxidative enzymes were also reduced in PC-3 and HeLa cells treated with UCMSCs-Sec. These findings could be an indicative that UCMSCs-Sec can promote cellular death and prevent the cellular division of cancer cells. The present study explores anticancer potential of secretome from USMSCs. This strategy could be a viable therapeutic option for the treatment of neoplastic cells.

Qiu's Cervical Prescription inhibit the invasion and growth of cervical cancer through LncRNA ATB/miR-126 pathway.

Cervical cancer (CC) is one of the most deadly cancers in women, its current treatments still result in poor outcomes and developing the novel targets and therapeutic strategies are urgently needed. Qiu's Cervical Prescription (QCP) is one of the traditional Chinese medicines used in the treatment of cervical cancer in China. Although its curative effect is remarkable, the internal mechanism of its treatment is still poorly understood. Recent studies have shown that LncRNA ATB might be used as a new proliferation marker for cancer diagnosis and prognosis. This study aimed to investigate the possible mechanism of action of QCP in the treatment of cervical cancer. The functional assays of migration and invasion in vitro using transwell assays and wound healing assays was performed to confirm the pro-carcinogenic effect of LncRNA ATB, and the changes of migration and invasion of HeLa cells were observed after treatment with QCP containing drug serum. The changes in tumor volume, general condition of transplanted tumor-bearing mice and expression of LncRNA ATB pathway-related proteins were detected by qPCR, Western blotting and HE staining after treatment with the QCP. We induced LncRNA ATB knockdown and overexpression in cervical cancer cell lines and detected the biological behavior changes in vitro. Furthermore, we established murine models using stable LncRNA ATB-shRNA HeLa cells or overexpression LncRNA ATB cells or normal Hela cells with QCP to evaluate how suppression of LncRNA ATB affects tumor growth. We showed that potential mechanism of QCP in the treatment of cervical cancer may be through inhibition of the LncRNA ATB/miR-126/TGFβ1 signaling axis. In conclusion, QCP may be a promising approach for the treatment of CC.

Triptolide-induced cuproptosis is a novel antitumor strategy for the treatment of cervical cancer

BackgroundCuproptosis is a unique copper-dependent form of cell death that is highly correlated with the metabolic state of cells. Triptolide exerts pharmacological activity by altering the regulation of metal ions. Cuproptosis is poorly understood in cancer, so in this study, we explored whether triptolide could induce cuproptosis in cervical cancer cells.MethodsThe human cervical cancer cell lines HeLa and SiHa, which primarily rely on oxidative phosphorylation, were treated with triptolide. Cell viability, proliferation and migration, copper levels and cuproptosis-related protein levels were evaluated in these cell lines. The copper ion chelator tetrathiomolybdate (TTM) was administered to determine whether it could reverse the cuproptosis induced by triptolide. In addition, a nude mouse cervical cancer xenograft model was established to determine the effects of triptolide on cuproptosis in isolated tumor tissues.ResultsThe copper concentration increased with triptolide treatment. The levels of cuproptosis -related proteins, such as FDX1, LIAS, and DLAT, in the HeLa and SiHa cell lines decreased with triptolide treatment. XIAP, the target of triptolide, played a role in cuproptosis by regulating COMMD1. The level of copper exporters (ATP7A/B) decreased, but the level of the copper importer (CTR1) did not change with triptolide treatment. Furthermore, triptolide inhibited cervical cancer growth and induced cuproptosis in vivo.ConclusionsIn summary, we report a new antitumor mechanism by which triptolide disrupted intracellular copper homeostasis and induced cuproptosis in cervical cancer by regulating the XIAP/COMMD1/ATP7A/B axis.

Ferroptosis-related gene transferrin receptor protein 1 expression correlates with the prognosis and tumor immune microenvironment in cervical cancer.

