American Journal of Cancer Research
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2026
·Vol. 16
·期 3
·1115
·
IF 3.1
Nan Liu,Mingyue Zhao,Lei Xu,Yeting Cui,Yu Tian,Juan Li,Xiaoyu Hu,Tongcun Zhang,Haining Zhen,Yanyang Tu
Glioma is the most aggressive tumor of the central nervous system and is associated with poor prognosis, especially in patients with high-grade gliomas. In this study, we investigated the biological role of inhibitor of kappa B kinase interacting protein (IKBIP) in promoting the progression of glioma. Analysis of the TCGA and GTEx databases revealed that IKBIP is upregulated in both lower-grade gliomas (LGG) and glioblastomas (GBM) compared with normal brain tissues. Kaplan-Meier survival analysis demonstrated that IKBIP upregulation is associated with shorter overall survival (OS) and disease-specific survival (DSS) in patients with LGG. Pan-cancer analysis indicated that IKBIP is aberrantly expressed in various malignant tumors, including gliomas. IKBIP knockdown inhibited the proliferation of glioma cells both in vitro and in vivo . Additionally, IKBIP knockdown in U251 and U87 glioma cell lines significantly suppressed their invasive capacity. Furthermore, IKBIP knockdown resulted in decreased expression of proteins associated with Wnt/β-catenin/epithelial-mesenchymal transition (EMT) pathway, including β-catenin, ZEB1, ZEB2, N-cadherin, whereas the expression of E-cadherin was increased. Conversely, IKBIP overexpression reduced the level of phosphorylated β-catenin (p-β-catenin) while increasing the expression of total β-catenin in glioma cells. Furthermore, we identified that transcription factor SP1 (Specificity Protein 1), which is also upregulated in glioma tissues and cell lines and is associated with the malignant phenotype of glioma, can bind to the promoter region of IKBIP. Upregulation of SPI in glioma cells significantly increased the expression level of IKBIP, while inhibiting the phosphorylation of β-catenin. These findings collectively suggest that upregulation of IKBIP promotes the proliferation and invasive behaviors of glioma cells by activating the Wnt/β-catenin/EMT pathway. Overall, our findings suggest that SP1-IKBIP axis facilitates the proliferation and invasion of glioma through Wnt/β-catenin-associated EMT, and SP1-IKBIP axis may represent a promising target for the clinical diagnosis and treatment of glioma.
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TOXICOLOGY AND APPLIED PHARMACOLOGY
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2026
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IF 3.4
Zizheng Lu,Minxiao Lin
In this research, we mainly focus on the mechanism of histone deacetylase sirtuin 2 (SIRT2) affecting the growth and metastasis of tongue cancer using in vitro and in vivo experiments. Human tongue cancer cells SCC-25, SCC-9, CAL-27, CAL-33 and human oral epithelial cells were cultured for cell line selection. In vitro , SCC-25 cells were manipulated with pcDNA3.1-SIRT2, pcDNA3.1-FZD1, pcDNA3.1-NC, or/and Wnt/β-catenin pathway inhibitor (MSAB) or activator (SKL2001), while CAL-33 cells were treated with siRNA-SIRT2, siRNA-NC or MSAB. The levels of H3K27ac, β-catenin (nuclear, cytoplasmic and total protein), and Wnt1/3a/7a were detected using WB. Based on data from the ENCODE database, the enrichment level of H3K27ac in the FZD1 promoter region was examined by ChIP experiment. Finally, an orthotopic xenograft tumor model in nude mice was constructed for in vivo validation. Re -expression of SIRT2 impaired the proliferative, invasive, and migratory behaviors of tongue cancer cells, while strengthening their apoptosis. Furthermore, SIRT2 decreased H3K27 acetylation, resulting in increased cytoplasmic β-catenin and decreased expression of FZD1, Wnt1/3a/7a, and nuclear β-catenin. FZD1 overexpression or the Wnt/β-catenin pathway activation partially compromised the inhibitory impacts of SIRT2 on the aforementioned behaviors of human tongue cancer cells. The in vivo validation suggested that SIRT2 played a regulatory role in FZD1 expression and Wnt/β-catenin pathway, thereby hindering the growth and metastasis of the orthotopic tongue cancer xenograft model. SIRT2 inhibits the transcriptional expression of FZD1 through H3K27 deacetylation to block the Wnt/β-catenin pathway, consequently suppressing the growth and metastasis of tongue cancer.
