Browse
Submit Data
Databases
API
Help

Dataset Information

19 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

USP22 exerts tumor-suppressive functions in colorectal cancer by decreasing mTOR activity.

ABSTRACT: USP22, the deubiquitinating subunit of the SAGA transcriptional cofactor complex, is a member of an 11-gene "death-from-cancer" signature. USP22 has been considered an attractive therapeutic target since high levels of its expression were associated with distant metastasis, poor survival, and high recurrence rates in a wide variety of solid tumors, including colorectal cancer (CRC). We sought to investigate the role of Usp22 during tumorigenesis in vivo using a mouse model for intestinal carcinogenesis with a tissue-specific Usp22 ablation. In addition, we assessed the effects of USP22 depletion in human CRC cells on tumorigenic potential and identified underlying molecular mechanisms. For the first time, we report that USP22 has an unexpected tumor-suppressive function in vivo. Intriguingly, intestine-specific Usp22 deletion exacerbated the tumor phenotype caused by Apc mutation, resulting in significantly decreased survival and higher intestinal tumor incidence. Accordingly, human CRC cells showed increased tumorigenic properties upon USP22 reduction in vitro and in vivo and induced gene expression signatures associated with an unfavorable outcome in CRC patients. Notably, USP22 loss resulted in increased mTOR activity with the tumorigenic properties elicited by the loss of USP22 being reversible by mTOR inhibitor treatment in vitro and in vivo. Here, we demonstrate that USP22 can exert tumor-suppressive functions in CRC where its loss increases CRC burden by modulating mTOR activity. Importantly, our data uncover a tumor- and context-specific role of USP22, suggesting that USP22 expression could serve as a marker for therapeutic stratification of cancer patients.

SUBMITTER: Kosinsky RL

PROVIDER: S-EPMC7205880 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

miR-1272 Exerts Tumor-Suppressive Functions in Prostate Cancer via HIP1 Suppression.

Project description:The development of novel therapies or the improvement of currently used approaches to treat prostate cancer (PCa), the most frequently diagnosed male tumor in developed countries, is an urgent need. In this regard, the functional characterization of microRNAs, molecules shown to regulate a number of cancer-related pathways, is instrumental to their possible clinical exploitation. Here, we demonstrate the tumor-suppressive role of the so far uncharacterized miR-1272, which we found to be significantly down-modulated in PCa clinical specimens compared to normal tissues. Through a gain-of-function approach using miRNA mimics, we showed that miR-1272 supplementation in two PCa cell models (DU145 and 22Rv1) reverted the mesenchymal phenotype by affecting migratory and invasive properties, and reduced cell growth in vitro and in vivo in SCID mice. Additionally, by targeting HIP1 encoding the endocytic protein HIP1, miR-1272 balanced EGFR membrane turnover, thus affecting the downstream AKT/ERK pathways, and, ultimately, increasing PCa cell response to ionizing radiation. Overall, our results show that miR-1272 reconstitution can affect several tumor traits, thus suggesting this approach as a potential novel therapeutic strategy to be pursued for PCa, with the multiple aim of reducing tumor growth, enhancing response to radiotherapy and limiting metastatic dissemination.

| S-EPMC7072756 | biostudies-literature

Long intergenic non-coding RNA LINC00485 exerts tumor-suppressive activity by regulating miR-581/EDEM1 axis in colorectal cancer.

Project description:Long non-coding RNAs (lncRNA) play a vital role in colorectal cancer (CRC) progression. To investigate the role of long intergenic non-coding RNA LINC00485 in CRC, we performed in vitro functional experiments. LoVo tumor-bearing and liver metastasis mice were used as in vivo models. We found that LINC00485 expression was significantly lower in CRC tissues and cancer cells than in paired normal samples and human normal colonic epithelial cells. Lower expression of LINC00485 predicted poor prognosis in CRC patients. LINC00485 knockdown promoted the proliferation, migration, and invasion of FHC cells, while LINC00485 overexpression weakened these abilities of LoVo cells. MicroRNA miR-581 was the downstream target of LINC00485, which was downregulated in CRC samples and cancer cells compared to normal tissues and normal colonic epithelial cells. MiR-581 overexpression induced proliferation, migration, and invasion of FHC cells, while miR-581 antagomir treatment produced opposite results. MiR-581 directly targeted the 3'UTR of EDEM1 and inhibited its expression and induction of epithelial-mesenchymal transition of CRC. In mouse models, LINC00485 knockdown or down-regulation of miR-581 significantly repressed CRC cell growth and prevented CRC liver metastasis. Overall, LINC00485 suppressed CRC tumorigenesis and progression by targeting the miR-581/EDEM1 axis. LINC00485 may be a potential therapeutic target for CRC.

| S-EPMC7906134 | biostudies-literature

ZMYND10, an epigenetically regulated tumor suppressor, exerts tumor-suppressive functions via miR145-5p/NEDD9 axis in breast cancer.