Ferroptosis is a non-apoptotic iron-dependent form of cell death implicated in various cancer pathologies. However, its precise role in tumor growth and progression of cervical cancer (CC) remains unclear. Transferrin receptor protein 1 (TFRC), a key molecule associated with ferroptosis, has been identified as influencing a broad range of pathological processes in different cancers. However, the prognostic significance of TFRC in CC remains unclear. The present study utilized bioinformatics to explore the significance of the ferroptosis-related gene TFRC in the progression and prognosis of CC. We obtained RNA sequencing data and corresponding clinical information on patients with CC from The Cancer Genome Atlas (TCGA), Genotype Tissue Expression (GTEx) and Gene Expression Omnibus (GEO) databases. Using least absolute shrinkage and selection operator (LASSO) Cox regression, we then generated a multigene signature of five ferroptosis-related genes (FRGs) for the prognostic prediction of CC. We investigated the relationship between TFRC gene expression and immune cell infiltration by employing single-sample GSEA (ssGSEA) analysis. The potential functional role of the TFRC gene was evaluated through gene set enrichment analysis (GSEA). Immunohistochemistry and qPCR was employed to assess TFRC mRNA and protein expression in 33 cases of cervical cancer. Furthermore, the relationship between TFRC mRNA expression and overall survival (OS) was investigated in patients. CC samples had significantly higher TFRC gene expression levels than normal tissue samples. Higher TFRC gene expression levels were strongly associated with higher cancer T stages and OS events. The findings of multivariate analyses illustrated that the OS in CC patients with high TFRC expression is shorter than in patients with low TFRC expression. Significant increases were observed in the levels of TFRC mRNA and protein expression in patients diagnosed with CC. Increased TFRC expression in CC was associated with disease progression, an unfavorable prognosis, and dysregulated immune cell infiltration. In addition, it highlights ferroptosis as a promising therapeutic target for CC.

LIMK1 promotes the development of cervical cancer by up-regulating the ROS/Src-FAK/cofilin signaling pathway.

In this study, we investigated the mechanism of action of LIMK1 in cervical cancer progression. The biological role of LIMK1 in regulating the growth, invasion, and metastasis of cervical cancer was studied in SiHa, CaSki cells and nude mice tumor models. The role of LIMK1 in the growth of cervical cancer was evaluated by HE staining. The role of LIMK1 in the invasion, metastasis, and proliferation of cervical cancer was evaluated by cell scratch, Transwell, and monoclonal experiments. The interaction among LIMK1, ROS, and Src was evaluated by Western blotting. The effects of regulating ROS and p-Src expression on LIMK1 in the migration/invasion and proliferation of cervical cancer cells were evaluated through cellular functional assays. Overexpression of LIMK1 promoted tumor growth in nude mice. Cell scratch, Transwell, and monoclonal experiments suggested that LIMK1 promoted the invasion, metastasis, and proliferation of cervical cancer cells. Western blotting suggested that LIMK1 can promote the expression of ROS-related proteins NOX2, NOX4, p-Src, and downstream proteins p-FAK, p-ROCK1/2, p-Cofilin-1, F-actin and inhibit the expression of p-SHP2 protein. Correction experiments showed that LIMK1 regulated the expression of p-FAK and p-Cofilin-1 proteins by regulating ROS and p-Src. Through the detection of cervical cancer cell functions, it was found that the activation of ROS and p-Src induced by LIMK1 is an early event that promotes the migration, proliferation, and invasion of cervical cancer cells. LIMK1 promotes the expression of F-actin and promotes the development of cervical cancer by regulating the oxidative stress/Src-mediated p-FAK/p-ROCK1/2/p-Cofilin-1 pathway.

The activation of Piezo1 channel promotes invasion and migration via the release of extracellular ATP in cervical cancer

