MOLECULAR CARCINOGENESIS
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2024
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IF 3
Junyi Jin,Yihui Wang,Yaoyuan Hu
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. STAM binding protein-like 1 (STAMBPL1), a key member of the COP9 signalosome subunit 5/serine protease 27/proteasome 26S subunit non-ATPase 7 (JAMM) family, is closely associated with tumor development. In this work, data from GSE101728 and GSE84402 chips were analyzed, and STAMBPL1 was selected as the target factor. This study aimed to reveal the potential function of STAMBPL1 in HCC. Clinical results showed that STAMBPL1 was significantly increased in tumor tissues of HCC patients, and its expression was strongly associated with tumor size and TNM stage. Furthermore, STAMBPL1-overexpressed Hep3B2.1-7 cell line or STAMBPL1-silenced SNU-182 cell line were established using lentivirus carrying cDNA encoding STAMBPL1 mRNA or shRNA targeting STAMBPL1, respectively. STAMBPL1-overexpressed cells exhibited a pronounced enhancement of proliferation in vitro and in vivo. Exogenous expression of STAMBPL1 increased the percentage of cells in the S phase and upregulated the expressions of CyclinD1 and Survivin. As expected, STAMBPL1 knockdown exhibited completely opposite effects, resulting in impaired tumorigenicity in vitro and in vivo. Mechanistically, STAMBPL1 activated Wnt/β-catenin pathway and increased the expression of downstream cancer-promoting genes. Interestingly, we found that STAMBPL1 was transcriptionally regulated by sterol regulatory element-binding protein 1 (SREBP1), a modulator of lipid metabolism, as evidenced by luciferase reporter and chromatin-immunoprecipitation (Ch-IP) assays. Notably, STAMBPL1 overexpression increased lipid accumulation in HCC cells and xenograft tumors. Totally our findings suggest that STAMBPL1 plays a vital role in the tumorigenicity of HCC cells. Modulation of Wnt/β-catenin and lipid metabolism may contribute to its pro-cancer effects. STAMBPL1 may serve as a therapeutic target of HCC.
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高影响因子
PHYTOMEDICINE
·
2025
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IF 8.3
Rui Hao,Tian Li,Beibei Zhou,Jiaxin Shao,Weibo Zhao,Beibei Jiao,Xia Sun,Jian Zhang
Background : Bushen Huoxue Formula (BSHXF), a traditional Chinese medicine, effectively treats premature ovarian insufficiency (POI) by modulating of lipid metabolism. Purpose : This study aimed to investigate the underlying mechanism through which BSHXF improves POI by regulating lipid metabolism. Methods Network pharmacology identified potential pathways associated with BSHXF in POI. A POI rat model was induced using subcutaneous corticosterone injections and treated with BSHXF to assess its efficacy. The impact of BSHXF on lipid metabolism, autophagy, and the LRP6/β-catenin signaling pathway was evaluated in these rats. Additionally, palmitic acid (PA)-induced granulosa cells (KGN cells) were used in vitro . A LRP6 inhibitor (Salinomycin sodium salt, Sal) was applied to these cells, followed by a series of molecular biology experiments to elucidate the specific regulatory role of BSHXF on lipid metabolism. Results : Network pharmacology analysis indicated that the Wnt/β-catenin signaling pathway is a potential target of BSHXF in POI. In vivo , BSHXF alleviated POI-like symptoms in rats, reduced lipid accumulation, suppressed excessive autophagy, and activated the LRP6/β-catenin signaling pathway. In vitro , Sal inhibited the ability of BSHXF-containing serum to activate LRP6/β-catenin signaling, reduce lipid accumulation, and counteract excessive autophagy in PA-induced KGN cells. This was accompanied by increased expression of LRP6 and β-catenin, enhanced lipogenesis, elevated lipid droplet formation, decreased lipid catabolism, and oxidation, and enhanced autophagic flux. Cycloheximide chase and Western blot analyses further confirmed that BSHXF stabilizes LRP6 by inhibiting its ubiquitin-proteasomal degradation. Conclusions : BSHXF activates LRP6/β-catenin signaling pathway by inhibiting the ubiquitination degradation of LRP6, thereby improving POI. This study reveals that BSHXF may improve POI by modulating LRP6 stability, thereby affecting lipid metabolism.
