CELLULAR SIGNALLING
·
2023
·
IF 4.8
Haiyan Zhao,Fangfang Bi,Mengyuan Li,Yuhan Diao,Chen Zhang
RING finger protein 180 (RNF180), an E3 ubiquitin ligase, is thought to be a tumor suppressor gene. However, the detailed mechanism of its effect on ovarian cancer (OV) has not been elucidated. Importin 4 (IPO4) which belongs to transport protein is reported to have cancer-promoting effects on OV. Here, we explored the potential signaling pathways related to RNF180 and IPO4. It was first verified that RNF180 is downregulated and IPO4 is upregulated in OV. By overexpressing or knocking down RNF180 in OV cells, we confirmed that RNF180 inhibited the malignant behaviors of OV cells both in vitro and in vivo . Bioinformatics analysis and proteomics experiments found that RNF180 could interact with IPO4 and promote the degradation of IPO4 through ubiquitination. In addition, overexpression of IPO4 removed the inhibitory effect of RNF180 on OV. We subsequently found that IPO4 could bind to the oncogene Sex determining Region Y-box 2 (SOX2). Knockdown of IPO4 in OV cells decreased SOX2 protein level in nucleus and promoted cyclin-dependent kinase inhibitory protein-1 (p21) expression. Overexpression of RNF180 also inhibited the expression of SOX2 in nucleus. All these results indicated that RNF180 inhibited the nuclear translocation of SOX2 by promoting ubiquitination of IPO4, which ultimately promoted the expression of p21 and then suppressed the progression of OV. This study verified the tumor suppressor effect of RNF180 on OV, elucidated the mechanism of the molecule network related to RNF180 and IPO4 in OV and identified for OV.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
ACTA HISTOCHEMICA
·
2025
·
IF 2.4
Ting Wang,Ruoan Jiang,Xueling Tang,Yingsha Yao,Peiyue Jiang
Background Cervical cancer is a major health burden in females worldwide, available studies indicated that sex-determining region Y-box 2 (SOX2) is closely related to the malignant phenotypes of multiple cancers including cervical cancer. However, the underlying mechanisms were blurred. Experimental Procedures A bioinformatics analysis was conducted to investigate the clinical correlation between SOX2 and cervical cancer. Transient transfection and lentivirus infection were utilized to achieve overexpression and knockdown of SOX2, respectively. The role of SOX2 in cervical cancer was confirmed by transwell and colony-forming assays. Immunoblot, dual-luciferase reporter, chromatin immunoprecipitation (ChIP), and biochemical experiments were employed. In addition, the xenograft models and immunohistochemistry (IHC) experiments were performed to validate the findings in vivo . Results The expression of SOX2 was significantly positively associated with the cell migration, invasion, and colony-forming abilities of cervical cancer cells. The following immunoblots revealed that the SOX2-induced malignant phenotypes might be related to the glycolysis process, since overexpressing SOX2 significantly promoted the hexokinase 2 (HK2) and glucose transporter-1 (GLUT1) expression, and increased the content of glucose and lactic acid. The further dual-luciferase reporter and ChIP experiments confirmed a binding relationship between SOX2 and HK2 promoter. More importantly, overexpressing SOX2 promoted tumor growth concomitant with a hyper-expression of HK2 and GLUT1 in xenograft tumor tissues, yet the treatment of glycolysis inhibitor significantly reversed those outcomes. Conclusion SOX2 promotes the malignant progression of cervical cancer by facilitating glycolysis.