BackgroundThe mechanosensitive ion channel Piezo1 has emerged as a potential prognostic and therapeutic target in different types of cancers. The aim of this study was to determine the expression levels and underlying mechanisms of Piezo1 in the invasion and migration processes in cervical cancer. MethodsInitially, we employed qRT-PCR, western blot, and immunohistochemical staining techniques to assess the disparity in Piezo1 expression in cervical cancer tissues and cells. Subsequently, we conducted wound healing, transwell assays and phalloidin staining to observe the effects of stable Piezo1 silencing and Piezo1 selective agonist Yoda1 on the invasion and migration capabilities. The release of extracellular ATP was assessed using the enhanced ATP assay kit. Furthermore, we conducted rescue experiments to investigate whether the activation of Piezo1 facilitates cervical cancer invasion and migration through extracellular ATP. Finally, we constructed xenograft tumor models to determine weather the Piezo1 selective agonist Yoda1 influenced the tumor growth in vivo. ResultsIn our study, we found that Piezo1 expression was elevated in both cervical cancer tissues and cells, with the highest levels observed in patients with lymph node metastasis. Knocking down Piezo1 resulted in a significant reduction in the invasion and migration capabilities of cervical cancer cells, whereas the use of the Piezo1 selective agonist Yoda1 enhanced these capabilities. Moreover, the activation of Piezo1 channels was found to regulate the release of extracellular ATP. Mechanistically, the activation of Piezo1 might facilitate cervical cancer invasion, migration, and pseudopodium formation through the release of extracellular ATP. And Piezo1 was an important molecule for the tumor growth of cervical cancer in vivo. ConclusionOur findings revealed that Piezo1 facilitated the invasion and migration of cervical cancer by releasing extracellular ATP, which might hold potential as a valuable target for prognostic and therapeutic interventions in cervical cancer.

Activation of AMPK inhibits cervical cancer growth by hyperacetylation of H3K9 through PCAF

BackgroundDysregulation in histone acetylation, a significant epigenetic alteration closely associated with major pathologies including cancer, promotes tumorigenesis, inactivating tumor-suppressor genes and activating oncogenic pathways. AMP-activated protein kinase (AMPK) is a cellular energy sensor that regulates a multitude of biological processes. Although a number of studies have identified the mechanisms by which AMPK regulates cancer growth, the underlying epigenetic mechanisms remain unknown.MethodsThe impact of metformin, an AMPK activator, on cervical cancer was evaluated through assessments of cell viability, tumor xenograft model, pan-acetylation analysis, and the role of the AMPK-PCAF-H3K9ac signaling pathway. Using label-free quantitative acetylproteomics and chromatin immunoprecipitation-sequencing (ChIP) technology, the activation of AMPK-induced H3K9 acetylation was further investigated.ResultsIn this study, we found that metformin, acting as an AMPK agonist, activates AMPK, thereby inhibiting the proliferation of cervical cancer both in vitro and in vivo. Mechanistically, AMPK activation induces H3K9 acetylation at epigenetic level, leading to chromatin remodeling in cervical cancer. This also enhances the binding of H3K9ac to the promoter regions of multiple tumor suppressor genes, thereby promoting their transcriptional activation. Furthermore, the absence of PCAF renders AMPK activation incapable of inducing H3K9 acetylation.ConclusionsIn conclusion, our findings demonstrate that AMPK mediates the inhibition of cervical cancer growth through PCAF-dependent H3K9 acetylation. This discovery not only facilitates the clinical application of metformin but also underscores the essential role of PCAF in AMPK activation-induced H3K9 hyperacetylation.

Structure-Based Discovery of Potential HPV E6 and EBNA1 Inhibitors: Implications for Cervical Cancer Treatment

