PGC1α suppresses kidney cancer progression by inhibiting collagen-induced SNAIL expression.
Ontology highlight
ABSTRACT:
SUBMITTER: Nam H
PROVIDER: S-EPMC7712461 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:ETS homologous factor (EHF) belongs to the epithelium-specific subfamily of the E26 transformation-specific (ETS) transcription factor family. Currently, little is known about EHF's function in cancer. We previously reported that ETS1 induces expression of the ZEB family proteins ZEB1/δEF1 and ZEB2/SIP1, which are key regulators of the epithelial-mesenchymal transition (EMT), by activating the ZEB1 promoters. We have found that EHF gene produces two transcript variants, namely a long form variant that includes exon 1 (EHF-LF) and a short form variant that excludes exon 1 (EHF-SF). Only EHF-SF abrogates ETS1-mediated activation of the ZEB1 promoter by promoting degradation of ETS1 proteins, thereby inhibiting the EMT phenotypes of cancer cells. Most importantly, we identified a novel point mutation within the conserved ETS domain of EHF, and found that EHF mutations abolish its original function while causing the EHF protein to act as a potential dominant negative, thereby enhancing metastasis in vivo. Therefore, we suggest that EHF acts as an anti-EMT factor by inhibiting the expression of ZEBs, and that EHF mutations exacerbate cancer progression.
| S-EPMC7955083 | biostudies-literature
Project description:BackgroundHippo/YAP pathway is known to be important for development, growth and organogenesis, and dysregulation of this pathway leads to tumor progression. We and others find that YAP is up-regulated in pancreatic ductal adenocarcinoma (PDAC) and associated with worse prognosis of patients. Activated pancreatic stellate cells (PSCs) forming the components of microenvironment that enhance pancreatic cancer cells (PCs) invasiveness and malignance. However, the role and mechanism of YAP in PDAC tumor-stromal interaction is largely unknown.MethodsThe expression of YAP in Pancreatic cancer cell lines and PDAC samples was examined by Western blot and IHC. The biological role of YAP on cancer cell proliferation, epithelial-mesenchymal transition (EMT) and invasion were evaluated by MTT, Quantitative real-time PCR analysis, Western blot analysis and invasion assay. The effect of YAP on PSC activation was evaluated by PC-PSC co-culture conditions and xenograft PDAC mouse model.ResultsFirstly, knockdown of YAP inhibits PDAC cell proliferation and invasion in vitro. In addition, YAP modulates the PC and PSC interaction via reducing the production of connective tissue growth factor (CTGF) from PCs, inhibits paracrine-mediated PSC activation under PC-PSC co-culture conditions and in turn disrupts TGF-β1-mediated tumor-stromal interactions. Lastly, inhibiting YAP expression prevents tumor growth and suppresses desmoplastic reaction in vivo.ConclusionsThese results demonstrate that YAP contributes to the proliferation and invasion of PC and the activation of PSC via tumor-stromal interactions and that targeting YAP may be a promising therapeutic strategy for PDAC treatment.
| S-EPMC5870346 | biostudies-literature
Project description:Cell growth and proliferation are tightly coupled to metabolism, and dissecting the signaling molecules which link these processes is an important step toward understanding development, regeneration, and cancer. The transcriptional regulator Yes-associated protein 1 (YAP) is a key regulator of liver size, development, and function. We now show that YAP can also suppress gluconeogenic gene expression. Yap deletion in primary hepatocytes potentiates the gluconeogenic gene response to glucagon and dexamethasone, whereas constitutively active YAP suppresses it. The effects of YAP are mediated by the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1. YAP inhibits its ability to bind to and activate transcription from the promoters of its gluconeogenic targets, and the effects of YAP are blunted upon its knockdown. In vivo, constitutively active YAP lowers plasma glucose levels and increases liver size.ConclusionYAP appears to reprogram cellular metabolism, diverting substrates away from the energy-consuming process of gluconeogenesis and toward the anabolic process of growth. (Hepatology 2017;66:2029-2041).