研究领域:
肿瘤学
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分子生物学
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癌症遗传学
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产品关联
DOI
PubMed
高影响因子
Molecular Genetics & Genomic Medicine
·
2020
·Vol. 8
·期 5
·e1195
·
IF 1.995
Fei Cui,Zhe-xue Hao,Jin Li,Ya-lei Zhang,Xu-kai Li,Jian-xing He
Background This study is aimed to unravel the genetic factors associated with microRNA (miRNA) expression in regulating sex-determining region Y-box 2 ( SOX2 )-mediated cisplatin resistance in small-cell lung cancer (SCLC). Methods The relevance of SOX2 expression in SCLC was analyzed in a panel of SCLC cells by quantitative real-time PCR (qPCR) and western blot (WB). We selected DMS114 cell line, in which SOX2 was amplified via lentiviral vector-mediated transfection of the SOX2 genes and tested for the half-maximal inhibitory concentration (IC 50 ) by MTS assay. High-throughput sequencing and screening of differentially expressed miRNAs between SOX2 -overexpressing and normal control cells were performed. Finally, miRanda software was used to verify the miRNAs bound with SOX2 and qPCR was used to identify the expression of miRNAs which were binding with SOX2 . Results Cisplatin-resistant SOX2 -overexpressing DMS114 cell lines were successfully developed, showing a statistically significant increase in SOX2 expression by qPCR and WB. Our results showed a typically higher IC 50 value in SOX2 -overexpressing cells compared with the negative controls. The high-throughput sequencing analysis revealed that 68 miRNAs were upregulated and 24 miRNAs were downregulated in the SOX2 -overexpressing cells. The 24 downregulated miRNAs were further verified. Of them, a cancer-related miRNA, hsa-miR-340-5p, showed a higher binding affinity with SOX2 in network regulation mapping, which was also found to be markedly downregulated under qPCR analysis. Conclusion We demonstrated that downregulated expression of hsa-miR-340-5p may affect cisplatin resistance by mediating SOX2 expression in SCLC cells, which may provide a potential target for the therapy of chemoresistant SCLCs.
研究领域:
肿瘤学
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分子生物学
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医学遗传学
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DOI
PubMed
高影响因子
Frontiers in Cell and Developmental Biology
·
2021
·
IF 6.684
Yang Juan,Peng Shuping,Zhang Keqiang
Background: Ovarian cancer (OC)is a deadly gynecological malignancy worldwide. It is urgent to identify diagnostic biomarkers of OC to disclose the underlying mechanism.Methods and Materials: Bioinformatics analysis was used to identify target genes. Gene expression was detected and altered by qRT-PCR and cell transfection, respectively. The interaction between RP11-499E18.1 and PAK2, as well as that between PAK2 and SOX2, was determined using RNA pulldown, RNA immunoprecipitation (RIP), and co-immunoprecipitation (co-IP) assay, respectively. Localizations of RP11-499E18.1, PAK2, and SOX2 were respectively determined employing immunohistochemical (IHC), IF, and FISH. The regulatory effects of RP11-499E18.1, PAK2, and SOX2 on OC cell proliferation, migration, colony formation, epithelial–mesenchymal transition (EMT)-related factor expression, and SOX2 nuclear translocation were determined. Finally, the effects of RP11-499E18.1 and PAK2 expression on the tumor growth in nude mice were determined.Results: RP11-499E18.1, PAK2, and SOX2 were selected in our study. RP11-499E18.1 was downregulated, while PAK2 and SOX2 was upregulated in OC tissues and cells. RP11-499E18.1 coexists in the nucleus and cytoplasm of OC cells. There is an interaction between RP11-499E18.1 and PAK2, as well as PAK2 and SOX2 in OC cells. Alteration of RP11-499E18.1 and PAK2 expression both had no influence on PAK2 and SOX2 levels, but PAK2 upregulation notably augmented p-SOX2 level. RP11-499E18.1 overexpression suppressed OC cell proliferation, migration, and colony formation, as well as SOX2 nuclear translocation. Besides, it inhibited tumor growth in nude mice. However, these effects were notably reversed by PAK2 upregulation and eventually offset by SOX2 knockdown. Additionally, RP11-499E18.1 overexpression reduced PAK2–SOX2 interaction and SOX phosphorylation, and increased the binding of RP11-499E18.1 by PAK2.Conclusion: These lines of evidence demonstrated that RP11-499E18.1 might play its tumor suppressor roles in OC via regulation of the RP11-499E18.1–PAK2–SOX2 axis. This research indicated that RP11-499E18.1 might be used as a diagnostic biomarker for OC in the future.