Cervical cancer is the fourth most diagnosed cancer and the fourth leading cause of cancer death in women globally. Its onset and progression have been attributed to high-risk human papillomavirus (HPV) types, especially 16 and 18, while the Epstein–Barr virus (EBV) is believed to also significantly contribute to cervical cancer growth. The E6 protein associated with high-risk HPV strains, such as HPV16 and HPV18, is known for its role in promoting cervical cancer and other anogenital cancers. E6 proteins contribute to the malignant transformation of infected cells by targeting and degrading tumor suppressor proteins, especially p53. On the other hand, EBV nuclear antigen 1 (EBNA1) plays a crucial role in the maintenance and replication of the EBV genome in infected cells. EBNA1 is believed to increase HPV E6 and E7 levels, as well as c-MYC, and BIRC5 cellular genes in the HeLa cell line, implying that HPV/EBV co-infection accelerates cervical cancer onset and growth. Thus, the E6 and EBNA1 antigens of HPV and EBV, respectively, are attractive targets for cervical cancer immunotherapy. This study, therefore, virtually screened for potential drug candidates with good binding affinity to all three oncoviral proteins, HPV16 E6, HPV18 E6, and EBNA1. The compounds were further subjected to ADMET profiling, biological activity predictions, molecular dynamics (MD) simulations, and molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) calculations. A total of six compounds comprising ZINC000013380012, ZINC000070454124, ZINC000014588133, ZINC000085568136, ZINC000095909247, and ZINC000085597263 demonstrated very strong affinity (≤−60 kJ/mol) to the three oncoviral proteins (EBNA1, HPV16 E6, and HPV18 E6) after being subjected to docking, MD, and MM/PBSA. These compounds demonstrated relatively stronger binding than the controls used, inhibitors of EBNA1 (VK-1727) and HPV E6 (baicalein and gossypetin). Biological activity predictions also corroborated their antineoplastic, p53-enhancing, Pin1 inhibitory, and JAK2 inhibitory activities. Further experimental testing is required to validate the ability of the shortlisted compounds to silence the insidious effects of HPV E6 and EBNA1 proteins in cervical cancers.

MicroRNA-875-5p inhibits the growth and metastasis of cervical cancer cells by promoting autophagy and apoptosis and inhibiting the epithelial-mesenchymal transition.

MicroRNA-875-5p (miR-875-5p) is a cancer-related microRNA. It has been demonstrated that miR-875-5p participates in the development of various types of cancer such as hepatocellular carcinoma, gastric carcinoma, prostate and bladder cancer. Previous research suggested that miR-875 is implicated in the development of cervical cancer cells. However, the exact role and function of miR-875-5p in cervical cancer remain unexplored. It is important to examine the role and function of miR-875-5p and the associated signaling pathway, as the findings may have diagnostic and therapeutic significance. Thus, in this study, we investigated the effect of miR-875-5p on the growth and metastasis of cervical cancer cells and the possible underlying mechanisms. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression of miR-875-5p in cervical cancer cells and normal cervical epithelium. After overexpression or co-expression of miR-875-5p in cells, the changes in cell function were analyzed. Western blot was used to detect the expression changes of epithelial-mesenchymal transition (EMT) -related proteins and autophagy-related proteins. Functional studies demonstrated that miR-875-5p overexpression significantly inhibited the proliferation, migration, invasion, and EMT, and promotes apoptosis and autophagy of cervical cancer cells., while miR-875-5p knockdown promoted the proliferation, migration, invasion, and EMT, and inhibited apoptosis and autophagy cervical cancer cells. Furthermore, Western blot results showed that overexpression of miR-875-5p downregulated the expressions of N-cadherin, Snail, Vimentin and microtubule-associated protein 1 light chain 3B I (LC3B I). Conversely, miR-875-5p upregulated the expression of E-cadherin. In conclusion, our findings suggest that miR-875-5p functions as a tumor inhibitor suppressing the growth and metastasis of cervical cancer. Overexpression of miR-875-5p inhibits malignant behavior and promotes autophagy and apoptosis in cervical cancer cells. These findings advance our understanding of the role and function of miR-875-5p in cervical cancer and could facilitate the development of early genetic markers or biomarkers and therapeutic targets for cervical cancer.

METTL3-mediated m6A methylation of SLC38A1 stimulates cervical cancer growth

The objective of this study was to better characterize the role of the glutamine transporter SLC38A1 in cervical cancer and explore the underlying mechanisms. Data from public databases and clinical cervical cancer tissue samples were used to assess the expression of SLC38A1 and its prognostic significance. Immunohistochemical staining, qRT-PCR, and Western blotting were used to evaluate the expression of relevant genes and proteins. Cell viability, cell cycle, apoptosis, and intracellular glutamine content were measured using CCK-8, flow cytometry, and biochemical assays. Additionally, the RNA immunoprecipitation (RIP) assay was used to examine the impact of METTL3/IGF2BP3 on the m6A modification of the SLC38A1 3′UTR. Both cervical cancer specimens and cells showed significantly increased expression of SLC38A1 and its expression correlated with an unfavorable prognosis. Knockdown of SLC38A1 inhibited cell viability and cell cycle progression, induced apoptosis, and suppressed tumor growth in vivo. Glutaminase-1 inhibitor CB-839 reversed the effects of SLC38A1 overexpression. METTL3 promoted m6A modification of SLC38A1 and enhanced its mRNA stability through IGF2BP3 recruitment. Moreover, METTL3 silencing inhibited cell viability, cell cycle progression, intracellular glutamine content, and induced apoptosis, but these effects were reversed by SLC38A1 overexpression. In conclusion, METTL3-mediated m6A methylation of SLC38A1 stimulates cervical cancer progression. SLC38A1 inhibition is a potential therapeutic strategy for cervical cancer.

