scholarly journals Cdc25A inhibits autophagy-mediated ferroptosis by upregulating ErbB2 through PKM2 dephosphorylation in cervical cancer cells

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Chen Wang ◽  
Jie Zeng ◽  
Li-Jie Li ◽  
Min Xue ◽  
Si-Li He
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Xenograft Model ◽  
Luciferase Assay ◽  
Mouse Xenograft Model ◽  
Cervical Cancer Cells ◽  
Cancer Tissues ◽  
Mtt Assays

AbstractCervical cancer is the leading cause of cancer-related deaths in women, and treatment for cervical cancer is very limited. Emerging evidence suggests that targeting ferroptosis is a promising way to treat cancer. Here, we investigated the role of ferroptosis in cervical cancer, with a focus on the Cdc25A/PKM2/ErbB2 axis. Cervical cancer cells were treated with sorafenib to induce ferroptosis. Cellular MDA/ROS/GSH/iron detection assays were used to measure ferroptosis. MTT assays were performed to assess cell viability. qRT-PCR, western blot, and immunostaining assays were performed to measure the levels of proteins. Autophagy was monitored by fluorescence microscopy. Nuclear and cytosolic fractions were isolated to examine the location of PKM2 modifications. Co-IP experiments were conducted to determine the Cdc25A/PKM2 interaction. ChIP assays were performed to measure the binding affinity between H3K9Ac and the ErbB3 promoter, and a dual luciferase assay was performed to examine the transcriptional activity of ErbB2. A nude mouse xenograft model was used to examine the effects of the Cdc25A/ErbB2 axis on tumour growth in vivo. Cdc25A was elevated in human cervical cancer tissues but was reduced during sorafenib-induced ferroptosis of cervical cancer cells. Overexpression of Cdc25A inhibited sorafenib-induced ferroptosis by dephosphorylating nuclear PKM2 and suppressing autophagy. Cdc25A regulated autophagy-induced ferroptosis by increasing ErbB2 levels via the PKM2–pH3T11–H3K9Ac pathway. Cdc25A increased the resistance of cervical cancer to sorafenib, while knockdown of ErbB2 blocked these effects. Cdc25A suppressed autophagy-dependent ferroptosis in cervical cancer cells by upregulating ErbB2 levels through the dephosphorylation of PKM2. These studies revealed that Cdc25A/PKM2/ErbB2 pathway-regulated ferroptosis could serve as a therapeutic target in cervical cancer.

scholarly journals MicroRNA-425 induces apoptosis and suppresses migration and invasion of human cervical cancer cells by targeting RAB2B

2021 ◽  
Vol 35 ◽  
pp. 205873842110161
Author(s):  
Yue Tian ◽  
Ying Luo ◽  
Jing Wang
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Migration And Invasion ◽  
Cervical Cancer Cells ◽  
Induction Of Apoptosis ◽  
Cancer Tissues ◽  
Human Cervical Cancer

Dysregulation of microRNA-425 (miR-425) has been reported in several human cancers. However, the role of miR-425 in human cervical cancer via modulation of RAB2B expression is still unclear. This study was therefore designed to examine the expression and decipher the role of miR-425 in cervical cancer. The qRT-PCR was used for expression analysis. MTT and EdU assays were used for the determination of cell viability and proliferation, respectively. Annexin V/PI staining was used to detect apoptosis. Wound healing and transwell assays were used to monitor cell migration and invasion. Western blotting was used for protein expression analysis. The in vivo study was performed in xenografted mice model. The results of the present study revealed miR-425 to be significantly ( P = 0.032) down-regulated in cervical cancer tissues and cell lines. Additionally, low expression of miR-425 was associated with significantly ( P = 0.035) lower survival rate of the cervical cancer patients. Overexpression of miR-425 resulted in significant ( P = 0.024) decline of cervical cancer cell proliferation via induction of apoptosis. The induction of apoptosis was associated with up-regulation of Bax and down-regulation of Bcl-2. Besides, the migration and invasion of cancer cells significantly ( P < 0.01) decreased under miR-425 overexpression. Additionally, miR-425 could inhibit the growth of xenografted tumors in vivo. In silico analysis and dual luciferase assay revealed RAB2B as the direct target of miR-425 in cervical cancer. RAB2B was found to be significantly ( P < 0.05) up-regulated in cervical cancer tissues and cell lines and miR-425 overexpression suppressed the expression of RAB2B. Additionally, silencing of RAB2B could suppress the growth of cervical cancer cells but its overexpression could rescue the tumor-suppressive effects of miR-425. Taken together, the results revealed the tumor-suppressive roe of miR-425 and point towards its therapeutic potential in the management of cervical cancer.

