The TTYH3/MK5 Positive Feedback Loop regulates Tumor Progression via GSK3-β/β-catenin signaling in HCC
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ABSTRACT:
SUBMITTER: Wang Y
PROVIDER: S-EPMC9274494 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundSustained adrenergic signaling secondary to chronic stress promotes cancer progression; however, the underlying mechanisms for this phenomenon remain unclear. Hepatocellular carcinoma (HCC) frequently develops within fibrotic livers rich in activated hepatic stellate cells (HSCs). Here, we examined whether the stress hormone norepinephrine (NE) could accelerate HCC progression by modulating HSCs activities.MethodsHCC cells were exposed to conditioned medium (CM) from NE-stimulated HSCs. The changes in cell migration and invasion, epithelial-mesenchymal transition, parameters of cell proliferation, and levels of cancer stem cell markers were analyzed. Moreover, the in vivo tumor progression of HCC cells inoculated with HSCs was studied in nude mice subjected to chronic restraint stress.ResultsCM from NE-treated HSCs significantly promoted cell migration and invasion, epithelial-mesenchymal transition (EMT), and expression of cell proliferation-related genes and cancer stem cell markers in HCC cells. These pro-tumoral effects were markedly reduced by depleting secreted frizzled related protein 1 (sFRP1) in CM. The pro-tumoral functions of sFRP1 were dependent on β-catenin activation, and sFRP1 augmented the binding of Wnt16B to its receptor FZD7, resulting in enhanced β-catenin activity. Additionally, sFRP1 enhanced Wnt16B expression, reinforcing an autocrine feedback loop of Wnt16B/β-catenin signaling. The expression of sFRP1 in HSCs promoted HCC progression in an in vivo model under chronic restraint stress, which was largely attenuated by sFRP1 knockdown.ConclusionsWe identify a new mechanism by which chronic stress promotes HCC progression. In this model, NE activates HSCs to secrete sFRP1, which cooperates with a Wnt16B/β-catenin positive feedback loop. Our findings have therapeutic implications for the treatment of chronic stress-promoted HCC progression.
| S-EPMC7158101 | biostudies-literature
Project description:Drug resistance strikingly limits the therapeutic effect of temozolomide (TMZ) (a common drug for glioma). Long non-coding RNA (lncRNA) RMRP has been found to be implicated in glioma progression. However, the effect of RMRP on TMZ resistance along with related molecular mechanisms is poorly defined in glioma. In the present study, RMRP, ZNRF3, and IGF2BP3 were screened out by bioinformatics analysis. The expression levels of lncRNAs and mRNAs were measured by RT-qPCR assay. Protein levels of genes were detected by western blot and immunofluorescence assays. ZNRF3 mRNA stability was analyzed using Actinomycin D assay. Cell proliferative ability and survival rate were determined by CCK-8 assay. Cell apoptotic pattern was estimated by flow cytometry. The effect of RMRP knockdown on the growth of TMZ-treated glioma xenograft tumors was explored in vivo. The relationships of IGF2BP3, RMRP, and ZNRF3 were explored by bioinformatics prediction analysis, RNA immunoprecipitation, luciferase, and RNA pull-down, and chromatin immunoprecipitation assays. The results showed that RMRP was highly expressed in glioma. RMRP knockdown curbed cell proliferation, facilitated cell apoptosis and reduced TMZ resistance in glioma cells, and hindered the growth of TMZ-treated glioma xenograft tumors. RMRP exerted its functions by down-regulating ZNRF3 in glioma cells. IGF2BP3 interacted with RMRP and ZNRF3 mRNA. IGF2BP3 knockdown weakened the interaction of Argonaute 2 (Ago2) and ZNRF3. RMRP reduced ZNRF3 expression and mRNA stability by IGF2BP3. RMRP knockdown inhibited β-catenin expression by up-regulating ZNRF3. The inhibition of Wnt/β-catenin signaling pathway by XAV-939 weakened RMRP-mediated TMZ resistance in glioma cells. β-catenin promoted RMRP expression by TCF4 in glioma cells. In conclusion, RMRP/ZNRF3 axis and Wnt/β-catenin signaling formed a positive feedback loop to regulate TMZ resistance in glioma. The sustained activation of Wnt/β-catenin signaling by RMRP might contribute to the better management of cancers.