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2026
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IF 6.7
Kangle Li,Hongjie Cui,Si Wang,Qianfu Gan,Qinghua Liu,Shuangbo Huang
Alterations in gut microbiota and its metabolites are associated with placental and fetal development. Although proline has been shown to enhance placental function and improve pregnancy outcomes, its interaction with the gut microbiota remains poorly understood. In this study, a gestational low-protein diet (LPD) leads to decreased fetal birth weight and impaired placental vascular development, as well as increased embryonic resorption rates; these effects are mitigated by dietary proline supplementation. Mechanistically, proline enhances the abundance of Akkermansia and the production of butyrate in the gut, thereby promoting placental angiogenesis by activating the placental Wnt/insulin-like growth factor 1 (Igf1) signaling pathway, ultimately alleviating fetal developmental impairment caused by LPD. Moreover, in an in vitro porcine vascular endothelial cell model under amino acid-restricted conditions, butyrate enhances angiogenesis by activating the Wnt/Igf1 signaling pathway. These findings reveal that targeting the dietary proline supply and gut microbiota may open new avenues for the prevention of intrauterine growth restriction.
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2023
·
IF 5.6
Runxiao Lv,Lili Du,Lunhao Bai
Osteoarthritis (OA) is a chronic joint disease characterized by the progressive degradation of articular cartilage. In this study, as determined by histological staining, the cartilage surface of the OA rats was damaged, defective and broken, and chondrocytes and proteoglycan were reduced. While moderate physical exercise showed protective effects on the cartilage. Besides, RNA-seq was performed to select a target protein and RNF125 (an E3 ubiquitin ligase) was decreased in the cartilage tissues of OA rats and increased after physiological exercise. However, the precise role of RNF125 in OA is still unknown. This work aimed to investigate the involvement and underlying mechanism of RNF125 in OA pathogenesis. Our results defined that adenovirus-mediated overexpression of RNF125 inhibited the degradation of extracellular matrix of chondrocytes induced by IL-1β, as revealed by increased chondrocyte viability, upregulated COL2A1 and ACAN levels, and downregulated MMP1, MMP13 and ADAMTS5 levels, which was abrogated by NR4A2 knockdown. In vivo, RNF125 relieved OA, manifested as reduced cartilage injury and increased chondrocytes. Mechanically, NFATC2 bound to the RNF125 promoter and directly regulated RNF125 transcription, as illustrated by luciferase reporter, Ch-IP and DNA pull-down assays. Furthermore, RNF125 overexpression inhibited the nuclear translocation of β-catenin, thus suppressing activation of the Wnt/β-catenin signaling pathway. Also, RNF125 as E3 ubiquitin ligase led to the ubiquitination and degradation of TRIM14 protein, and TRIM14 overexpression efficiently reversed the effects of RNF125 overexpression on OA progression. Totally, this study provides new insights into OA pathogenesis regulated by RNF125. RNF125 may be a novel biomarker for OA therapy.
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CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
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2023
·Vol. 50
·期 7
·561-572
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IF 2.9
Yawei He,Wanjing Chen,Liang Yu,Yanwei Liu,Yunsheng Cheng,Xianghua Li,Gang Yu
Aerobic glycolysis is critical for the energy metabolism of cancer cells. This study focuses on the regulation of forkhead box A2 (FOXA2) on pyruvate kinase M2 (PKM2) and their effects on the glycolytic activity and malignant phenotype of thyroid carcinoma (THCA) cells. By analysing four Gene Expression Omnibus datasets and querying bioinformatics systems, we obtained FOXA2 as a poorly expressed transcription factor in THCA. Later, we validated decreased mRNA and protein levels of FOXA2 in THCA cells by quantitative polymerase chain reaction and western blot assays. FOXA2 upregulation in THCA cells suppressed the glucose uptake and lactate production, and it reduced the extracellular acidification rate, but increased the oxygen consumption rate of cells. Meanwhile, the FOXA2 overexpression blocked the proliferation and mobility, and the tumourigenic activity of cancer cells. The chromatin immunoprecipitation and luciferase assays showed that FOXA2 bound to PKM2 promoter and suppressed the transcription of PKM2, which was highly expressed in THCA cells. Further upregulation of PKM2 elevated the β-catenin, c-Myc and cyclin D1 levels and restored the glycolytic activity as well as the malignant properties of cancer cells. Collectively, this work reveals that FOXA2 suppresses aerobic glycolysis and progression of THCA by blocking PKM2 transcription and inactivating the Wnt/β-catenin pathway.