scholarly journals The potential oncogenic and MLN4924-resistant effects of CSN5 on cervical cancer cells

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Huilin Zhang ◽  
Ping He ◽  
Qing Zhou ◽  
Yan Lu ◽  
Bingjian Lu
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cervical Cancer Cell ◽  
Cervical Cancers ◽  
Cervical Cancer Cells

Abstract Background CSN5, a member of Cop9 signalosome, is essential for protein neddylation. It has been supposed to serve as an oncogene in some cancers. However, the role of CSN5 has not been investigated in cervical cancer yet. Methods Data from TCGA cohorts and GEO dataset was analyzed to examine the expression profile of CSN5 and clinical relevance in cervical cancers. The role of CSN5 on cervical cancer cell proliferation was investigated in cervical cancer cell lines, Siha and Hela, through CSN5 knockdown via CRISPR–CAS9. Western blot was used to detect the effect of CSN5 knockdown and overexpression. The biological behaviors were analyzed by CCK8, clone formation assay, 3-D spheroid generation assay and cell cycle assay. Besides, the role CSN5 knockdown in vivo was evaluated by xenograft tumor model. MLN4924 was given in Siha and Hela with CSN5 overexpression. Results We found that downregulation of CSN5 in Siha and Hela cells inhibited cell proliferation in vitro and in vivo, and the inhibitory effects were largely rescued by CSN5 overexpression. Moreover, deletion of CSN5 caused cell cycle arrest rather than inducing apoptosis. Importantly, CSN5 overexpression confers resistance to the anti-cancer effects of MLN4924 (pevonedistat) in cervical cancer cells. Conclusions Our findings demonstrated that CSN5 functions as an oncogene in cervical cancers and may serve as a potential indicator for predicting the effects of MLN4924 treatment in the future.

scholarly journals TM7SF2 regulates cell proliferation and apoptosis by activation of C-Raf/ERK pathway in cervical cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yichi Xu ◽  
Xin Chen ◽  
Shuya Pan ◽  
Zhi-wei Wang ◽  
Xueqiong Zhu
Keyword(s):  
Cervical Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Cholesterol Metabolism ◽  
Vital Role ◽  
Erk Pathway ◽  
Tumorigenesis And Progression ◽  
Cervical Cancer Cells ◽  
Cancer Tissues

AbstractTransmembrane 7 superfamily member 2 (TM7SF2) coding an enzyme involved in cholesterol metabolism has been found to be differentially expressed in kinds of tissues. Nevertheless, the role of TM7SF2 in the regulation of growth and progression among various cancers is unclear. In this study, the immunohistochemistry (IHC) assay, real-time RT-PCR and western blotting analysis were used to determine the TM7SF2 expression in cervical cancer tissues. Next, we used multiple methods to determine the ability of cell proliferation, migration, invasion, apoptosis, and cell cycle in cervical cancer cells after TM7SF2 modulation, such as CCK8 assay, colony formation assay, Transwell assay, wound healing assay, and flow cytometry. Our results revealed that upregulation of TM7SF2 facilitated cell proliferation and metastasis, suppressed cell apoptosis and prevented G0/G1 phase arrests in C33A and SiHa cells. Consistently, the opposite effects were observed after TM7SF2 knockout in cervical cancer cells. Further, we found that TM7SF2 participated in promoting tumorigenesis and progression via activation of C-Raf/ERK pathway in cervical cancer, which can be partly reversed by Raf inhibitor LY3009120. Moreover, TM7SF2 overexpression contributed to enhancement of xenograft tumor growth in vivo. Our findings indicated that TM7SF2 plays a vital role in tumor promotion by involving in C-Raf/ERK activation. Therefore, TM7SF2 could serve as a therapeutic target in future cervical cancer treatment.