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BULLETIN OF EXPERIMENTAL BIOLOGY AND MEDICINE
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2026
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IF 0.6
Fan Qian-qian,Qin Hui-fen,Liu Yu-qiong
The study examined the effects of a plant product artemisinin (ARS) on epithelial–mesenchymal transition and drug resistance in cervical cancer cells mediated via the Wnt/β-catenin signaling pathway. ARS inhibited invasion and migration of CaSki and HeLa cancer cells, up-regulated expression of ICAM-1, MMP-9, and E-cadherin proteins, as well as down-regulated expression of vimentin. In both cell lines, ARS down-regulated mRNA and protein expression of P-glycoprotein, ATP-binding cassette transporters B and G2; it also reduced expression of β-catenin protein. In comparison with the cells treated with Wnt/β-catenin pathway inhibitor iCRT3, the combined treatment of the cells with ARS and iCRT3 reduced their invasion and migration, down-regulated expression of MMP-9, ICAM-1, vimentin, and β-catenin proteins, as well as up-regulated expression of E-cadherin.
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PHYTOMEDICINE
·
2026
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IF 11.3
Jiajian Wang,Yongnan Su,Lanqing Zhang,Hanchuan Mou,Wei Wu,Yunxin Xia,Fei Yu,Fan Yang,Jihong Zhang
ABPP identifies valine-containing protein (VCP) as a KBA01 direct action target. • KBA01 specifically degrades p53 R273 by targeting VCP. • Distinct from p53 degraders, KBA01 has a unique role in disrupting the dominant negative effect of p53 R273H Background Mutant p53 is closely associated with tumor proliferation and metastasis, making an attractive therapeutic target in cancer treatment. Buxus alkaloids exhibit antibacterial and antiviral properties, however, research into their antitumor potential remains limited. KBA01, a triterpenoid alkaloid isolated from the leaves and stems of Buxus bodinieri Levl, activates the p53 signaling pathway in colorectal cancer cells; however, its drug targets and mechanism of action remain unclear. Purpose To identify the molecular target of KBA01 and elucidate how it suppresses tumor growth through activation of the p53 signaling pathway. Methods Activity-based protein profiling (ABPP) assay was performed to identify the potential target of KBA01. Wound healing, cell colony formation and transwell assays were conducted to elucidate the effects of KBA01 on cell proliferation, migration, and invasion. Western blot, RT-qPCR, Immunoprecipitation (IP), Co-Immunoprecipitation (Co-IP), Electrophoretic mobility shift assay (EMSA), Chromatin immunoprecipitation (ChIP), and Luciferase reporter assays were applied to investigate the effects of KBA01 on p53 function. The colorectal cancer xenograft experiment was performed to evaluate the in vivo anticancer activity. Results KBA01 targets Valosin-containing protein (VCP), reducing its interaction with p53 R273H and thereby promoting the ubiquitination and degradation of mutant p53. Consequently, KBA01 disrupts the dominant negative effect of mutant p53. KBA01 elevated the p53 downstream targeted genes p21 and PUMA mRNA and protein levels, thereby activating the p53 signaling pathway and ultimately inhibiting tumor growth and metastasis in vitro . In addition, KBA01 inhibits the Wnt/β-catenin pathway in tumor cells harboring mutant p53. Further in vivo studies demonstrated that KBA01 significantly suppressed tumor growth in colorectal cancer xenograft models by inducing mutant p53 depletion and reactivating p53 downstream target genes, achieving a tumor inhibition rate of 61.39%. Conclusion These findings identify VCP as the molecular target of KBA01 and suggest that KBA01 selectively promotes the degradation of mutant p53 R273H, thereby alleviating its dominant-negative effect and restoring p53 signaling. Collectively, this study broadens the potential pharmacological applications of Buxus alkaloids and supports the further investigation of KBA01 as a lead compound for mutant p53-targeted therapy. Download: Download high-res image (255KB) Download: Download full-size image
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INTERNATIONAL UROLOGY AND NEPHROLOGY
·
2026
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IF 2.2
Chen Huihui,Zhang Guolei,Jin Jingjing,Cheng Mei Juan,Zhang Dongxue,Niu Zhezhe,Zhu Rongfang,Qian Yuetong,Liang Xiangnan,He Lei,Zhou Wei,Zhang Shenglei,Bai Yaling,Xu Jin Sheng