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ONCOLOGY REPORTS
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2023
·Vol. 49
·期 3
·1-14
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IF 4.2
Sijia Han,Xueying Jin,Tianyu Hu,Feng Chi
Breast cancer remains the most common malignancy and the leading cause of cancer‑associated mortality in women worldwide. Lysosomal protein transmembrane 5 (LAPTM5), a lysosomal membrane protein, plays an important role in several human malignancies. However, the biological functions and mechanism of LAPTM5 in breast cancer remain unclear. In the present study, the potential tumor‑promoting effect of LAPTM5 was predicted by bioinformatics analysis. LAPTM5 was highly expressed in breast cancer clinical specimens. Moreover, in vitro studies demonstrated that cell proliferation, migration and invasion, as well as the process of epithelial‑mesenchymal transition (EMT) were promoted by LAPTM5 overexpression and were suppressed by LAPTM5 downregulation in vitro. The tumor‑promoting effects of LAPTM5 were also confirmed by xenograft tumor assay in vivo. It was found that the tumor‑promoting effects of LAPTM5 were partly dependent on the activation of the Wnt/β‑catenin signaling pathway. Furthermore, dual‑luciferase and chromatin immunoprecipitation assays verified that the transcription factor forkhead box protein 3 (FOXP3) directly bound to the promoter of LAPTM5 and negatively regulated its expression. Taken together, the present findings indicated that LAPTM5, negatively regulated by FOXP3, promoted the malignant phenotypes of breast cancer through activating the Wnt/β‑catenin signaling pathway.
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Journal of Orthopaedic Translation
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2022
·
IF 4.889
Feng-wei Zhang,Li-yang Peng,Chuan-Jian Shi,Jian-chi Li,Feng-xiang Pang,Wei-ming Fu,Xiao-hua Pan,Jin-fang Zhang
Background Osteosarcoma (OS) is a common type of malignant bone tumor in adolescents with high risk of metastasis. However, the clinical management still remains unsatisfactory. Traditional Chinese medicine (TCM) has been widely considered as an alternative treatment, and their extracts have proved to possess great potential for drug discovery. Baicalein (BA), the active pharmaceutical ingredient of rhizoma coptidis , was proved to have anti-tumor properties in OS, but the mechanism remains poorly understood. Methods The potential anti-cancer effects on cell growth, cell cycle, apoptosis and migration were examined in OS cells. Moreover, the lncRNA-Neighboring Enhancer of FOXA2 (lncRNA-NEF) and Wnt/β-catenin signaling were detected by qPCR and Western blotting assays. The in vivo effect of GA on tumor growth was investigated using a xenograft mice model. Results In the present study, BA was found to significantly suppress tumor growth in vitro and in vivo. And it was also found to inhibit the invasion and metastasis as well. As for the mechanism investigation, lncRNA-NEF was obviously upregulated by BA in OS cells, and thus induced the inactivation of Wnt/β-catenin signaling. Moreover, lncRNA-NEF knockdown partially reversed the BA-induced anti-cancer activities; and successfully compensated the suppressive effect on Wnt/β-catenin signaling. We therefore suggested that BA induced the inactivation of Wnt/β-catenin signaling through promoting lncRNA-NEF expression. Conclusions In conclude, our results demonstrated that BA suppressed tumor growth and metastasis in vitro and in vivo through an lncRNA-NEF driven Wnt/β-catenin regulatory axis, in which lncRNA-NEF was upregulated by BA, and thus induced the inactivation of Wnt/β-catenin signaling. The Translational potential of this article The findings derived from this study validates the anti-cancer activity of BA in OS and provides a novel underlying mechanism, which suggest that BA may be a potential candidate to develop the effective drug for OS patients.