scholarly journals YTHDF1 Aggravates the Progression of Cervical Cancer Through m6A-Mediated Up-Regulation of RANBP2

2021 ◽  
Vol 11 ◽  
Author(s):  
Haocheng Wang ◽  
Qingya Luo ◽  
Jianyi Kang ◽  
Qinglv Wei ◽  
Yu Yang ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
The Poor ◽  
Cervical Cancer Cells ◽  
On Line ◽  
Induced Apoptosis

N6-methyladenosine (m6A) is the most common post-transcriptional modification of RNA in eukaryotes, which has been demonstrated to play important roles in various cancers. YTHDF1 acts as a crucial m6A “reader” and regulates the fate of m6A modified mRNA. However, its role in cervical cancer remains unknown. In this study, we showed that YTHDF1 was highly expressed in cervical cancer, and was closely associated with the poor prognosis of cervical cancer patients. YTHDF1 knockdown suppressed the growth, migration and invasion, and induced apoptosis of cervical cancer cells. Moreover, YTHDF1 knockdown inhibited tumorigenesis of cervical cancer cells in vivo. Through combined on-line data analysis of RIP-seq, meRIP-seq and Ribo-seq upon YTHDF1 knockdown, RANBP2 was identified as the key target of YTHDF1 in cervical cancer cells. YTHDF1 regulated RANBP2 translation in an m6A-dependent manner without effect on its mRNA expression. RANBP2 potentiated the growth, migration and invasion of cervical cancer cells. Our study demonstrated the oncogenic role of YTHDF1 in cervical cancer by regulating RANBP2 expression and YTHDF1 represents a potential target for cervical cancer therapy.

scholarly journals microRNA-375 released from extracellular vesicles of bone marrow mesenchymal stem cells exerts anti-oncogenic effects against cervical cancer

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Feng Ding ◽  
Jinhua Liu ◽  
Xiaofei Zhang
Keyword(s):  
Cervical Cancer ◽  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Cervical Cancer Cells ◽  
Marrow Mesenchymal Stem Cells

Abstract Background Cervical cancer is the most prevalent gynecological malignancies accompanied by high mortality, where finding a more effective therapeutic option for cervical cancer is necessary. The inhibitory role of microRNAs (miRNAs) derived from the extracellular vesicles (EVs) of the bone marrow mesenchymal stem cells (BMSCs) was analyzed in cervical cancer. Methods Expression of miR-375 was examined by RT-qPCR in cervical cancer cell lines. The targeting relation between miR-375 and maternal embryonic leucine zipper kinase (MELK) was predicted by bioinformatics analysis and verified by dual-luciferase reporter gene assay. Isolated BMSCs were transfected with lentivirus-mediated vectors, followed by EV extraction. The morphology of EVs was then identified using a NanoSight particle size analyzer and transmission electron microscope (TEM). The biological properties of cervical cancer cells were evaluated using Transwell, EdU, and TUNEL assays, respectively. Xenograft tumors in nude mice were observed to assess cervical tumorigenesis in vivo. Results Low expression of miR-375 and high expression of MELK were detected in cervical cancer samples. MELK was identified as the target gene of miR-375, which was negatively correlated with miR-375 levels. Overexpression of miR-375 suppressed proliferation, migration, and invasion of cervical cancer cells, but enhanced cell apoptosis by cooperating with downregulated MELK expression. miR-375 transferred from BMSC-derived EVs exerted the same effects on cell biological activities. Xenograft assays in vivo proved that miR-375 from BMSC-derived EVs inhibited tumor growth. Conclusion The present study highlighted the role of miR-375 from BMSC-derived EVs in suppressing the progression of cervical cancer, which may contribute to the discovery of novel potential biomarkers for cervical cancer therapy.

scholarly journals miR-31 Functions as an Oncomir Which Promotes Epithelial-Mesenchymal Transition via Regulating BAP1 in Cervical Cancer

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Nan Wang ◽  
Yong Li ◽  
Jianhong Zhou
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Luciferase Reporter ◽  
Luciferase Reporter Gene ◽  
Mesenchymal Transition ◽  
Gene Assay ◽  
Cervical Cancer Cells

