Cell Death & Disease
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2019
·Vol. 10
·期 11
·1-16
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IF 5.959
Tan Peng,Xu Yunke,Du Yichao,Wu Lile,Guo Bing,Huang Shiyao,Zhu Jinhui,Li Bo,Lin Fujun,Yao Lei
Speckle-type POZ domain protein (SPOP), an adaptor in the E3 ubiquitin ligase complex, recognizes substrates and promotes protein degradation via the ubiquitin-proteasome system. It appears to help regulate progression of several cancers, and we show here that it acts as a tumor suppressor in pancreatic cancer. Our analysis of patient tissues showed decreased SPOP expression, which was associated with poor prognosis. SPOP knockdown in SW1990 (in vitro/vivo) and PANC-1 (in vitro) cells led to significantly greater proliferation, migration, and invasion. Co-immunoprecipitation experiments in SW1990 cells showed that SPOP interacted with the stem-cell marker NANOG, and this interaction has recently been shown to play a critical role in regulating progression of prostate cancer. We showed that, in one patient with pancreatic cancer, the expression of a truncated form of SPOP (p.Q360*) lacking the nuclear localization signal led to nuclear accumulation of NANOG, which promoted growth and metastasis of pancreatic cancer cells. Our results suggest that SPOP suppresses progression of pancreatic cancer by promoting the ubiquitination and subsequent degradation of NANOG. These results identify the SPOP-NANOG interaction as a potential therapeutic target against pancreatic cancer.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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DOI
PubMed
高影响因子
CANCER LETTERS
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2023
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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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DOI
PubMed
高影响因子
Environment & Health
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2026
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IF 8.8
Yanyi Zhao,Hanyue Li,Renjun Yang,Nuoya Yin,Francesco Faiola
Humans are frequently exposed to diverse environmental pollutants that may pose potential risks during early embryonic development. Advances in stem cell toxicology have introduced new opportunities for environmental toxicity assessment, enabling the development of physiologically relevant models based on human induced pluripotent stem cells (iPSCs). However, current systems remain limited by low throughput and the inability to achieve real-time monitoring. In this study, we established a NANOG-EGFP iPSC reporter line by precisely inserting a T2A-EGFP cassette into the endogenous NANOG locus using CRISPR/Cas9, enabling dynamic and quantitative visualization of pluripotency status. Using this reporter system, we systematically evaluated the effects of 38 representative environmental pollutants spanning six major chemical categories, including bisphenols, per- and polyfluoroalkyl substances (PFAS), halogenated flame retardants, organophosphate esters, neonicotinoids, and phenolic compounds. Most pollutants induced varying degrees of reduction in NANOG-EGFP expression, suggesting perturbation of core transcriptional networks involved in pluripotency maintenance rather than nonspecific cytotoxic effects. Notably, bisphenol B (BPB), bisphenol Z (BPZ), perfluorobutanesulfonic acid (PFBS), tributyl phosphate (TnBP), tris(2-chloroethyl) phosphate (TCEP), and 3,5-di-tert-butyl-4-hydroxybenzoic acid (BHT-COOH) exhibited pronounced low-dose activity, causing significant suppression of NANOG-EGFP signals even at 10 nmol/L. Furthermore, during neuroectoderm differentiation, several bisphenols and PFAS delayed the normal downregulation of NANOG, indicating disruption of the tightly regulated timing of pluripotency exit and lineage transition during early developmental progression. Overall, the NANOG-EGFP iPSC reporter model provides a sensitive, stable, and practical platform for high-throughput screening of environmental toxicants and offers mechanistically informed insight into how pollutant exposure may interfere with early human developmental regulatory programs.