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BONE
·
2022
·
IF 4.626
Senxin Cai,Yuchun Zou,Yong Zhao,Hanyu Lin,Dali Zheng,Linyu Xu,Youguang Lu
Aims Mechanical stress overload in the temporomandibular joint (TMJ) is an important cause of TMJ osteoarthritis (TMJOA). Whether secreted frizzled-related proteins (SFRPs) play important roles in the development of mechanical stress-induced TMJOA remains controversial. In this study, we investigated the roles of the Wnt/β-catenin signaling and SFRPs in the progression of mechanical stress-induced TMJOA. Methods We investigated the progression of mechanical stress-induced TMJOA using an in vivo model via modified increased occlusal vertical dimension (iOVD) malocclusion and an in vitro model in which isolated chondrocytes were subjected to mechanical stress. The effects of inhibition of Wnt/β-catenin signal on TMJOA induced by mechanical stress were studied by in vitro drug added and in vivo intra-articular injection of XAV-939. TMJOA progression, Wnt/β-catenin signaling and SFRPs was assessed by Cone beam computed tomography (CBCT) analysis, histochemical and immunohistochemical (IHC) staining, quantitative real-time PCR (qRT–PCR), Western blotting (WB), and immunofluorescence (IF) staining. Results Our in vivo results showed that iOVD-induced mechanical stress in the TMJ disrupted mandible growth, induced OA-like changes in TMJ cartilage, and increased OA-related cytokine expression. In addition, iOVD activated Wnt/β-catenin signaling and suppressed Sfrp1 , Sfrp3 , and Sfrp4 expression in condylar cartilage. Moreover, our in vitro study showed that stress disrupted homeostasis , activated Wnt/β-catenin signaling and inhibited SFRP3 and SFRP4 expression in chondrocytes. Suppression of Wnt/β-catenin signaling with XAV-939 promoted SFRP3 and SFRP4 expression and rescued mechanical stress-induced cartilage degeneration in vivo and in vitro. Conclusions Our work suggests that mechanical stress reduces SFRPs expression both in vivo and in vitro and promotes TMJOA via Wnt/β-catenin signaling. Suppression of Wnt/β-catenin signaling promotes SFRPs expression, especially SFRP3 and SFRP4 expression, and rescues mechanical stress-induced cartilage degeneration. Wnt/β-catenin signaling and SFRPs may represent potential therapeutic targets for TMJOA.
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EUROPEAN JOURNAL OF PHARMACOLOGY
·
2020
·
IF 3.263
Fei-fei Pan,Yan-Biao Zheng,Chuan-Jian Shi,Feng-wei Zhang,Jin-fang Zhang,Wei-ming Fu
Hepatocellular Carcinoma (HCC) is one of the leading causes of cancer-related deaths in the world. However, the effective pharmacological approaches remain scanty in clinical practice. As a bioactive flavonoid , apigenin (API) is enriched in common fruits and vegetables. Although pharmacological activities of API have been widely investigated, its biological function in HCC remains obscure. In the present study, we found that API strongly suppressed cell growth and induced apoptosis in HCC cells. Using a xenograft mice model, API was demonstrated to inhibit the in vivo tumor growth. It is known that the long non-coding RNA H19, which is frequently elevated in HCC, plays a vital role in mediating tumorigenesis and cancer progression. Our results demonstrated that H19 was down-regulated by API, and thereby induced the inactivation of the canonical Wnt/β-catenin signaling. In conclusion, our results demonstrated that API was able to suppress tumor growth of HCC through H19-mediated Wnt/β-catenin signaling regulatory axis, suggesting that API may be a promising candidate for developing novel therapeutic approaches against liver cancer.
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ARCHIVES OF ORAL BIOLOGY
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2020
·
IF 1.931
Ying Bian,Juan Xiang
Background Osteogenic differentiation of human periodontal ligament cells (hPDLCs) is crucial for regenerate periodontal tissues. In this study, we investigated the function of salvianolic acid B (Sal B) in osteogenesis of hPDLCs. Methods HPDLCs were isolated from healthy third molar roots. HPDLCs at passage 3 were identified by morphological observation and immunohistochemistry of vimentin . The viability of hPDLCs incubated with Sal B at concentrations of 0μM, 0.1μM, 0.5μM, 1μM and 5μM were measured by CCK-8 assay. To evaluate the effect of Sal B on osteogenic differentiation of hPDLCs, the alkaline phosphatase (ALP) activity, osteogenic differentiation markers, and mineralized nodules were determined by ALP kit, qRT-PCR and alizarin red S staining, respectively. To confirm the function of Sal B in hPDLCs involved in Wnt/β-catenin signaling pathway , hPDLCs were incubated with Sal B or co-incubated with Sal B and DKK-1 (a inhibitor of Wnt/β-catenin). The levels of Wnt/β-catenin signaling pathway and osteogenic differentiation-associated indicators were then determined. Results HPDLCs showed a typical fibroblast-like and spindle-shaped, with vimentin-positive. The viability of hPDLCs had no obvious change with stimulation of Sal B at various doses. Sal B promoted the increase of ALP activity, osteogenic differentiation markers levels, mineralized nodules and activation of Wnt/β-catenin signaling pathway, and DKK-1 could block those effects of Sal B on hPDLCs. Conclusion Sal B promoted osteogenesis of hPDLCs through Wnt/β-catenin signaling pathway, which providing a potential drug for periodontitis treatment .
