A Positive Feedback Loop of E2F4-Mediated Activation of MNX1 Regulates Tumour Progression in Colorectal Cancer
Ontology highlight
ABSTRACT:
SUBMITTER: Li J
PROVIDER: S-EPMC10539396 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Abnormal antioxidant capacity of cancer is closely related to tumor malignancy. Modulation of oxidative stress status is a novel anticancer therapeutic target. Nrf2 is a key regulator of various antioxidant enzymes, but the mechanism of its deubiquitination remains largely unclear. This study unveiled that Nrf2 received post-transcriptional regulation from a proteasome-associated deubiquitinating enzyme, USP11, in colorectal cancer (CRC). It was found that USP11 was overexpressed in CRC tissues acting as an oncogene by inhibiting mitochondrial apoptosis, and USP11 managed to maintain balance in the production and elimination of reactive oxygen species (ROS). Mechanistically, we identified a feedback loop between USP11 and Nrf2 maintaining the redox homeostasis. USP11 stabilized Nrf2 by deubiquitinating and protecting it from proteasome-mediated degradation. Interestingly, we also map that Nrf2 could bind to the antioxidant reaction element (ARE) in the USP11 promoter to promote its transcription. Hence, USP11/Nrf2 positive feedback loop inhibited mitochondrial apoptosis of CRC cells by activating Nrf2/ARE signaling pathway, thus promoting CRC progression. Schematic diagram of the mechanism by which USP11/Nrf2 positive feedback loop inhibited mitochondrial apoptosis in CRC cells. This study found that USP11 was highly expressed in colorectal cancer (CRC) tissue and was associated with poor prognosis. In CRC, the inhibition of USP11 expression could promote the ubiquitination degradation of Nrf2, thereby inhibiting the Nrf2/ARE signaling pathway. This led to an increase in reactive oxygen species in the cell, causing mitochondrial apoptosis. In addition, Nrf2 could bind to the promoter region of USP11 to promote its transcription, both of which formed positive feedback loop.
| S-EPMC11609304 | biostudies-literature
Project description:BackgroundMiR-452-5p plays an essential role in the development of a variety of tumors, but little is known about its biological function and mechanism in colorectal cancer (CRC).MethodsThe expression levels of miR-452-5p in CRC tissues and cells were detected by real-time quantitative PCR (qRT-PCR). Besides, the biological effects of miR-452-5p on CRC were investigated by functional experiments in vitro and in vivo. Furthermore, bioinformatics analysis, dual-luciferase reporter assay, chromatin immunecipitation assay, western blotting and recovery experiments were implemented to investigate the underlying molecular mechanism.ResultsThe expression level of miR-452-5p was up-regulated in CRC tissues. MiR-452-5p promoted CRC cell proliferation, cell cycle transition and chemoresistance, and inhibited cell apoptosis. Moreover, miR-452-5p directly targeted PKN2 and DUSP6 and subsequently activated the ERK/MAPK signaling pathway, and it was transcriptionally regulated by c-Jun.ConclusionTo conclude, miR-452-5p expression is up-regulated in CRC, which promotes the progression of CRC by activating the miR-452-5p-PKN2/DUSP6-c-Jun positive feedback loop. These findings indicate that miR-452-5p may act as a potential therapeutic target and clinical response biomarker for CRC.
| S-EPMC7993669 | biostudies-literature
Project description:BackgroundRenal cell carcinoma (RCC) originates from renal tubular epithelial cells and is mainly classified into three histological types, including clear cell renal cell carcinoma (ccRCC) which accounts for about 75% of all kidney cancers and is characterized by its strong invasiveness and poor prognosis. Hence, it is imperative to understand the mechanisms underlying the occurrence and progression of ccRCC to identify effective biomarkers for the early diagnosis and the prognosis prediction.MethodsThe mRNA level of TTC13 was quantified by RT-PCR, while the protein level was determined by western blot and immunohistochemistry (IHC) staining. Cell proliferation was measured by cck-8, and cell apoptosis was detected by flow cytometry. The binding of STAT3 to the promoter region of TTC13 was determined by the luciferase reporter assay and chip experiments. STAT3 nuclear translocation was assessed by immunofluorescence staining.ResultsWe found that TTC13 was up-regulated in ccRCC, and TTC13 promoted cell proliferation as well as inhibited cell apoptosis and autophagy of ccRCC through wnt/β-catenin and IL6-JAK-STAT3 signaling pathways. Furthermore, TTC13 might play a role in the immune infiltration and immunotherapy of ccRCC. Mechanistically, STAT3 activated the transcription of TTC13 gene.ConclusionsSTAT3 directly regulated TTC13 expression through a positive feedback loop mechanism to promote ccRCC cell proliferation as well as reduce cell apoptosis and autophagy. These findings suggested new and effective therapeutic targets for more accurate and personalized treatment strategies.