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DOI
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
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2022
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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
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分子生物学
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癌症研究
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DOI
PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
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2026
·Vol. 1870
·期 11
·130988
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IF 2.9
Jingxian Han,Lei Hua,Siqi Zhang,Bin Yang,Zhiying Li,Xiangguang Meng
Background Heart failure (HF) remains a leading cause of death worldwide. Stem cells represent a promising strategy for myocardial regeneration due to their differentiation potential and paracrine effects. This study investigated the effect of human pericardial fluid Sca-1 + /Nanog + cells Conditioned Medium (hPFCs-CM) on doxorubicin (DOX)-induced damage to AC16 cardiomyocytes using transcriptomic analysis. Methods Human AC16 cardiomyocytes were divided into Control (CON), DOX, DOXh, and hPFCs groups. Cell viability, cytotoxicity (LDH release), reactive oxygen species (ROS) levels, and apoptosis were assessed. Transcriptomic sequencing was performed on CON, DOX, and DOXh groups. MYH3 and IFI16 genes were knocked down using siRNA, followed by Western blot analysis of apoptosis. Results DOX significantly increased ROS and apoptosis compared with CON group ( P < 0.05), while hPFCs-CM attenuated these effects ( P < 0.05). RNA-seq identified 52 differentially expressed genes between DOX and DOXh groups (adj P < 0.05). Three target genes ( MYH3 , IFI16 , and KCTD14 ) were selected for RT-qPCR validation. Further functional assays revealed that MYH3 knockdown significantly potentiated the anti-apoptotic activity of hPFCs-CM ( P < 0.05), whereas IFI16 knockdown showed no significant effect. Conclusion hPFCs-CM effectively attenuated DOX-induced AC16 cardiomyocyte damage through MYH3, providing potential molecular targets for future mechanistic studies in myocardial injury treatment.
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高影响因子
Translational Lung Cancer Research
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2024
·Vol. 13
·期 10
·2698
·
IF 4
Ziying Zhao,Xiaoqing Feng,Huijuan Wu,Shuisheng Chen,Changsong Ma,Ziyun Guan,Luwen Lei,Kejing Tang,Xiao Chen,Yong Dong,Yubo Tang
Background Lung cancer is one of the most common malignant tumors worldwide. Despite advances in lung cancer treatment, patients still face challenges related to drug resistance and recurrence. Current methods for evaluating anti-cancer drug activity are insufficient, as they rely on two-dimensional (2D) cell culture and animal models. Therefore, the development of an in vitro drug evaluation model capable of predicting individual sensitivity to anti-cancer drugs would greatly enhance the success rate of drug treatments for lung cancer patients. The purpose of this research is to utilise conditional reprogramming technology to cultivate patient-derived lung cancer cells and to construct an in vitro 3D culture model using sodium alginate (SA) and gelatin. The aim is to study the biological characteristics of cells in the 3D culture model and to further investigate the sensitivity of anti-cancer drugs based on the alginate-gelatin 3D culture model. This approach provides new means and insights for personalized precision anti-cancer therapy and the development of new anti-cancer drugs. Methods Conditional reprogramming technology was used to generate conditionally reprogrammed lung adenocarcinoma cells (CRLCs). Alginate-gelatin hydrogel micro-beads were created to explore their potential use in the assessment of anti-cancer drugs. Cell proliferation was also examined using the MTS assay method. Live/dead staining was performed to estimate cell distribution and viability using calcein acetoxymethyl ester/propidium iodide (calcein-AM/PI) double staining. Protein expression was assessed by Western blot. Results The cells grown in the three-dimensional (3D) culture were in a state of continuous proliferation, and there was an obvious phenomenon of cell mass growth. The drug sensitivity assay results demonstrated that compared with the 2D-grown cells, the CRLCs grown in the alginate-gelatin hydrogel micro-beads exhibited more resistance to anti-cancer drugs. The results also showed that the 3D-cultured CRLCs showed greater protein expression levels of stem cell hallmarks, such as Nanog Homeobox (NANOG), SRY-Box Transcription Factor 2 (SOX-2), and aldehyde dehydrogenase 1 family member A1 (ALDH1A1), than the 2D-grown cells. Conclusions These findings suggest that the 3D hydrogel cell culture models more closely mimicked the in vivo biological and clinical behavior of cells, and demonstrated higher innate resistance to anti-cancer drugs than the 2D cell culture models, and thus could serve as valuable tools for diagnosis, drug screening, and personalized medicine.