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FASEB JOURNAL
·
2020
·Vol. 34
·期 3
·3583-3593
·
IF 4.966
Bu Yang,Shangfu Li,Zheng Chen,Feng Feng,Lei He,Bin Liu,Tianwei He,Xuan Wang,Ruiqiang Chen,Zihao Chen,Peigen Xie,Limin Rong
Background Amyloid β peptide (Aβ) is involved in osteoporosis, but the effects of Aβ on osteoblast and bone formation remain unclear. In this study, we investigated the effect of Aβ on bone formation. Methods An animal model of osteoporosis was established by ovariectomy in C57BL/6 mice. The mice received intraperitoneal injection of Aβ. The effect of Aβ on the osteogenic differentiation of human bone marrow stromal stem cells (hBMSCs) and differentiation of both pre-osteoblasts and pre-osteoclasts in a co-culture system were investigated. Results In the animal study, intraperitoneal injection of Aβ for 8 weeks promoted early and late osteogenic differentiation of hBMSCs. Aβ treatment significantly elevated osterix + (osteoblastic) cells but decreased TRAP + cells (osteoclasts) in the distal femur bone. In vitro study showed that Aβ treatment significantly enhanced matrix mineralization and osteogenic markers (Runx2 and osteocalcin). Aβ treatment activated Wnt/β-catenin signaling in hBMSCs. The effect of Aβ was blocked by DKK1 (a Wnt/β-catenin inhibitor) treatment. In the co-culture system, Aβ treatment significantly increased the ALP activities of MC3T3-E1 cells (pre-osteoblasts) but reduced the TRAP + RAW264.7 cells (pre-osteoclasts). Aβ treatment upregulated TCF1 and OPG proteins in MC3T3-E1 cells. Aβ treatment upregulated IκB-α but downregulated NFATc1protein in RAW264.7 cells. These effects were blocked by XAV-939 (a Wnt signaling antagonist), and then rescued by additional Wnt3a (a Wnt agonist). Conclusion Aβ treatment simultaneously promoted osteogenic differentiation via Wnt/β-catenin signaling, and inhibited osteoclasts differentiation via the OPG/RANKL/RANK system, suggesting Aβ is a positive regulator of osteoblast differentiation and bone formation.
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ONCOGENE
·
2020
·Vol. 39
·期 37
·6024-6040
·
IF 7.971
Lin Binyan,Li Yongxu,Wang Tiepeng,Qiu Yangmin,Chen Zhenzhong,Zhao Kai,Lu Na
Metastatic breast cancer is characterized by high mortality and limited therapeutic target. During tumor metastasis, cytoskeletal reorganization is one of the key steps in the migration and invasion of breast cancer cells. Collapsin response mediator protein 2 (CRMP2) is a cytosolic phosphoprotein that plays an important role in regulating cytoskeletal dynamics. Previous researches have reported that altered CRMP2 expression is associated with breast cancer progression, but the underlying mechanism remains poorly understood. Here, we show that CRMP2 expression is reduced in various subtypes of breast cancers and negatively correlated with lymphatic metastasis. Overexpression of CRMP2 significantly inhibits invasion and stemness in breast cancer cells, while downregulation of CRMP2 promotes cell invasion, which is not required for tubulin polymerization. Mechanistic studies demonstrate that CRMP2 interacts with RECK, prevents RECK degradation, which, in turn, blocks NF-κB and Wnt signaling pathways. Furthermore, we find that phosphorylation of CRMP2 at T514 and S522 remarkably abolishes its functions to bind with RECK and to inhibit cell invasion. Pharmacologic rescue of CRMP2 expression suppressed breast cancer metastasis in vitro and in vivo and stimulated a synergetic effect with FN-1501 that induces CRMP2 dephosphorylation. Collectively, this study highlights the potential of CRMP2 as a therapeutic target in breast cancer metastasis and reveals a distinct mechanism of CRMP2.
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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