研究领域:
肿瘤学
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分子生物学
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癌症生物学
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产品关联
DOI
PubMed
高影响因子
IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL
·
2022
·Vol. 59
·期 1
·1-9
·
IF 2.723
Chen Sunyu,Xiao Zhanhao,Jiang Wenjin
Osteogenic differentiation is a crucial process of new bone formation. This study aimed to explore the roles and mechanism of SRY-Box Transcription Factor 2 (SOX2) on proliferation and osteogenic differentiation of MC3T3-E1 cells. Bone morphogenetic protein 2 (BMP2) was used to induce the osteogenic differentiation of MC3T3-E1 cells. The expression of SOX2 was determined by quantitative real-time PCR (RT-PCR) at different time points after induction. The SOX2 overexpression plasmids were constructed and transfected into MC3T3-E1 cells. Osteogenic differentiation was evaluated by Alizarin Red S staining and alkaline phosphatase (ALP) assay. The expressions of osteogenic differentiation markers including runt-related transcription factor 2 (Runx2), osteopontin (OPN), and osteocalcin (OCN) were detected by western blot assay. Luciferase reporter and CHIP assays were used to confirm that SOX2 regulated the transcriptional activation of leucine-rich repeat-containing G protein–coupled receptor 4 (LGR4). We found that SOX2 was down-regulated upon BMP2-induced osteogenic differentiation in MC3T3-E1 cells. Overexpression of SOX2 effectively inhibited osteogenic differentiation with decreased ALP activity, calcification, and osteogenic differentiation markers’ expression including Runx2, OPN, and OCN. LGR4 was identified as a target of SOX2, and the inhibitory effect of SOX2 on osteogenic differentiation was reversed by knockdown of LGR4. The present study confirmed that SOX2 suppressed osteogenic differentiation of MC3T3-E1 cells through targeting LGR4, which possesses a therapeutic strategy for bone formation and generation.
研究领域:
分子生物学
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细胞生物学
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骨骼生物学
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转录调控
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF VIROLOGY
·
2018
·Vol. 92
·期 17
·
IF 4.368
Cong-Cong Wu,Xuan Jiang,Xian-Zhang Wang,Xi-Juan Liu,Xiao-Jun Li,Bo Yang,Han-Qing Ye,Thomas Harwardt,Man Jiang,Hui-Min Xia,Wei Wang,William J. Britt,Christina Paulus,Michael Nevels,Min-Hua Luo
The mechanisms underlying neurodevelopmental damage caused by virus infections remain poorly defined. Congenital human cytomegalovirus (HCMV) infection is the leading cause of fetal brain development disorders. Previous work has linked HCMV infection to perturbations of neural cell fate, including premature differentiation of neural progenitor cells (NPCs). Here, we show that HCMV infection of NPCs results in loss of the SOX2 protein, a key pluripotency-associated transcription factor. SOX2 depletion maps to the HCMV major immediate early (IE) transcription unit and is individually mediated by the IE1 and IE2 proteins. IE1 causes SOX2 downregulation by promoting the nuclear accumulation and inhibiting the phosphorylation of STAT3, a transcriptional activator of SOX2 expression. Deranged signaling resulting in depletion of a critical stem cell protein is an unanticipated mechanism by which the viral major IE proteins may contribute to brain development disorders caused by congenital HCMV infection.IMPORTANCE Human cytomegalovirus (HCMV) infections are a leading cause of brain damage, hearing loss, and other neurological disabilities in children. We report that the HCMV proteins known as IE1 and IE2 target expression of human SOX2, a central pluripotency-associated transcription factor that governs neural progenitor cell (NPC) fate and is required for normal brain development. Both during HCMV infection and when expressed alone, IE1 causes the loss of SOX2 from NPCs. IE1 mediates SOX2 depletion by targeting STAT3, a critical upstream regulator of SOX2 expression. Our findings reveal an unanticipated mechanism by which a common virus may cause damage to the developing nervous system and suggest novel targets for medical intervention.
研究领域:
病毒学
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神经科学
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发育生物学
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细胞生物学
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DOI
PubMed
高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
·
2019
·Vol. 38
·期 1
·1-15
·
IF 5.646
Li Zizhuo,Chen Yaodong,An Tingting,Liu Pengfei,Zhu Jiyuan,Yang Haichao,Zhang Wei,Dong Tianxiu,Jiang Jian,Zhang Yu,Jiang Maitao,Yang Xiuhua
Background Nuciferine (NF), extracted from the leaves of N. nucifera Gaertn, has been shown to exhibit anti-tumor and anti-viral pharmacological properties. It can also penetrate the blood brain barrier (BBB). However, the mechanism by which NF inhibits glioblastoma (GBM) progression is not well understood. We aimed to determine the anti-tumor effect of NF on GBM cell lines and clarify the potential molecular mechanism involved.Methods U87MG and U251 cell lines were used in vitro to assess the anti-tumor efficacy of NF. Cytotoxicity, viability, and proliferation were evaluated by MTT and colony formation assay. After Annexin V-FITC and PI staining, flow cytometry was performed to evaluate apoptosis and cell cycle changes in NF-treated GBM cells. Wound healing and Transwell assays were used to assess migration and invasion of GBM cells. Western blot analysis, immunofluorescence staining, immunohistochemistry, and bioinformatics were used to gain insights into the molecular mechanisms. Preclinical therapeutic efficacy was mainly estimated by ultrasound and MRI in xenograft nude mouse models.Results NF inhibited the proliferation, mobility, stemness, angiogenesis, and epithelial-to-mesenchymal transition (EMT) of GBM cells. Additionally, NF induced apoptosis and G2 cell cycle arrest. Slug expression was also decreased by NF via the AKT and STAT3 signaling pathways. Interestingly, we discovered that NF affected GBM cells partly by targeting SOX2, which may be upstream of the AKT and STAT3 pathways. Finally, NF led to significant tumor control in GBM xenograft models.Conclusion sNF inhibited the progression of GBM via the SOX2-AKT/STAT3-Slug signaling pathway. SOX2-targeting with NF may offer a novel therapeutic approach for GBM treatment.