研究领域:
肿瘤学
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药理学
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生物技术
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细胞生物学
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分子生物学
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PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
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2022
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IF 5.999
Yuhui Wang,Shilong Ma,Xuanyu Liu,Yan Wei,Haofeng Xu,Ziwei Liang,Yinchun Hu,Xiaojie Lian,Di Huang
Hepatocellular carcinoma (HCC) is one of the deadliest tumors in the world with a high rate of recurrence and metastasis. Therefore, the most pressing issue today is the development of new drugs, diagnostic and therapeutic approaches for effective cancer treatment. Cancer stem cells (CSCs) play a pivotal role in tumor recurrence, tumor resistance, and tumor metastasis, which provides a new perspective on the development of liver cancer. In the study, a high-temperature thermal breakdown approach was used to create composite magnetic nanocubes modified by polyethyleneimine (PEI) and hyaluronic acid (HA). The Fe 3 O 4 nanocubes can recognize HCC stem cells via receptor−ligand binding of HA and CD44 (HA receptor). While loading a small molecule LDN193189 inhibited the expression of stemness-related genes OCT4 and Nanog . More crucially, the Fe 3 O 4 nanocubes significantly suppressed HCC cell proliferation and migration by regulating the expression of epithelial-mesenchymal transition (EMT) process markers E-cadherin, Vimentin , and N-cadherin. Dual targeting using magnetic and receptor-mediated targeting improved the uptake of the drug delivery system. Our findings imply that the medication delivery method might be a potential therapeutic strategy for HCC.
研究领域:
癌症生物学
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纳米技术
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药学
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分子生物学
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PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2023
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IF 5.8
Mengyan Wang,Xiaowei Wang,Wenxia Zhao,Yang Li,Meilian Cai,Kexin Wang,Xiaoming Xi,Cong Zhao,Huimin Zhou,Rongguang Shao,Guimin Xia,Yefan Zhang,Wuli Zhao
Cancer stem cells (CSCs), a subpopulation of tumor cells with the features of self-renewal, tumor initiation, and insensitivity to common physical and chemical agents, are the key to cancer relapses , metastasis, and resistance. Accessible CSCs inhibitory strategies are primarily based on small molecule drugs, yet toxicity limits their application. Here, we report a liposome loaded with low toxicity and high effectiveness of miriplatin, lipo-miriplatin (LMPt) with high miriplatin loading, and robust stability, exhibiting a superior inhibitory effect on CSCs and non-CSCs. LMPt predominantly inhibits the survival of oxaliplatin-resistant (OXA-resistant) cells composed of CSCs. Furthermore, LMPt directly blocks stemness features of self-renewal, tumor initiation, unlimited proliferation, metastasis, and insensitivity. In mechanistic exploration, RNA sequencing (RNA-seq) revealed that LMPt downregulates the levels of pro-stemness proteins and that the β-catenin-mediated stemness pathway is enriched. Further research shows that either in adherent cells or 3D-spheres, the β-catenin-OCT4/NANOG axis, the vital pathway to maintain stemness, is depressed by LMPt. The consecutive activation of the β-catenin pathway induced by mutant β-catenin (S33Y) and OCT4/NANOG overexpression restores LMPt’s anti-CSCs effect, elucidating the key role of the β-catenin-OCT4/NANOG axis. Further studies revealed that the strengthened binding of β-catenin and β-TrCP initiates ubiquitination and degradation of β-catenin induced by LMPt. In addition, the Apc Min/+ transgenic mouse model, in which colon tumors are spontaneously formed, demonstrates LMPt’s potent anti-non-CSCs activity in vivo.
研究领域:
肿瘤学
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药理学
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分子生物学
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癌症研究
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DOI
PubMed
高影响因子
ANALYTICAL BIOCHEMISTRY
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2014
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IF 2.305
Deependra Tyagi,Javier Batista Perez,Amita Nand,Cheng Zhiqiang,Peizhe Wang,Jie Na,Jingsong Zhu
Surface plasmon resonance imaging (SPRi) has emerged as a versatile biosensor to detect a wide range of biomolecular interactions with divergent potential applications. However, the use of this advanced-level technology for stem cell lysate study is still not much explored. Cell lysates are significant biological analytes used for disease diagnostics and proteomic studies, but their complex nature limits their use as an analyte for SPRi biosensors. Here, we review the problems associated with the use of SPRi for stem cell lysate study and examine the role of surface chemistry, running buffer, and blocking solution in order to minimize nonspecific adsorption (NSA). We detect the expression of Oct4, Sox2, Nanog , Rex1 , and Lin28 biomarkers present in mouse embryonic stem cell (mESC) lysate against their corresponding antibodies immobilized on the sensor surface with reduced NSA. The current study shows that the conjunction of SPRi and microarray can be used as a label-free, high-throughput, and rapid technique for detection of biomarkers and their relative abundance in stem cell lysate study.
研究领域:
生物传感
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干细胞生物学
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蛋白质组学
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分析化学
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生物技术
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）