MicroRNA-31 (miR-31) functions as tumor suppressors or oncogenes that are involved in tumor behavior. However, the function of miR-31 in cervical carcinogenesis remains unclear. The aim of this study was to validate the potential role of miR-31 and BRCA1-associated protein-1 (BAP1) on regulating epithelial-mesenchymal transition (EMT) in cervical cancer. In the present study, qRT-PCR assay revealed that the expression of miR-31 was upregulated in human cervical cancer cells and clinical tissues. Results of wound healing and cell migration assay revealed that knockdown of miR-31 inhibited cell metastasis and migration. Bioinformatic and dual-luciferase reporter gene assay showed that BAP1 was the direct target of miR-31. Furthermore, the results revealed that miR-31 promoted proliferation and EMT in cervical cancer cells and accelerated the development of tumor growth in vivo xenograft experiment by inhibiting BAP1 expression. Overall, these results highlight an important role of miR-31 functioning as an oncomir which could promote EMT in cervical cancer via downregulating BAP1 expression. Thus, downregulation of miR-31 could be a novel approach for the molecular treatment of cervical cancers and other malignancies.

scholarly journals ER-α36 Promotes the Malignant Progression of Cervical Cancer Mediated by Estrogen via HMGA2

2021 ◽  
Vol 11 ◽  
Author(s):  
Chunyan Wang ◽  
Tianli Zhang ◽  
Kun Wang ◽  
Shuo Zhang ◽  
Qing Sun ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Poor Prognosis ◽  
High Mobility ◽  
High Expression ◽  
Cervical Cancer Cells

ObjectivesEstrogen is proven to promote the malignant behaviors of many cancers via its receptors. Estrogen receptor alfa 36 (ER-α36) is a newly identified isoform of estrogen receptor alfa (ER-α), the role of ER-α36 in regulating the effects of estrogen and its potential impact on human cervical cancer is poorly understood.MethodsImmunohistochemistry staining was used to evaluate the expression of ER-α36, estrogen receptor alfa 66 (ER-α66) and their prognostic values in cervical cancer. The effects of ER-α36 and ER-α66 on the proliferation and metastasis of cervical cancer were measured in vitro. A xenograft tumor assay was used to study the tumorigenesis role of ER-α36 in vivo. Furthermore, the functional gene at the downstream of ER-α36 was obtained via next-generation sequencing, and the biological functions of high mobility group A2 (HMGA2) in cervical cancer cells were investigated in vitro.ResultsER-α36 was over-expressed in cervical cancer tissues and elevated ER-α36 expression was associated with poor prognosis in cervical cancer patients. High expression of ER-α36 promoted the proliferation, invasion and metastasis of cervical cancer cells mediated by estrogen, while silencing ER-α36 had the opposite effects. Further research showed that HMGA2 was a downstream target of ER-α36 in cervical cancer cells. The oncogenic effect of ER-α36 was attenuated after HMGA2 knockdown.ConclusionsHigh expression of ER-α36 was correlated with a poor prognosis in cervical cancer by regulating HMGA2. ER-α36 could be a prognostic biomarker and a target for cervical cancer treatment.

scholarly journals MicroRNA-96-5p Facilitates the Viability, Migration, and Invasion and Suppresses the Apoptosis of Cervical Cancer Cells byNegatively Modulating SFRP4

2020 ◽  
Vol 19 ◽  
pp. 153303382093413 ◽  
Author(s):  
Huiling Zhang ◽  
Ruxin Chen ◽  
Jinyan Shao
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Clinical Stage ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Related Protein ◽  
Siha Cells ◽  
Gene Assay ◽  
Cervical Cancer Cells ◽  
Cancer Tissues