The Role of SARS-CoV-2 Spike Protein in the Growth of Cervical Cancer Cells.

Recently developed vaccines for the SARS-CoV-2 virus utilize endogenous production of the virus' spike protein (SP), allowing the host to develop an immune response. As a result of the novelty of this virus and its vaccines, little is known overall about the potential effects of the SP on the pathogenesis of neoplasia, either from vaccination or from infection. This study was designed to investigate whether SARS-CoV-2 SP has any direct effect on SiHa cervical cancer cells. The effects of SARS-CoV-2 SP on cervical cancer cell proliferation and apoptosis were investigated by using clonogenic cell survival assay, quick cell proliferation assay, and caspase-3 activity kits in a widely-used cervical cancer cell line, SiHa. RT-PCR and immunohistochemistry were also performed to determine the potential molecular mechanisms. The growth and proliferation of SiHa cancer cells were inhibited by SARS-CoV-2 SP. SARS-CoV-2 SP also induced apoptosis in SiHa cancer cells. The anti-proliferative effect of SARS-CoV-2 SP on SiHa cancer cells was associated with the up-regulation of the anti-proliferative molecule p53. The pro-apoptotic effect of SARS-CoV-2 SP on SiHa cells was associated with the up-regulation of the pro-apoptotic molecule TRAIL. SARS-CoV-2 SP inhibits the growth of cervical cancer via up-regulation of p53 and TRAIL. Further studies are needed to elaborate on the potential effects of the SARS-CoV-2 SP on other cancer cell lines and normal physiological cell lines for comparison.

SOX21-AS1 Augmented Cervical Cancer Growth by Triggering FZD3 to Activate the Wnt/β-Catenin Signaling Pathway.

Long non-coding RNA (LncRNA) SOX21-AS1 has been reported that it plays an important role in biological processes of several cancers. However, how it functions in cervical cancer (CC) still remain unclear. This investigation seeks to explore the impact of SOX21-AS1 on CC cell proliferation, invasion and migration and its association to the FZD3 and the Wnt/β-catenin signaling pathway. SOX21-AS1 expression levels were detected using real-time quantitative PCR in 20 cases of cervical cancer together with its adjacent tissues and several cervical cancer cell lines. Transgenic technology and functional experiments were conducted to confirm the carcinogenic properties of SOX21-AS1, and western blot was utilized to analyze the regulatory network composed of SOX21-AS1, FZD3 and the Wnt/β-catenin signaling pathway in CC. Through bioinformatics analysis, we found that the expression of SOX21-AS1 in CC was the highest among 16 kinds of tumor tissues. Moreover, clinical specimens confirmed that both CC tissues and cell lines possessed elevated SOX21-AS1 expressions (P<0.01). CC cells which stably expressed upregulated SOX21-AS1 were noted to possesses higher rates of metastasis, invasion and proliferation, lower apoptotic rates and higher expression of FZD3,β-catenin and c-myc (P<0.01). Conversely, the use of small interfering RNA to inhibit the expression of SOX21-AS1 yielded the opposite results (P<0.01). SOX21-AS1 functions as an oncogenic LncRNA which enhances CC cell metastasis, invasion and proliferation through FZD3 upregulation via Wnt/β-catenin-signaling pathway activation. This LncRNA may represent an important biomarker for CC patients.