| S-EPMC8520527 | biostudies-literature
Project description:Non-coding RNAs play essential roles in breast cancer progression by regulating proliferation, differentiation, invasion, and metastasis. However, our understanding of most microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) in breast cancer is still limited. miR-586 has been identified as an important factor in the progression of some types of cancer, but its exact function and relative regulation mechanisms in breast cancer development need to be further investigated. In this study, we showed miR-586 functioned as an oncogene by promoting breast cancer proliferation and metastasis both in vitro and in vivo. Meanwhile, miR-586 induced Wnt/β-catenin activation by directly targeting Wnt/β-catenin signaling antagonists SFRP1 and DKK2/3. Moreover, we demonstrated that LINC01189 functioned as a tumor suppressor and inhibited breast cancer progression through inhibiting an epithelial-mesenchymal transition (EMT)-like phenotype by sponging miR-586. In addition, β-catenin/TCF4 transactivated ZEB1, resulting in a transcriptional repression of LINC01189 expression. In conclusion, our data uncovered the LINC01189-miR-586-ZEB1 feedback loop and provided a novel mechanism participating in the regulation of Wnt/β-catenin signaling in breast cancer progression.
| S-EPMC8408558 | biostudies-literature
Project description:Resistance to molecular targeted therapies is a significant challenge for advanced colorectal cancer (CRC). Understanding the underlying mechanisms and developing effective strategies against regorafenib resistance are highly desired in the clinic. Here, we screened the expression of chemokine receptors and identified CC chemokine receptor 2 (CCR2) as a top upregulated gene in regorafenib-resistant cells. CCR2 silencing alleviated drug tolerance in regorafenib-resistant cells, while overexpression of CCR2 enhanced CRC cells resistance to regorafenib. Moreover, CCR2-mediated regorafenib tolerance was demonstrated to be associated with AKT/GSK3β-regulated β-catenin stabilization. In turn, β-catenin modulation is sufficient to trigger the transcriptional activation of CCR2 expression. Clinically, high-CCR2 expression was correlated to shorter overall survival and disease-free survival of patients. A positive correlation between CCR2 and nuclear β-catenin expression was observed in a cohort of CRC tissues. Altogether, these findings suggest β-catenin and CCR2 are part of a positive-feedback loop, which sustains a high CCR2 expression level, conferring CRC cells resistance to regorafenib. Thus, targeting CCR2 may be a useful therapeutic strategy to alleviate regorafenib tolerance to increase the efficacy of CRC treatments.
| S-EPMC6733926 | biostudies-literature
Project description:Glioma has been a major healthcare burden; however, the specific molecular regulatory mechanism underlying its initiation and progression remains to be elucidated. Although it is known that many miRNAs are involved in the regulation of malignant phenotypes of glioma, the role of miR-4476 has not been reported yet. In the present study, we identify miR-4476 as an upregulated microRNA, which promotes cell proliferation, migration, and invasion in glioma. Further mechanistic analyses indicate that the adenomatous polyposis coli (APC), a negative regulator of the Wnt/?-catenin signaling pathway, is a direct target of miR-4476 and mediates the oncogenic effects of miR-4476 in glioma. C-Jun, a downstream effector of the Wnt/?-catenin signaling, is upregulated by miR-4476 overexpression. In turn, c-Jun could positively regulate miR-4476 expression by binding to the upstream of its transcription start site (TSS). Furthermore, in our clinical samples, increased miR-4476 is an unfavorable prognostic factor, and its expression positively correlates with c-Jun expression but negatively correlates with that of APC. In conclusion, our study demonstrates that miR-4476 acts as a tumor enhancer, directly targeting APC to stimulate its own expression and promoting the malignant phenotypes of glioma.