| S-EPMC6082140 | biostudies-literature
Project description:Scutellaria baicalensis (S. baicalensis) is a plant that is widely used for medicinal purposes. Baicalein, one of the primary bioactive compounds found in S. baicalensis, is thought to possess antitumor activity, although the specific mechanisms remain unclear. Therefore, the present study aimed to evaluate the ability of baicalein to disrupt the proliferation and metastatic potential of colorectal cancer (CRC) cells; a rapid and sensitive ultra?high performance liquid chromatography?tandem mass spectrometric method was employed for the identification of baicalein in an S. baicalensis aqueous extract and in rat plasma. To investigate the effects of baicalein, Cell Counting Kit?8 (CCK?8), western blotting, wound?healing and Transwell assays were performed. The data indicated that baicalein was absorbed into the blood and was able to effectively disrupt the proliferation, migration and invasion abilities of CRC cells in a dose? and time?dependent manner. Baicalein treatment was also revealed to decrease the expression of epithelial?mesenchymal transition (EMT)?promoting factors including vimentin, Twist1, and Snail, but to upregulate the expression of E?cadherin in CRC cells. The expression levels of cell cycle inhibitory proteins p53 and p21 also increased following baicalein treatment. In addition, Snail?induced vimentin and Twist1 upregulation, as well as E?cadherin downregulation, were reversed following treatment with baicalein. In conclusion, the results of the present study indicate that baicalein may suppress EMT, at least in part, by decreasing Snail activity.
| S-EPMC7185271 | biostudies-literature
Project description:Klotho is an anti-aging protein predominantly expressed in renal tubular epithelial cells. Although Klotho was recently identified as a tumor suppressor gene in a variety of cancers, the potential role and molecular events for Klotho in renal cell carcinoma (RCC) remain obscure. In the present study, immunohistochemical staining in tissue microarrays containing 125 RCC samples showed that intratumoral Klotho levels were negatively correlated with tumor size, TNM stage and nuclear grade. The overall survival rate of RCC patients with high Klotho expression was significantly higher than that of patients with low Klotho expression. Functional analysis after gain and loss of Klotho expression revealed that Klotho blunted epithelial-mesenchymal transition and cellular migration and invasion in RCC. Also, no alteration of ?-2,6-sialidase activity was found after Klotho overexpression in RCC. The molecular signals for this phenomenon involved the Klotho-mediated inhibition of PI3K/Akt/GSK3?/Snail pathway. Importantly, compared to localized RCC tissues, advanced RCC tissues exhibited low Klotho expression accompanied with high pAkt and Snail expression. These results indicate Klotho acts as a tumor suppressor by inhibiting PI3K/Akt/GSK3?/Snail signaling, thus suppressing epithelial-mesenchymal transition and tumor migration and invasion during RCC progression. As a result, Klotho might be used as a potential therapy for advanced RCC.
| S-EPMC7657207 | biostudies-literature
Project description:BACKGROUND:Circular RNAs (circRNAs), a subclass of non-coding RNAs, play essential roles in tumorigenesis and aggressiveness. Our previous study has identified that circAGO2 drives gastric cancer progression through activating human antigen R (HuR), a protein stabilizing AU-rich element-containing mRNAs. However, the functions and underlying mechanisms of circRNAs derived from HuR in gastric cancer progression remain elusive. METHODS:CircRNAs derived from HuR were detected by real-time quantitative RT-PCR and validated by Sanger sequencing. Biotin-labeled RNA pull-down, mass spectrometry, RNA immunoprecipitation, RNA electrophoretic mobility shift, and in vitro binding assays were applied to identify proteins interacting with circRNA. Gene expression regulation was observed by chromatin immunoprecipitation, dual-luciferase assay, real-time quantitative RT-PCR, and western blot assays. Gain- and loss-of-function studies were performed to observe the impacts of circRNA and its protein partner on the growth, invasion, and metastasis of gastric cancer cells in vitro and in vivo. RESULTS:Circ-HuR (hsa_circ_0049027) was predominantly detected in the nucleus, and was down-regulated in gastric cancer tissues and cell lines. Ectopic expression of circ-HuR suppressed the growth, invasion, and metastasis of gastric cancer cells in vitro and in vivo. Mechanistically, circ-HuR interacted with CCHC-type zinc finger nucleic acid binding protein (CNBP), and subsequently restrained its binding to HuR promoter, resulting in down-regulation of HuR and repression of tumor progression. CONCLUSIONS:Circ-HuR serves as a tumor suppressor to inhibit CNBP-facilitated HuR expression and gastric cancer progression, indicating a potential therapeutic target for gastric cancer.