CircMAST1 inhibits cervical cancer progression by hindering the N4-acetylcytidine modification of YAP mRNA

BackgroundCervical cancer (CCa) is the fourth most common cancer among females, with high incidence and mortality rates. Circular RNAs (circRNAs) are key regulators of various biological processes in cancer. However, the biological role of circRNAs in cervical cancer (CCa) remains largely unknown. This study aimed to elucidate the role of circMAST1 in CCa.MethodsCircRNAs related to CCa progression were identified via a circRNA microarray. The relationship between circMAST1 levels and clinicopathological features of CCa was evaluated using the clinical specimens and data of 131 patients with CCa. In vivo and in vitro experiments, including xenograft animal models, cell proliferation assay, transwell assay, RNA pull-down assay, whole-transcriptome sequencing, RIP assay, and RNA-FISH, were performed to investigate the effects of circMAST1 on the malignant behavior of CCa.ResultsCircMAST1 was significantly downregulated in CCa tissues, and low expression of CircMAST1 was correlated with a poor prognosis. Moreover, our results demonstrated that circMAST1 inhibited tumor growth and lymph node metastasis of CCa. Mechanistically, circMAST1 competitively sequestered N-acetyltransferase 10 (NAT10) and hindered Yes-associated protein (YAP) mRNA ac4C modification to promote its degradation and inhibit tumor progression in CCa.ConclusionsCircMAST1 plays a major suppressive role in the tumor growth and metastasis of CCa. In particular, circMAST1 can serve as a potential biomarker and novel target for CCa.

Tumor cells-derived extracellular vesicles carry circ_0064516 competitively inhibit microRNA-6805-3p and promote cervical cancer angiogenesis and tumor growth

ABSTRACT Background The current study tried to elucidate the regulatory role of tumor cell-derived exosomes (Exos)-circ_0064516 in angiogenesis and growth of cervical cancer. Research design and methods Related cirRNAs and downstream target genes were identified through bioinformatics analysis. Exos were isolated from cervical cancer cell line CaSki, followed by co-cultured with human umbilical vein endothelial cells (HUVECs). Then, the roles of circ_0064516, miR-6805-3p, and MAPK1 in migration and angiogenesis of HUVECs were assayed. Furthermore, xenografted tumors were transplanted into nude mice for in vivo validation. Results In vitro assay validated highly expressed circ_0064516 in cervical cancer cells. Tumor cell-derived Exos carried circ_0064516 to HUVECs. circ_0064516 increased MAPK1 expression by binding to miR-6805-3p, thus enhancing migration and angiogenesis. Exos containing circ_0064516 also promoted tumorigenesis of cervical cancer cells in nude mice. Conclusions We confirmed the oncogenic role of tumor cell-derived Exos carrying circ_0064516 in cervical cancer progression through miR-6805-3p/MAPK1.

Protective effect of tretinoin on cervical cancer growth and proliferation through downregulation of pFAK2 expression.

Cervical cancer, a life-threatening disease, is the seventh most commonly detected cancer among women throughout the world. The present study investigated the effect of tretinoin on cervical cancer growth and metastasis in vitro and in vivo in the mice model. Cell Counting Kit-8, clonogenic survival, and transwell chamber assays were used for determination cells proliferation, colony formation, and invasiveness. Western blotting assay was used for assessment of protein expression whereas AutoDock Vina and Discovery studio software for in silico studies. Tretinoin treatment significantly (p < .05) reduced the proliferation of HT-3 and Caski cells in concentration-based manner. Incubation with tretinoin caused a significant decrease in clonogenic survival of HT-3 and Caski cells compared with the control cultures. The invasive potential of HT-3 cells was decreased to 18%, whereas that of Caski cells to 21% on treatment with 8 μM concentration of tretinoin. In HT-3 cells, tretinoin treatment led to a prominent reduction in p-focal adhesion kinase (FAK), matrix metalloproteinases (MMP)-2, and MMP-9 expression in HT-3 cells. Treatment of the cervical cancer mice model with tretinoin led to a prominent decrease in tumor growth. The metastasis of tumor in model cervical cancer mice group was effectively inhibited in spleen, intestines, and peritoneal cavity. In silico studies showed that tretinoin interacts with alanine, proline, isoleucine, and glycine amino acid residues of FAK protein to block its activation. The 2-dimensional diagram of interaction of tretinoin with FAK protein revealed that tretinoin binds to alanine and glycine amino acids through conventional hydrogen bonding. In summary, tretinoin suppressed the proliferation, colony formation, and invasiveness of cervical cancer cells in vitro. It decreased the expression of activated focal adhesion kinase, MMP-2, and MMP-9 in HT-3 cells in dose-dependent manner. In silico studies showed that tretinoin interacts with alanine and glycine amino acids through conventional hydrogen bonding. In vivo data demonstrated that treatment of the cervical cancer mice model with tretinoin led to a prominent decrease in tumor growth. Therefore, tretinoin can be developed as an effective therapeutic agent for cervical cancer treatment.