| S-EPMC7181615 | biostudies-literature
Project description:IntroductionTumor-associated calcium signal transducer 2 (Trop2) has been used as a transport gate for cytotoxic agents into cells in antibody-drug conjugate designs because of its expression in a wide range of solid tumors. However, the specific role of Trop2 itself in breast cancer progression remains unclear and small molecules targeting Trop2 have not yet been reported.ObjectivesTo screen small molecules targeting Trop2, and to reveal its pharmacological effects and the molecular mechanisms of action.MethodsSmall molecule targeting Trop2 was identified by cell membrane chromatography, and validated by cellular thermal shift assay and point mutation analyses. We investigated the pharmacological effects of Trop2 inhibitor using RNA-seq, human foreskin fibroblast (HFF)-derived extracellular matrix (ECM), Matrigel drop invasion assays, colony-forming assay, xenograft tumor model, 4T1 orthotopic metastasis model and 4T1 experimental metastasis model. The molecular mechanism was determined using immunoprecipitation, mass spectrometry, immunofluorescence, immunohistochemistry and Western blotting.ResultsHere we identified Bruceine D (BD) as the inhibitor of Trop2, and demonstrated anti-metastasis effects of BD in breast cancer. Notably, Lys307 and Glu310 residues of Trop2 acted as critical sites for BD binding. Mechanistically, BD suppressed Trop2-induced cancer metastasis by blocking the formation of Trop2/β-catenin positive loop, in which the Trop2/β-catenin complex prevented β-catenin from being degraded via the ubiquitin-proteosome pathway. Destabilized β-catenin caused by BD reduced nucleus translocation, leading to the reduction of transcription of Trop2, the reversal of epithelial-mesenchymal transition (EMT) process, and the inhibition of ECM remodeling, further inhibiting cancer metastasis. Additionally, the inhibitory effects of BD on lung metastatic colonization and the beneficial effects of BD on prolongation of survival were validated in 4T1 experimental metastasis model.ConclusionsThese results support the tumor-promoting role of Trop2 in breast cancer by stabilizing β-catenin in Trop2/β-catenin positive loop, and suggest Bruceine D as a promising candidate for Trop2 inhibition.
| S-EPMC10982870 | biostudies-literature
Project description:BackgroundSETD1A, a member of SET1/MLL family H3K4 methyltransferases, is involved in the tumorigenesis of numerous cancers. However, the biological role and mechanism of SETD1A in non-small cell lung cancer (NSCLC) remain to be elucidated.MethodsThe expression of SETD1A, NEAT1, EZH2, and β-catenin in NSCLC tissues and cell lines was detected by qRT-PCR, immunohistochemistry and western blotting. The regulatory mechanisms were validated by chromatin immunoprecipitation, co-immunoprepitation and luciferase reporter assay. The self-renewal, cisplatin sensitivity and tumorigenesis of NSCLC cells were analyzed using sphere formation, CCK-8, colony formation assays and xenograft tumor models.ResultsSETD1A expression was significantly increased in NSCLC and its overexpression predicted a poor prognosis of patients with NSCLC. Functional experiments showed that SETD1A positively regulated cancer stem cell property and negatively regulated cisplatin sensitivity in NSCLC cells via the Wnt/β-catenin pathway. Next, we found that SETD1A positively regulated the Wnt/β-catenin pathway via interacting with and stabilizing β-catenin. The SET domain is dispensable for the interaction between SETD1A and β-catenin. Furthermore, we identified that SETD1A bound to the promoters of NEAT1 and EZH2 to activate gene transcription by inducing H3K4me3 enrichment. Rescue experiments showed that SETD1A promoted the Wnt/β-catenin pathway and exerted its oncogenic functions in NSCLC, at least, partly through NEAT1 and EZH2 upregulation. In addition, SETD1A was proven to be a direct target of the Wnt/β-catenin pathway, thus forming a positive feedback loop in NSCLC cells.ConclusionSETD1A and Wnt/β-catenin pathway form a positive feedback loop and coordinately contribute to NSCLC progression.