研究领域:
肿瘤学
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药理学
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神经科学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
CANCER LETTERS
·
2023
·
IF 9.7
Jiaoshun Chen,Haoxiang Zhang,Chaoyang Xiu,Chenggang Gao,Shihong Wu,Jianwei Bai,Qiang Shen,Tao Yin
In eukaryotes, N 6 -methyladenosine (m6A) is the most prevalent epigenetic alteration. Methyltransferase-like 3 (METTL3) is a key player in the control of m6A, although its function in pancreatic cancer is incompletely understood. In this study, we examined the role that METTL3 plays in pancreatic cancer cell proliferation and stemness. We discovered that in pancreatic cancer cells, METTL3-mediated m6A alterations regulate ID2 as a downstream target. The stability of ID2 mRNA was decreased and m6A modification was effectively eliminated by METTL3 knockdown in pancreatic cancer cells. We also demonstrate that m6a-YTHDF2 is necessary for the METTL3-mediated stabilization of ID2 mRNA. Additionally, we show that ID2 controls the stemness molecules NANOG and SOX2 via the PI3K-AKT pathway to support pancreatic cancer growth and stemness maintenance. Our data suggest that METTL3 may post-transcriptionally upregulate ID2 expression in an m6A-YTHDF2-dependent manner to further promote the stabilization of ID2 mRNA, which may be a new target for pancreatic cancer treatment.
研究领域:
癌症生物学
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分子生物学
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
2024
·Vol. 15
·期 11
·1-12
·
IF 8.1
Zhang Jin,Maimaiti Aynuer,Chang Xihan,Sun Pengcheng,Chang Xiaohan
Cervical cancer is a leading cause of cancer-related death among women and its recurrence and metastasis poses challenges to treatment. Discoidin domain receptor 1 (DDR1) was associated with cellular migration and invasion in several types of cancers. However, its function in cervical cancer is still unclear. In this study, we found that DDR1 was significantly more expressed in cervical cancer samples than in normal tissues. SRY-Box transcription factor 2 (SOX2), a known oncogene in cervical cancer, showed a positive correlation with DDR1 and regulated DDR1 transcription, contributing to the elevated expression of DDR1 in cervical cancer. Regarding the function of DDR1 in cervical cancer, the overexpression of DDR1 caused an increase in the migration, invasion, and epithelial-mesenchymal transition (EMT) of cervical cancer cells. In contrast, cervical cancer cells with reduced DDR1 expression exhibited a lower migration rate, fewer invasive cells, and decreased levels of EMT markers. In vivo, mice injected with cervical cancer cells with overexpressed DDR1 showed more pulmonary metastasis and nodule number. Opposite results were found in mice injected with DDR1 silenced cervical cancer cells. Since DDR1 can cause phosphorylation of downstream targets, a phosphorylation omics was employed to reveal the downstream targets of DDR1, including eukaryotic translation initiation factor 4E binding protein 1 and EPH receptor A2. Furthermore, DDR1 bound directly with Src homology 2 domain of growth factor receptor bound protein 2 (GRB2) which mediated the function of DDR1 in the malignant behaviors of cervical cancer and the phosphorylation of downstream targets. In conclusion, DDR1 binds directly to GRB2 and then affects downstream phosphorylation signals, ultimately exacerbating the metastasis of cervical cancer cells. This work sheds light on the mechanism by which DDR1 functions in cervical cancer cells, providing therapeutic strategy for the treatment of cervical cancer.