Elevated INHBA Promotes Tumor Progression of Cervical Cancer.

Objectives: This study aimed to explore the role of inhibin subunit beta A (INHBA) in the progression of cervical cancer (CCa) and investigate its potential as a therapeutic target. Specifically, the objectives were to assess the expression levels of INHBA in CCa, examine its correlation with patient survival, and elucidate its impact on CCa cell proliferation, cell cycle regulation, migration, invasion, and in vivo tumor growth and metastasis. Methods: To achieve the objectives, we conducted a comprehensive set of experimental methods. INHBA expression in CCa was analyzed, and its association with patient survival was assessed using clinical data. In vitro experiments involved the investigation of INHBA's effects on CCa cell proliferation, cell cycle dynamics, migration, and invasion through the epithelial-mesenchymal transition (EMT) process. Additionally, in vivo experiments were performed to evaluate the influence of INHBA on CCa growth and lung metastasis. Results: The results of this study revealed upregulated expression of INHBA in CCa, with a significant association between high INHBA expression and poor patient survival. Functionally, INHBA was found to promote the proliferation of CCa cells, regulate the cell cycle, and enhance migration and invasion through the EMT process in vitro. Moreover, in vivo experiments demonstrated that INHBA facilitated the growth and lung metastasis of CCa. Conclusion: In conclusion, our findings suggest that INHBA plays a crucial role in the progression of cervical cancer. The upregulation of INHBA is associated with poor patient survival, and its involvement in promoting key aspects of cancer progression makes it a potential therapeutic target for CCa treatment. These results provide valuable insights into the molecular mechanisms underlying CCa and offer a foundation for further exploration of targeted therapeutic interventions.

Synergistic celecoxib and dimethyl-celecoxib combinations block cervix cancer growth through multiple mechanisms.

The synergistic inhibitory effect of celecoxib (CXB) and dimethyl-celecoxib (DMC) plus paclitaxel (PA) or cisplatin (CP) on human cervix HeLa and SiHa cells was assessed at multiple cellular levels in order to elucidate the biochemical mechanisms triggered by the synergistic drug combinations. The effect of CXB (5 μM)/CP (2 μM) or CXB (5 μM)/PA (15 μM) and DMC (15 μM)/CP (5 μM) or DMC (15 μM)/PA (20 μM) for 24 h was assayed on cancer cell proliferation, energy metabolism, mitophagy, ROS production, glycoprotein-P activity, DNA stability and apoptosis/necrosis. Drug combinations synergistically decreased HeLa and SiHa cell proliferation (>75%) and arrested cellular cycle by decreasing S and G2/M phases as well as the Ki67 content (HeLa) by 7.5-30 times. Cell viability was preserved (>90%) and no apparent effects on non-cancer cell growth were observed. Mitochondrial and glycolytic protein contents (44-95%) and ΔΨm (45-50%) in HeLa cells and oxidative phosphorylation and glycolysis fluxes (70-90%) in HeLa and SiHa cells were severely decreased, which in turn promoted a drastic fall in the ATP supply (85-88%). High levels of mitophagy proteins in HeLa cells and active mitochondrial digestion in HeLa and SiHa cells was observed. Mitochondrial fission and microtubule proteins were also affected. Intracellular ROS content (2-2.3-fold) and ROS production was stimulated (2.3-4 times), whereas content and activity of glycoprotein-P (45-85%) were diminished. DNA fragmentation was not observed and apoptosis/necrosis was not detected suggesting that cell death could be mainly associated to mitophagy induction. CXB or DMC combination with canonical chemotherapy may be a promising chemotherapy strategy against cervical cancer growth, because it can selectively block multiple cell processes including inhibition of energy pathways and in consequence ATP-dependent processes such as cell proliferation, glycoprotein-P activity, ROS production and mitophagy, with no apparent effects on non-cancer cells.