| S-EPMC10621595 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, and identification of novel targets is necessary for its diagnosis and treatment. This study aimed to investigate the biological function and clinical significance of tweety homolog 3 (TTYH3) in HCC. TTYH3 overexpression promoted cell proliferation, migration, and invasion and inhibited HCCM3 and Hep3B cell apoptosis. TTYH3 promoted tumor formation and metastasis in vivo. TTYH3 upregulated calcium influx and intracellular chloride concentration, thereby promoting cellular migration and regulating epithelial-mesenchymal transition-related protein expression. The interaction between TTYH3 and MK5 was identified through co-immunoprecipitation assays and protein docking. TTYH3 promoted the expression of MK5, which then activated the GSK3β/β-catenin signaling pathway. MK5 knockdown attenuated the activation of GSK3β/β-catenin signaling by TTYH3. TTYH3 expression was regulated in a positive feedback manner. In clinical HCC samples, TTYH3 was upregulated in the HCC tissues compared to nontumor tissues. Furthermore, high TTYH3 expression was significantly correlated with poor patient survival. The CpG islands were hypomethylated in the promoter region of TTYH3 in HCC tissues. In conclusion, we identified TTYH3 regulates tumor development and progression via MK5/GSK3-β/β-catenin signaling in HCC and promotes itself expression in a positive feedback loop.
| S-EPMC9274494 | biostudies-literature
Project description:ObjectiveColorectal cancer (CRC) is a prevalent malignant tumor with a high fatality rate. CircPDIA4 has been shown to have a vital role in cancer development by acting as a facilitator. Nevertheless, the impact of the circPDIA4/miR-9-5p/SP1 axis on development of CRC has not been studied.MethodsWestern blot, immunohistochemistry, and reverse transcription-quantitative polymerase chain reaction assays were used to analyze gene expression. The CCK-8 assay was used to assess cell growth. The Transwell assay was used to detect invasion and migration of cells. The luciferase reporter and RNA immunoprecipitation tests were used to determine if miR-9-5p and circPDIA4 (or SP1) bind to one another. An in vivo assay was used to measure tumor growth.ResultsIt was shown that circPDIA4 expression was greater in CRC cell lines and tissues than healthy cell lines and tissues. CircPDIA4 knockdown prevented the invasion, migration, and proliferation of cells in CRC. Additionally, the combination of circPDIA4 and miR-9-5p was confirmed, as well as miR-9-5p binding to SP1. Rescue experiments also showed that the circPDIA4/miR-9-5p/SP1 axis accelerated the development of CRC. In addition, SP1 combined with the promoter region of circPDIA4 and induced circPDIA4 transcription. CircPDIA4 was shown to facilitate tumor growth in an in vivo assay.ConclusionsThe circPDIA4/miR-9-5p/SP1 feedback loop was shown to aggravate CRC progression. This finding suggests that the ceRNA axis may be a promising biomarker for CRC patient treatment.
| S-EPMC11523275 | biostudies-literature
Project description:GLI1, a key transcription factor of the Hedgehog (Hh) signaling pathway, plays an important role in the development of cancer. However, the function and mechanisms by which GLI1 regulates gene transcription are not fully understood in gastric cancer (GC). Here, we found that GLI1 induced the proliferation and metastasis of GC cells, accompanied by transcriptional upregulation of INHBA. This increased INHBA expression exerted a promoting activity on Smads signaling and then transcriptionally activated GLI1 expression. Notably, our results demonstrate that disrupting the interaction between GLI1 and INHBA could inhibit GC tumorigenesis in vivo. More intriguingly, we confirmed the N6-methyladenosine (m6A) activation mechanism of the Helicobacter pylori/FTO/YTHDF2/GLI1 pathway in GC cells. In conclusion, our study confirmed that the GLI1/INHBA positive feedback loop influences GC progression and revealed the mechanism by which H. pylori upregulates GLI1 expression through m6A modification. This positive GLI1/INHBA feedback loop suggests a novel noncanonical mechanism of GLI1 activity in GC and provides potential therapeutic targets for GC treatment.