Purpose Vascular calcification (VC) is highly prevalent and a significant cardiovascular risk factor in patients with chronic kidney disease (CKD). Secreted frizzled-related protein 1 (SFRP1) is a secreted glycoprotein closely associated with the Wnt/β-catenin pathway which plays a crucial role in bone formation, but its function and mechanism in VC remain unknown. Methods Serum and radial artery tissues were collected from CKD patients with or without VC. The cellular model of VSMCs’ calcification was established under high-phosphate conditions in vitro. Western blot, qRT-PCR, and immunofluorescence were used to detect SFRP1 expression. The function of SFRP1 was identified by transfection with sh-SFRP1 and pCMV3-SFRP1 plasmid. Results Initially, bioinformatics analysis showed that SFRP1 expression was significantly elevated in high-phosphate-stimulated rat VSMCs. Subsequently, we discovered that the expression of SFRP1 was dramatically increased in the calcified arteries of CKD patients. Functionally, when SFRP1 was knocked down, the calcification process and the expression of Runx2 were attenuated. In contrast, SFRP1 overexpression exacerbated the β-GP-induced VSMCs’ calcification. Mechanistically, we confirmed the activation of Wnt/β-catenin signaling in the in vitro calcification model and this activation was inhibited by SFRP1 knockdown. Furthermore, when the Wnt/β-catenin signaling was enhanced with LiCl, the suppressing effect of SFRP1 knockdown on β-GP-induced osteogenic transdifferentiation of VSMCs was reversed, and calcification was promoted. Conclusion We identified that SFRP1 promoted vascular calcification in CKD partly by regulating the Wnt/β-catenin/Runx2 axis, suggesting that SFRP1 may be a potential biomarker and therapeutic target for VC in CKD.
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Pharmaceuticals
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2026
·Vol. 19
·期 3
·469
·
IF 5.7
Lili Li,Xiaoya Zhang,Guangyuan Tang,Jianxin Wu,Qing Huang
Background: Glabridin, a natural compound derived fromGlycyrrhiza glabraL., possesses skin-lightening effects. This study aims to further elucidate the depigmentation mechanism of glabridin by investigating its effects on melanogenesis and melanin transfer.Methods: We initially confirmed the anti-melanogenic effects of glabridin in MNT-1 human melanoma cells. Then, we investigated the mechanism of its anti-melanogenic effect by evaluating the protein expression of β-catenin and MITF via Western blot. To investigate melanin transfer, we compared glabridin’s efficacy with that of niacinamide, a recognized inhibitor of melanosome transfer and employed two complementary experimental models: (1) α-melanocyte-stimulating hormone (α-MSH)-stimulated MNT-1 cells to analyze dendrite formation, and (2) a UVB-irradiated co-culture system of MNT-1 cells and HaCaT keratinocytes to evaluate melanin transfer.Results: By measuring glabridin’s effects on melanin content, tyrosinase activity, and melanogenesis-related protein expression confirmed its inhibition of melanin synthesis. Further investigation demonstrated that glabridin suppresses melanogenesis by downregulating β-catenin and MITF, indicating inhibition of the Wnt/β-catenin pathway. Furthermore, in α-MSH-treated MNT-1 cells, both glabridin and niacinamide were found to suppress dendrite formation and elongation. In a UVB-exposed co-culture system, both glabridin and niacinamide inhibited melanin transfer to keratinocytes. Mechanistically, these effects were linked to the regulation of Rho GTPases (Rac1, RhoA, Cdc42) and suppression of F-actin reorganization.Conclusions: This study provides, for the first time, evidence that the skin-lightening effect of glabridin involves two complementary mechanisms: inhibition of melanogenesis through suppression of the Wnt/β-catenin pathway, and attenuation of both dendricity and melanin transfer via the influence of Rho family GTPases expression.
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Journal of Oncology
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2022
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IF 4.501
Hongliang You,Dao Wang,Linlin Wei,Jiao Chen,Huanhuan Li,Yufeng Liu
Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer, with a feature of easy to induce multidrug resistance and relapse. Abundant studies have proved that iron overload strengthens the growth and metastasis of tumor cells. Herein, we found that deferoxamine (DFO) effectively decreased the concentration of intracellular iron in ALL cells. DFO inhibited proliferation, induced apoptosis, and obstructed cell cycle of ALL cells, whereas DFO and dextriferron (Dex) used in combination significantly decreased the sensitivity of ALL cells to DFO. Reactive oxygen species (ROS) level was reduced in ALL cells treated with DFO, and the combination of DFO and Dex reversed the effects of DFO. In vivo, DFO inhibited mouse tumor growth. Besides, cyclinD1, β-catenin, c-Myc, hypoxia inducible factor 1 (HIF-1), p-p38MAPK, and p-ERK1/2 protein levels were significantly downregulated, and the levels of prolyl hydroxylase-2 (PHD-2) were upregulated after treated with DFO, whereas Dex treatment reversed those in vivo and in vitro. In conclusion, DFO inhibited the proliferation and ALL xenograft tumor growth, obstructed the cell cycle, and induced apoptosis of ALL cells, probably via inactivating the ROS/HIF-1α, Wnt/β-catenin, and p38MAPK/ERK signaling.