Alantolactone Induced Apoptosis and DNA Damage of Cervical Cancer through ATM/CHK2 Signaling Pathway.

Traditional Chinese Medicine, known for its minimal side effects and significant clinical efficacy, has attracted considerable interest for its potential in cancer therapy. In particular, Inula helenium L. has demonstrated effectiveness in inhibiting a variety of cancers. This study focuses on alantolactone (ALT), a prominent compound from Inula helenium L., recognized for its anti-cancer capabilities across multiple cancer types. The primary objective of this study is to examine the influence of ALT on the proliferation, apoptosis, cell cycle, and tumor growth of cervical cancer (CC) cells, along with its associated signaling pathways. To determine protein expression alterations, Western blot analysis was conducted. Furthermore, an in vivo model was created by subcutaneously injecting HeLa cells into nude mice to assess the impact of ALT on cervical cancer. Our research thoroughly investigates the anti-tumor potential of ALT in the context of CC. ALT was found to inhibit cell proliferation and induce apoptosis in SiHa and HeLa cell lines, particularly targeting ataxia-telangiectasia mutated (ATM) proteins associated with DNA damage. The suppression of DNA damage and apoptosis induction when ATM was inhibited underscores the crucial role of the ATM/cell cycle checkpoint kinase 2 (CHK2) axis in ALT's anti-tumor effects. In vivo studies with a xenograft mouse model further validated ALT's effectiveness in reducing CC tumor growth and promoting apoptosis. This study offers new insights into how ALT combats CC, highlighting its promise as an effective anti-cervical cancer agent and providing hope for improved treatment outcomes for CC patients.

Foxm1-Mediated Transcriptional Inactivation of NLRP3 Inflammasome Promotes Immunosuppression in Cervical Cancer.

Foxm1 functions as an oncogene in multiple human malignancies, including cervical cancer. However, the potential of Foxm1 in the tumor microenvironment (TME) is still unknown. The purpose of the present study is to investigate the role of Foxm1 in CD8+ T cell anti-tumor immunity. RT-qPCR is conducted to calculate mRNA levels. JASPAR is used to predict the binding sites between Foxm1 and NLRP3. ChIP assay is performed to verify the occupancy of Foxm1 on the promoter of NLRP3. Modulatory relationship between Foxm1 and NLRP3 is verified by luciferase assay. In vivo assays are conducted to further verify the role of Foxm1/NLRP3 axis in cervical cancer. HE staining assay is applied for histological analysis. Flow cytometry is conducted to determine the functions of immune cells. We found that Foxm1 knockdown decreases tumor burden and suppresses tumor growth of cervical cancer. Foxm1 knock-down promotes the infiltration of CD8+ T cells. Foxm1 deficiency inhibits the exhaustion of CD8+ T cells and facilitates the maintenance of CD8+ effector and stem-like T cells. Moreover, Foxm1 transcriptionally inactivates NLRP3 and suppresses the expression of innate cytokines IL-1β and IL-18. However, inhibition of NLRP3 inflammasome or neutralizing IL-1β and IL-18 inhibits anti-tumor immunity and promoted tumor growth in Foxm1 deficiency in CD8+ T cells. In summary, targeting Foxm1 mediates the activation of NLRP3 inflammasome and stimulates CD8+ T cell anti-tumor immunity in cervical cancer.

The deubiquitinase OTUB2 promotes cervical cancer growth through stabilizing FOXM1

The deubiquitinase OTUB2 promotes cervical cancer growth through stabilizing FOXM1