| S-EPMC8513302 | biostudies-literature
Project description:IntroductionNuclear accumulation of β-catenin is important for cancer development and it is found to overlap with p68 (DDX5) immunoreactivity in most breast cancers, as indicated by both clinical investigations and studies in cell lines. In this study, we aim to investigate the regulation of p68 gene expression through β-catenin/transcription factor 4 (TCF4) signaling in breast cancer.MethodsFormalin-fixed paraffin-embedded sections derived from normal human breast and breast cancer samples were used for immunohistochemical analysis. Protein and mRNA expressions were determined by immunoblotting and quantitative RT-PCR respectively. Promoter activity of p68 was checked using luciferase assay. Occupancy of several factors on the p68 promoter was evaluated using chromatin immunoprecipitation. Finally, a syngeneic mouse model of breast cancer was used to assess physiological significance.ResultsWe demonstrated that β-catenin can directly induce transcription of p68 promoter or indirectly through regulation of c-Myc in both human and mouse breast cancer cells. Moreover, by chromatin immunoprecipitation assay, we have found that both β-catenin and TCF4 occupy the endogenous p68 promoter, which is further enhanced by Wnt signaling. Furthermore, we have also established a positive feedback regulation for the expression of TCF4 by p68. To the best of our knowledge, this is the first report on β-catenin/TCF4-mediated p68 gene regulation, which plays an important role in epithelial to mesenchymal transition, as shown in vitro in breast cancer cell lines and in vivo in an animal breast tumour model.ConclusionsOur findings indicate that Wnt/β-catenin signaling plays an important role in breast cancer progression through p68 upregulation.
| S-EPMC4308923 | biostudies-literature
Project description:Nuclear factor erythroid-2-related factor 2 (Nrf2), a master transcription factor in the antioxidant response, has been found to be ubiquitously expressed in various cancer cells and in the regulation tumor proliferation, invasion, and chemoresistance activities. The regulatory roles of Nrf2 in controlling Hepatocellular carcinoma (HCC) progression remain unclear. In this study, we demonstrated that Nrf2 was significantly elevated in HCC cells and tissues and was correlated with poor prognosis of HCCs. Consistently, Nrf2 significantly promoted HCC cell growth both in vitro and in vivo. Further investigation suggested a novel association of Nrf2 with Platelet-Derived Growth Factor-A (PDGFA). Nrf2 promoted PDGFA transcription by recruiting specificity protein 1 (Sp1) to its promoter, resulting in increased activation of the AKT/p21 pathway and cell cycle progression of HCC cells. As a feedback loop, PDGFA enhanced Nrf2 expression and activation in an AKT dependent manner. In line with these findings, expression of Nrf2 and PDGFA were positively correlated in HCC tissues. Taken together, this study uncovers a novel mechanism of the Nrf2/PDGFA regulatory loop that is crucial for AKT-dependent HCC progression, and thereby provides potential targets for HCC therapy.
| S-EPMC5323163 | biostudies-literature
Project description:p28(GANK) (also known as PSMD10 or gankyrin) is a novel oncoprotein that is highly expressed in hepatocellular carcinoma (HCC). Through its interaction with various proteins, p28(GANK) mediates the degradation of the tumor suppressor proteins Rb and p53. Although p53 was reported to downregulate ?-catenin, whether p28(GANK) is involved in the regulation of ?-catenin remains uncertain. Here we report that both growth factors and Ras upregulate p28(GANK) expression through the activation of the phosphoinositide 3-kinase-AKT pathway. Upregulation of p28(GANK) expression subsequently enhanced the transcription activity of ?-catenin. This effect was observed in p53-deficient cells, suggesting a p53-independent mechanism for the p28(GANK)-mediated activation of ?-catenin. p28(GANK) overexpression also reduced E-cadherin protein levels, leading to increased release of free ?-catenin into the cytoplasm from the cadherin-bound pool. Interestingly, exogenous expression of p28(GANK) resulted in elevated expression of the endogenous protein. We also observed that both ?-catenin and c-Myc were transcriptional activators of p28(GANK), and a correlation between p28(GANK) overexpression and c-Myc, cyclin D1 and ?-catenin activation in primary human HCC. Together, these results suggest that p28(GANK) expression is regulated by a positive feedback loop involving ?-catenin, which may play a critical role in tumorigenesis and the progression of HCC.
| S-EPMC3193485 | biostudies-literature