研究领域:
肿瘤学
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分子生物学
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癌症生物学
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产品关联
DOI
PubMed
高影响因子
PHARMACOLOGICAL RESEARCH
·
2021
·
IF 7.658
Jinzhu Zhao,Leilei Li,Zhijia Wang,Linlin Li,Mingjing He,Shuhua Han,Yalong Dong,Xiaojie Liu,Wen Zhao,Yu Ke,Cong Wang
Cancer drug resistance is a formidable obstacle that enhances cancer stem-like cell properties, tumour metastasis and relapse. Luteolin (Lut) is a natural flavonoid with strong antitumor effects. However, the underlying mechanism(s) by which Lut protects against paclitaxel-resistant (PTX-resistant) cancer cell remains unknown. Herein, we found that Lut significantly attenuated the stem-like properties of PTX-resistant cancer cells by downregulating the expression of SOX2 protein. Additionally, further study showed that Lut could inhibit the PI3K/AKT pathway to decrease the phosphorylation level of AKT(S473) and UBR5 expression, which is an ubiquitin E3 ligase that promotes SOX2 degradation. In addition, Lut also inhibited PTX-resistant cancer cell migration and invasion by blocking epithelial-mesenchymal transition (EMT) . Importantly, Lut inhibited the tumorigenic ability of oesophageal PTX-resistant cancer cells and showed no obvious toxicity in vivo. Thus, Lut has potential as a promising agent for drug-resistant oesophageal cancer therapy.
研究领域:
癌症生物学
·
药理学
·
分子生物学
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DOI
PubMed
高影响因子
ENVIRONMENTAL SCIENCE & TECHNOLOGY
·
2021
·
IF 9.028
Tingting Ku,Fang Hao,Xiaoxi Yang,Ziyu Rao,Qian S. Liu,Nan Sang,Francesco Faiola,Qunfang Zhou,Guibin Jiang
The tremendous potential for graphene quantum dots (GQDs) in biomedical applications has led to growing concerns of their health risks in human beings. However, present studies mainly focused on oxidative stress, apoptosis, and other general toxicity effects; the knowledge on the developmental toxicity and the related regulatory mechanisms is still far from sufficient. Our study revealed the development retardation of mouse embryonic stem cells (mESCs) caused by GQDs with a novel DNA methylation epigenetic mechanism. Specifically, GQDs were internalized into cells mainly via energy-dependent endocytosis, and a significant fraction of internalized GQDs remained in the cells even after a 48-h clearance period. Albeit with unobservable cytotoxicity or any influences on cell pluripotency, significant retardation was found in the in vitro differentiation of the mESCs into embryoid bodies (EBs) with the upregulation of Sox2 levels in GQD pretreatment groups. Importantly, this effect could be contributed by GQD-induced inhibition in CpG methylation of Sox2 through altering methyltransferase and demethyltransferase transcriptional expressions, and the demethyltransferase inhibitor, bobcat339 hydrochloride, reduced GQD-induced upregulation of Sox2. The current study first demonstrated that GQDs compromised the differentiation program of the mESCs, potentially causing development retardation. Exposure to this nanomaterial during gestation or early developmental period would cause adverse health risks and is worthy of more attention.
研究领域:
纳米技术
·
干细胞生物学
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表观遗传学
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毒理学
✓ 已验证
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2022
·
IF 8.101
Jin Li,Zi-Hui Wang,Ya-Min Dang,Dan-Ni Li,Zhen Liu,Da-Peng Dai,Jian-Ping Cai
MTH1 protein can sanitize the damaged (d)NTP pool and MTH1 inhibitors have been developed to impede the growth of rapidly proliferating tumor cells; however, the effect of MTH1 inhibition on breast cancer stemness has not been reported yet. Here, we constructed breast cancer cell lines with the stable depletion of MTH1. MTH1 suppression clearly increased the ratio of CD44 + CD24 −/low subpopulations and promoted the formation of tumorspheres in MCF7 and T47D cells. RNA expression profiling, RT–qPCR and Western blotting showed the upregulation of master stem cell transcription factors Sox2 , Oct4 and Nanog in MTH1 knockdown cells. GSEA suggested and Western blotting verified that MTH1 knockdown increased the expression of phosphorylated STAT3 (Tyr705). Furthermore, we indirectly demonstrated that the increased concentration of 8-oxo-dGTP and 8-oxo-GTP in MTH1 -knockdown cells and exogenous 8-oxoGTP, rather than 8-oxo-dGTP, could significantly increase the phosphorylation of STAT3. In conclusion, this work indicates that MTH1 inhibition increased the proportion of breast cancer stem cells (BCSCs) and promoted stemness properties in MCF7 cells.
研究领域:
肿瘤学
·
分子生物学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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