Purpose: The current study was intended to research the functional role and regulatory mechanism of microRNA-96-5p in the progression of cervical cancer. Methods: MicroRNA-96-5p expression in cervical cancer tissues was assessed by quantitative real-time polymerase chain reaction. The association between microRNA-96-5p expression and clinicopathological features of patients with cervical cancer was analyzed. MTT, flow cytometry, wound healing, and transwell assay were performed to evaluate the viability, apoptosis, migration, and invasion of Hela and SiHa cells. Targetscan, dual-luciferase reporter gene assay, and RNA pull-down analysis were constructed to evaluate the target relationship between microRNA-96-5p and secreted frizzled-related protein 4. Results: MicroRNA-96-5p was overexpressed in cervical cancer tissues, and microRNA-96-5p expression was markedly associated with the clinical stage and lymph node metastasis of patients with cervical cancer. Overexpressed microRNA-96-5p facilitated the viability, migration, invasion, and inhibited the apoptosis of Hela and SiHa cells, whereas suppression of microRNA-96-5p exerted the opposite trend. Secreted frizzled-related protein 4 was proved to be a target of microRNA-96-5p. Silencing of secreted frizzled-related protein 4 eliminated the anti-tumor effect of microRNA-96-5p on cervical cancer cells. Conclusions: MicroRNA-96-5p facilitated the viability, migration, and invasion and inhibited the apoptosis of cervical cancer cells via negatively regulating secreted frizzled-related protein 4.

scholarly journals Oncogenic lncRNA ZNF561-AS1 is essential for colorectal cancer proliferation and survival through regulation of miR-26a-3p/miR-128-5p-SRSF6 axis

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Zizhen Si ◽  
Lei Yu ◽  
Haoyu Jing ◽  
Lun Wu ◽  
Xidi Wang
Keyword(s):  
Colorectal Cancer ◽  
Rna Binding ◽  
Xenograft Model ◽  
Luciferase Reporter ◽  
Cancer Proliferation ◽  
Mouse Xenograft ◽  
Mouse Xenograft Model

Abstract Background Long non-coding RNAs (lncRNA) are reported to influence colorectal cancer (CRC) progression. Currently, the functions of the lncRNA ZNF561 antisense RNA 1 (ZNF561-AS1) in CRC are unknown. Methods ZNF561-AS1 and SRSF6 expression in CRC patient samples and CRC cell lines was evaluated through TCGA database analysis, western blot along with real-time PCR. SRSF6 expression in CRC cells was also examined upon ZNF561-AS1 depletion or overexpression. Interaction between miR-26a-3p, miR-128-5p, ZNF561-AS1, and SRSF6 was examined by dual luciferase reporter assay, as well as RNA binding protein immunoprecipitation (RIP) assay. Small interfering RNA (siRNA) mediated knockdown experiments were performed to assess the role of ZNF561-AS1 and SRSF6 in the proliferative actives and apoptosis rate of CRC cells. A mouse xenograft model was employed to assess tumor growth upon ZNF561-AS1 knockdown and SRSF6 rescue. Results We find that ZNF561-AS1 and SRSF6 were upregulated in CRC patient tissues. ZNF561-AS1 expression was reduced in tissues from treated CRC patients but upregulated in CRC tissues from relapsed patients. SRSF6 expression was suppressed and enhanced by ZNF561-AS1 depletion and overexpression, respectively. Mechanistically, ZNF561-AS1 regulated SRSF6 expression by sponging miR-26a-3p and miR-128-5p. ZNF561-AS1-miR-26a-3p/miR-128-5p-SRSF6 axis was required for CRC proliferation and survival. ZNF561-AS1 knockdown suppressed CRC cell proliferation and triggered apoptosis. ZNF561-AS1 depletion suppressed the growth of tumors in a model of a nude mouse xenograft. Similar observations were made upon SRSF6 depletion. SRSF6 overexpression reversed the inhibitory activities of ZNF561-AS1 in vivo, as well as in vitro. Conclusion In summary, we find that ZNF561-AS1 promotes CRC progression via the miR-26a-3p/miR-128-5p-SRSF6 axis. This study reveals new perspectives into the role of ZNF561-AS1 in CRC.

Paeonol triggers apoptosis in HeLa cervical cancer cells: the role of mitochondria-related caspase pathway

2021 ◽  
Author(s):  
Jikun Du ◽  
Daibo Song ◽  
Jinwen Li ◽  
Yuanhua Li ◽  
Baohong Li ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Caspase Pathway ◽  
Cervical Cancer Cells
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