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Foods
·
2021
·Vol. 11
·期 1
·49
·
IF 4.35
Fuhua Li,Huiming Yan,Ling Jiang,Jichun Zhao,Xiaojuan Lei,Jian Ming
Ulcerative colitis (UC) is a chronic and nonspecific inflammatory disease of the colon and rectum, and its etiology remains obscure. Cherry polyphenols showed potential health-promoting effects. However, both the protective effect and mechanism of cherry polyphenols on UC are still unclear. This study aimed to investigate the potential role of the free polyphenol extract of cherry in alleviating UC and its possible mechanism of action. Our study revealed that the free polyphenol extract of cherry management significantly alleviated UC symptoms, such as weight loss, colon shortening, the thickening of colonic mucous layer, etc. The free polyphenol extract of cherry treatment also introduced a significant reduction in levels of malondialdehyde (MDA), myeloperoxidase (MPO) and nitric oxide (NO), while causing a significant elevation in levels of catalase (CAT), glutathione (GSH-Px), superoxide dismutase (SOD), as well as the downregulation of pro-inflammatory cytokines. This indicated that such positive effects were performed through reducing oxidative damage or in a cytokine-specific manner. The immunofluorescence analysis of ZO-1 and occludin proteins declared that the free polyphenol extract of cherry had the potential to prompt intestinal barrier function. The reduced expression levels of β-catenin, c-myc, cyclin D1 and GSK-3β suggested that the cherry extract performed its positive effect on UC by suppressing the Wnt/β-ctenin pathway. This finding may pave the way into further understanding the mechanism of cherry polyphenols ameliorating ulcerative colitis.Keywords:ulcerative colitis;cherry polyphenol;anti-inflammatory;antioxidant;Wnt/β-catenin signaling pathway
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ACTA BIOCHIMICA POLONICA
·
2021
·Vol. 68
·期 4
·765-774
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IF 2.149
Shaoyi Li,Yong Li,Bibo Tan,Zhaojie An
Krüppel-like factor 1 (KLF1) is a transcription factor that exhibits promoting effect in cervical cancer, but its correlation with gastric cancer (GC) has not been reported yet. In this study, we explored the role and potential mechanism of KLF1 in GC progression by using a series of experimental methods including RT-qPCR, Western blot, CCK-8 assay, EdU staining, and cell cycle analysis. KLF1 was found to be elevated in GC tissues (n=415) compared with the normal tissues by applying UALCAN to analyze datasets from The Cancer Genome Atlas (TCGA). The upregulation of KLF1 was also validated in GC cell lines. Functional studies proved that RNA interference-mediated silencing of KLF1 inhibited GC cell growth, as evidenced by the decreased cell viability, DNA synthesis, and arrested cell cycle in G1 phase. Moreover, KLF1 knockdown exerted the inhibitory effects on cell migration and invasion as well as the epithelial-mesenchymal transition (EMT) in GC cells. Conversely, overexpression of KLF1 had the opposite effects on GC progression. Furthermore, we proved that the activation of Wnt/β-catenin pathway was markedly inhibited by KLF1 knockdown and promoted by KLF1 overexpression. The blockade of Wnt/β-catenin pathway rescued the effects of KLF1 overexpression. These results suggested that KLF1 promoted the growth, migration, invasion, and EMT process in GC cells, and this promotion was achieved by activating the Wnt/β-catenin pathway. This work will be helpful for searching the potential therapeutic targets for treatment of GC.