| S-EPMC6852727 | biostudies-literature
Project description:NOP14, which is functionally conserved among eukaryotes, has been implicated in cancer development. Here, we show that NOP14 is poorly expressed in breast cancer cells and invasive breast cancer tissues. In vivo and in vitro studies indicated that NOP14 suppressed the tumorigenesis and metastasis of breast cancer cells. Further investigations revealed that NOP14 enhanced ER? expression and inhibited the Wnt/?-catenin pathway by up-regulating NRIP1 expression. Survival analysis indicated that low NOP14 expression was significantly associated with poor overall survival (P = 0.0006) and disease-free survival (P = 0.0007), suggesting that NOP14 is a potential prognostic factor in breast cancer. Taken together, our findings reveal that NOP14 may suppress breast cancer progression and provide new insights into the development of targeted therapeutic agents for breast cancer.
| S-EPMC4694860 | biostudies-other
Project description:Cellular transformation and cancer progression is accompanied by changes in the metabolic landscape. Master co-regulators of metabolism orchestrate the modulation of multiple metabolic pathways through transcriptional programs, and hence constitute a probabilistically parsimonious mechanism for general metabolic rewiring. Here we show that the transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator 1α (PGC1α) suppresses prostate cancer progression and metastasis. A metabolic co-regulator data mining analysis unveiled that PGC1α is downregulated in prostate cancer and associated with disease progression. Using genetically engineered mouse models and xenografts, we demonstrated that PGC1α opposes prostate cancer progression and metastasis. Mechanistically, the use of integrative metabolomics and transcriptomics revealed that PGC1α activates an oestrogen-related receptor alpha (ERRα)-dependent transcriptional program to elicit a catabolic state and metastasis suppression. Importantly, a signature based on the PGC1α-ERRα pathway exhibited prognostic potential in prostate cancer, thus uncovering the relevance of monitoring and manipulating this pathway for prostate cancer stratification and treatment.
| S-EPMC4884178 | biostudies-literature
Project description:BackgroundTissue factor pathway inhibitor 2 (TFPI2) participates in carcinogenesis of various tumors, and is associated with poor survival of breast cancer patients. However, the effect and underlying mechanism of TFPI2 on breast cancer progression remains to be investigated.MethodsThe expression level of TFPI2 in breast cancer tissues and cell lines was examined via qRT-PCR (quantitative real-time polymerase chain reaction) and immunohistochemistry. CCK8 (Cell Counting Kit-8), colony formation, wound healing or transwell assays were used to detect cell viability, proliferation, migration or invasion, respectively. In vivo subcutaneous xenotransplanted tumor model was established to detect tumorigenic function of TFPI2, and the underlying mechanism was evaluated by immunohistochemistry and western blot.ResultsTFPI2 was down-regulated in breast cancer tissues and cell lines, and was associated with poor prognosis of patients diagnosed with breast cancer. Over-expression of TFPI2 inhibited cell viability, proliferation, migration and invasion of breast cancer cells. Mechanistically, Twist-related protein 1 (TWIST1) was negatively associated with TFPI2 in breast cancer patients, whose expression was decreased by TFPI2 over-expression or increased by TFPI2 knockdown. Moreover, TWIST1 could up-regulate integrin α5 expression. Functional assays indicated that the inhibition abilities of TFPI2 over-expression on breast cancer progression were reversed by TWIST1 over-expression. In vivo subcutaneous xenotransplanted tumor model also revealed that over-expression of TFPI2 could suppress breast tumor growth via down-regulation of TWIST1-mediated integrin α5 expression.ConclusionsTFPI2 suppressed breast cancer progression through inhibiting TWIST-integrin α5 pathway, providing a new potential therapeutic target for breast cancer treatment.
| S-EPMC7133004 | biostudies-literature
Project description:Elevated lipid metabolism promotes cancer cell proliferation. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancers, characterized by ectopic lipid accumulation. However, the relationship between aberrant lipid metabolism and tumorigenesis in ccRCC is not thoroughly understood. Here, we demonstrate that ring finger protein 20 (RNF20) acts as a tumor suppressor in ccRCC. RNF20 overexpression repressed lipogenesis and cell proliferation by inhibiting sterol regulatory element-binding protein 1c (SREBP1c), and SREBP1 suppression, either by knockdown or by the pharmacological inhibitor betulin, attenuated proliferation and cell cycle progression in ccRCC cells. Notably, SREBP1c regulates cell cycle progression by inducing the expression of pituitary tumor-transforming gene 1 (PTTG1), a novel target gene of SREBP1c. Furthermore, RNF20 overexpression reduced tumor growth and lipid storage in xenografts. In ccRCC patients, RNF20 downregulation and SREBP1 activation are markers of poor prognosis. Therefore, RNF20 suppresses tumorigenesis in ccRCC by inhibiting the SREBP1c-PTTG1 axis.
| S-EPMC5660462 | biostudies-literature