CELLULAR AND MOLECULAR LIFE SCIENCES
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2025
·Vol. 82
·期 1
·1-20
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IF 6.2
Lu Lingjia,Wang Fenfen,Wang Ting,Xing Ziyu,Jiang Peiyue
Cervical cancer is a common cancer among women worldwide. It has been revealed that hypoxia contributes to the progression of cervical cancer. In our study, we discovered that hypoxia indeed promoted the malignant phenotypes of cervical cancer cells by enhancing glycolysis. Loss-of-function experiments showed that hypoxia treatment upregulated the octamer-binding transcriptional factor 4 (OCT4) expression via glycolysis. Through the RNA-sequence and enrichment analyses, we found that hypoxia induced the enrichment of the calcium signaling pathway and upregulation of Calcium Release-Activated Calcium Modulator 3 (ORAI3), which could be abrogated by silencing OCT4. Notably, overexpressing ORAI3 has similar effects on the malignant phenotypes of HeLa and SiHa cells as those of hypoxia. Furthermore, silencing ORAI3 or inactivating calcium signals significantly reversed OCT4-induced malignant progression of cervical cancer both in vitro and in vivo. ChIP and dual-luciferase reporter results confirmed that OCT4 contributed to the transcription of ORAI3. Mechanically, hypoxia upregulated OCT4 expression by facilitating glycolysis, and OCT4 overexpression enhanced the transcription of ORAI3, activating the calcium signaling pathway and ultimately promoting the malignant progression of cervical cancer. Our study reveals novel molecular mechanisms by which hypoxia induces the progression of cervical cancer, providing a new strategy for treating cervical cancer.
研究领域:
肿瘤学
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分子生物学
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细胞信号转导
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癌症代谢
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转录调控
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Biology Direct
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2026
·Vol. 21
·期 1
·151
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IF 5.5
Dai Mugen,Wang Jianbo,Xu Qing,Shao Yixiu,Wang Han,Wu Xiaomeng,Pan Jundi,Ye Bin
Background Gastric cancer (GC) is one of the most lethal malignancies worldwide, and hepatic metastasis is a major cause of its poor clinical prognosis. The stemness regulator octamer-binding transcription factor 4 (OCT4) drives the migration, invasion and metastasis of GC cells. As a RING-type E3 ubiquitin ligase, Checkpoint with Forkhead-associated and RING finger domains (CHFR) has been identified as a key promoter of metastasis in advanced GC. However, the precise molecular mechanisms underlying CHFR-mediated modulation of GC metastasis remain unclear. Results This study systematically explored the biological functions and molecular mechanism of CHFR in GC via public data analysis, in vitro cell experiments and in vivo hepatic metastasis models. Functional assays revealed that CHFR overexpression enhanced the stemness and metastatic capacity of GC cells but inhibited cell proliferation. Mechanistically, CHFR stabilized OCT4 protein by blocking itchy E3 ubiquitin-protein ligase (ITCH)-mediated ubiquitination and proteasomal degradation of OCT4. Molecular docking predicted a direct interaction between CHFR and ITCH, and site mutation studies showed that their binding interface was essential for CHFR-induced OCT4 stabilization. DynaMut2 and FoldX mutagenesis confirmed Tyr530 (CHFR) and Thr222 (ITCH) as critical interfacial residues, whose alanine substitution weakened complex binding. Biochemical Co-IP ubiquitination assays verified CHFR targets ITCH for proteasomal degradation to suppress ITCH-dependent OCT4 breakdown. OCT4 knockdown rescue experiments further validated OCT4 as the essential downstream mediator of CHFR-induced glycolytic reprogramming, stemness and invasion in GC cells. Importantly, in vivo xenograft assays demonstrated that CHFR overexpression significantly promoted GC liver metastasis, whereas simultaneous overexpression of CHFR and ITCH reversed this metastatic phenotype. Conclusion CHFR enhances the stemness and metastatic progression of advanced GC cells by antagonizing ITCH-dependent OCT4 degradation, highlighting the CHFR/ITCH/OCT4 axis as a therapeutic target for GC treatment.
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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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PubMed
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ENVIRONMENTAL HEALTH PERSPECTIVES
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2023
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IF 10.4
Chenke Xu,Chenhao Zhang,Yanan Liu,Haojia Ma,Feifan Wu,Yingting Jia,Jianying Hu
Background: Amniogenesis is a key event in biochemical pregnancy, and its failure may result in human embryonic death. However, whether and how environmental chemicals affect amniogenesis remain largely unknown. Objectives: The objective of the present study was to screen chemicals that may disrupt amniogenesis in an amniotic sac embryoid model and to investigate the potential mechanism of amniogenesis failure, with a focus on organophosphate flame retardants (OPFRs). Methods: This study developed a high-throughput toxicity screening assay based on transcriptional activity of octamer-binding transcription factor 4 ( Oct4 ). For the two positive OPFR hits with the strongest inhibitory activity, we used time-lapse and phase-contrast imaging to assess their effects on amniogenesis. Associated pathways were explored by RNA-sequencing and western blotting, and potential binding target protein was identified through a competitive binding experiment. Results: Eight positive hits exhibiting Oct4 expression were identified, with 2-ethylhexyl-diphenyl phosphate (EHDPP) and isodecyl diphenyl phosphate (IDDPP) showing the strongest inhibitory activity. EHDPP and IDDPP were found to disrupt the rosette-like structure of the amniotic sac or inhibit its development. Functional markers of squamous amniotic ectoderm and inner cell mass were also found disrupted in the EHDPP- and IDDPP-exposed embryoids. Mechanistically, embryoids exposed to each chemical exhibited abnormal accumulation of phosphorylated nonmuscle myosin (p-MLC-II) and were able to bind to integrin β 1 ( ITG β 1 ). Conclusion: The amniotic sac embryoid models suggested that OPFRs disrupted amniogenesis likely by inhibiting the ITG β 1 pathway, thus providing direct in vitro evidence associating OPFRs with biochemical miscarriage. https://doi.org/10.1289/EHP11958
研究领域:
发育生物学
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生殖毒理学
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分子生物学
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环境健康科学
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干细胞模型
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PubMed
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REPRODUCTIVE TOXICOLOGY
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2024
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IF 3.3
Hanwen Zhang,Yu Li,Na Li,Yilong Miao,Shaochen Sun,Ling Gu,Bo Xiong
Perfluorooctanoic acid (PFOA) exposure severely affects the health of animals and humans, including early embryonic development, but the effective approaches to improve the quality of embryos exposed to PFOA have not been explored. Here, we report that nicotinamide mononucleotide (NMN) can be used to attenuate the impairment of mouse early embryos caused by PFOA exposure. We find that NMN supplementation maintains the normal spindle assembly and proper chromosome alignment by restoring the acetylation level of microtubule to enhance the mitotic capacity of embryos at zygotic cleavage stage under PFOA exposure. In addition, NMN exerts its beneficial effect by enhancing mitochondrial function and eliminating accumulated reactive oxygen species (ROS), which in turn alleviates DNA damage and apoptosis in PFOA-exposed 2-cell embryos. Moreover, NMN ameliorates the quality of PFOA-exposed blastocysts via recovering the octamer-binding transcription factor 4 (Oct4) expression, the actin dynamics, and the total number of cells. Collectively, our findings demonstrate that supplementation with NMN is a feasible strategy to restore the compromised early embryonic development under PFOA exposure, providing a scientific basis for application of NMN to increase the female fertility.
研究领域:
生殖生物学
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毒理学
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发育生物学
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分子生物学
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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
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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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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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高影响因子
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