| S-EPMC11247559 | biostudies-literature
Project description:Tob1, a Tob/BTG anti-proliferative protein family member, functions as a tumour suppressor in many cancers. Here, we reveal a unique oncogenic role of Tob1 in colon cancer. Tob1 expression was upregulated during colon cancer progression, was significantly correlated with tumour size and tumour differentiation, and was a prognostic indicator of colon cancer. Unlike in other cancers, where nuclear Tob1 performs anticancer activity, Tob1 is predominantly localized in the cytosol of colon cancer cells, where this protein binds and stabilizes β-catenin to activate Wnt/β-catenin signalling, which in turn enhances Tob1 expression, thus forming a positive feedback loop to promote cell proliferation. Moreover, Tob1 deficiency led to reduced tumourigenesis in AOM/DSS-treated and ApcMin/+ mice. Our findings provide important insights into a previously unrecognized oncogenic role of Tob1 in colon cancer and suggest that Tob1 is an adverse prognostic factor and therapeutic target for colon cancer.
| S-EPMC6240287 | biostudies-literature
Project description:The microarray analysis was designed to test the effects of HES5.3 siRNAs, Atoh7 siRNAs and nt siRNAs on gene expression in embryonic chick retina.
2013-03-01 | E-MTAB-1430 | biostudies-arrayexpress
Project description:Cells respond to cytotoxic DNA double-strand breaks by recruiting repair proteins to the damaged site. Phosphorylation of the histone variant H2AX at S139 and Y142 modulate its interaction with downstream DNA repair proteins and their recruitment to DNA lesions. Here we report ATM-dependent ZNF506 localization to the lesion through MDC1 following DNA damage. ZNF506, in turn, recruits the protein phosphatase EYA, resulting in dephosphorylation of H2AX at Y142, which further facilitates the recruitment of MDC1 and other downstream repair factors. Thus, ZNF506 regulates the early dynamic signaling in the DNA damage response (DDR) pathway and controls progressive downstream signal amplification. Cells lacking ZNF506 or harboring mutations found in cancer patient samples are more sensitive to radiation, offering a potential new therapeutic option for cancers with mutations in this pathway. Taken together, these results demonstrate how the DDR pathway is orchestrated by ZNF506 to maintain genomic integrity.
| S-EPMC6048040 | biostudies-literature
Project description:How to distinguish indolent from aggressive disease remains a great challenge in prostate cancer (PCa) management. Cullin 4B (CUL4B) is a scaffold protein and exhibits oncogenic activity in a variety of human malignancies. In this study, we utilized PCa tissue specimens, cell lines and xenograft models to determine whether CUL4B contributes to PCa progression and metastasis. Here, we show that CUL4B expression highly correlates with the aggressiveness of PCa. CUL4B expression promotes proliferation, epithelial-mesenchymal transition, and metastatic potential of PCa cells, whereas CUL4B knockdown inhibits. Mechanically, CUL4B positively regulates SOX4, a key regulator in PCa, through epigenetic silencing of miR-204. In turn, SOX4 upregulates CUL4B expression through transcriptional activation, thereby fulfilling a positive feedback loop. Clinically, CUL4B+/SOX4+ defines a subset of PCa patients with poor prognosis. Bioinformatics analysis further reveals that Wnt/ß-catenin activation signature is enriched in CUL4B+/SOX4+ patient subgroup. Intriguingly, Wnt inhibitors significantly attenuates oncogenic capacities of CUL4B in vitro and in vivo. Together, our study identifies CUL4B as a key modulator of aggressive PCa by a positive feedback loop that interacts with SOX4. This regulatory circuit may have a crucial role in PCa progression.
| S-EPMC6418142 | biostudies-literature