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ACTA HISTOCHEMICA
·
2021
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IF 2.479
Xue Liu,Yumeng Shao,Xinyue Zhang,Xiang Ji,Min Xie,Huaman Liu
The precise etiology and pathogenesis of idiopathic pulmonary fibrosis are not completely understood, and no satisfactory treatment exists. This work aimed to examine the effects of calycosin (CA, an isoflavone compound) on pulmonary fibrosis (PF) and explore the underlying mechanism. In this study, we established a mice model of PF induced by 5 mg/mL bleomycin (BLM), and mice were orally administrated with 7 mg/kg or 14 mg/kg CA once a day for three weeks. In vitro , after pretreated with 80 μM CA, MLE-12 cells were stimulated with 10 ng/mL transforming growth factor-β1 (TGF-β1) for inducing epithelial-mesenchymal transition (EMT). The results showed that CA treatment ameliorated the severity of fibrosis and the lung tissue damage, as well as suppressed the secretion of inflammation factors in a dose-dependent manner of the PF mice model induced by BLM. Subsequently, CA inhibited the BLM-induced PF progression by repressing EMT, evidenced by the reverse of the downregulation of E-cadherin and the upregulation of vimentin, α-SMA, and fibronectin. Moreover, the elevated phosphorylation of AKT and GSK3β induced by BLM (or TGF-β1) was decreased by CA treatment, leading to the rescue of the high expression of β-catenin. CA prevented the translocation of β-catenin from the cytoplasm to the nucleus. The repressed effects of CA on the TGF-β1-induced EMT and the AKT/GSK3β/β-catenin axis, as well as the translocation of β-catenin were all reversed by a AKT activator SC79. Taken together, CA ameliorated PF by the EMT inhibition upon suppressing the AKT/GSK3β/β-catenin signaling pathway.
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PHYTOMEDICINE
·
2021
·
IF 5.34
Yongmei Li,Zean Zhao,Jian Luo,Yanqing Jiang,Lu Li,Yanyu Chen,Leqi Zhang,Qinghua Huang,Ying Cao,Pingzheng Zhou,Ting Wu,Jianxin Pang
Background Hyperuricemia (HUA) is characterized by abnormal serum uric acid (UA) levels and demonstrated to be involved in renal injury leading to hyperuricemic nephropathy (HN). Apigenin (API), a flavonoid naturally present in tea, berries, fruits, and vegetables, exhibits various biological functions, such as antioxidant and anti-inflammatory activity. Purpose To investigate the effect of API treatment in HN and to reveal its underlying mechanisms. Methods The mice with HN were induced by potassium oxonate intraperitoneally and orally administered for two weeks. The effects of API on renal function, inflammation, fibrosis, and uric acid (UA) metabolism in mice with HN were evaluated. The effects of API on urate transporters were further examined in vitro . Results The mice with HN exhibited abnormal renal urate excretion and renal dysfunction accompanied by increased renal inflammation and fibrosis. In contrast, API reduced the levels of serum UA, serum creatinine (CRE), blood urea nitrogen (BUN) and renal inflammatory factors in mice with HN. Besides, API ameliorated the renal fibrosis via Wnt/β-catenin pathway suppression. Furthermore, API potently promoted urinary UA excretion and inhibited renal urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) in mice with HN. In vitro , API competitively inhibited URAT1 and GLUT9 in a dose-dependent manner, with IC 50 values of 0.64 ± 0.14 μM and 2.63 ± 0.69 μM, respectively. Conclusions API could effectively attenuate HN through co-inhibiting UA reabsorption and Wnt/β-catenin pathway, and thus it might be a potential therapy to HN.
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CHEMOSPHERE
·
2020
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IF 5.778
Qi Qin,Bingwei Yang,Zixuan Liu,Lei Xu,Erqun Song,Yang Song
Polychlorinated biphenyls (PCBs) are persistent industrial pollutants that have been linked to breast cancer progression. However, their molecular mechanism(s) are currently unclear. Our previous assessment suggested that the highly reactive PCB metabolite 2,3,5-trichloro-6-phenyl-[1,4]-benzoquinone (PCB29-pQ) induces the metastasis of breast cancer. Here, our data illustrate that PCB29-pQ increases cancer stem cell (CSC) marker expression, resulting in an increase in the epithelial-mesenchymal transition (EMT) in MDA-MB-231 breast cancer cells; further, the Wnt/β-catenin pathway also becomes activated by PCB29-pQ. When the Wnt/β-catenin pathway is inhibited, the promotion of CSC properties and EMT by PCB29-pQ were accordingly reversed. In addition, the overproduction of reactive oxygen species (ROS) mediated by PCB29-pQ plays a key role in Wnt/β-catenin activation. Collectively, our current data designated the regulatory role of Wnt/β-catenin in PCB29-pQ-triggered acquisition of CSC properties and EMT.
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