Project description:BACKGROUND:Recent studies suggested that ZMYND10 is a potential tumor suppressor gene in multiple tumor types. However, the mechanism by which ZMYND10 inhibits breast cancer remains unclear. Here, we investigated the role and mechanism of ZMYND10 in breast cancer inhibition. RESULTS:ZMYND10 was dramatically reduced in multiple breast cancer cell lines and tissues, which was associated with promoter hypermethylation. Ectopic expression of ZMYND10 in silenced breast cancer cells induced cell apoptosis while suppressed cell growth, cell migration and invasion in vitro, and xenograft tumor growth in vivo. Furthermore, molecular mechanism studies indicated that ZMYND10 enhances expression of miR145-5p, which suppresses the expression of NEDD9 protein through directly targeting the 3'-untranslated region of NEDD9 mRNA. CONCLUSIONS:Results from this study show that ZMYND10 suppresses breast cancer tumorigenicity by inhibiting the miR145-5p/NEDD9 signaling pathway. This novel discovered signaling pathway may be a valid target for small molecules that might help to develop new therapies to better inhibit the breast cancer metastasis.

| S-EPMC6894283 | biostudies-literature

Estrogen receptor β exerts tumor suppressive effects in prostate cancer through repression of androgen receptor activity.

Project description:Estrogen receptor β (ERβ) was first identified in the rodent prostate and is abundantly expressed in human and rodent prostate epithelium, stroma, immune cells and endothelium of the blood vessels. In the prostates of mice with inactivated ERβ, mutant phenotypes include epithelial hyperplasia and increased expression of androgen receptor (AR)-regulated genes, most of which are also upregulated in prostate cancer (PCa). ERβ is expressed in both basal and luminal cells in the prostate while AR is expressed in luminal but not in the basal cell layer which harbors the prostate stem cells. To investigate the mechanisms of action of ERβ and its potential cross-talk with AR, we used RNA-seq to study the effects of estradiol or the synthetic ligand, LY3201, in AR-positive LNCaP PCa cells which had been engineered to express ERβ. Transcriptomic analysis indicated relatively few changes in gene expression with ERβ overexpression, but robust responses following ligand treatments. There is significant overlap of responsive genes between the two ligands, estradiol and LY3201 as well as ligand-specific alterations. Gene set analysis of down-regulated genes identified an enrichment of androgen-responsive genes, such as FKBP5, CAMKK2, and TBC1D4. Consistently, AR transcript, protein levels, and transcriptional activity were down-regulated following ERβ activation. In agreement with this, we find that the phosphorylation of the CAMKK2 target, AMPK, was repressed by ligand-activated ERβ. These findings suggest that ERβ-mediated signaling pathways are involved in the negative regulation of AR expression and activity, thus supporting a tumor suppressive role for ERβ in PCa.

| S-EPMC7228066 | biostudies-literature

FAM83A exerts tumor?suppressive roles in cervical cancer by regulating integrins.

Project description:Family with sequence similarity 83 member A (FAM83A) has been recently observed to be upregulated in various types of cancer and hypothesized to be serve as an oncogene. The present study aimed to determine the functional roles and the underlying molecular mechanism of FAM83A in cervical cancer. The results demonstrated that although FAM83A expression was increased in cervical cancer compared with normal tissues, the expression levels of FAM83A were decreased in patients with advanced FIGO stage, deep stromal invasion, poor differentiation and/or lymph node metastasis and negatively associated with short survival time of patients with cervical cancer. FAM83A knockdown promoted cell proliferative, migratory and invasive abilities of CaSki and HeLa cells. A mouse xenograft model demonstrated that FAM83A knockdown promoted tumor growth in vivo. Mechanistically, RNA sequencing results revealed that knockdown of FAM83A increased the transcription of genes mainly associated with oncogenesis?associated pathways. In addition, FAM83A knockdown increased the protein levels of ?1, ?3, ?5, ?4 and ?5 integrins in vitro and in vivo, and the expression of FAM83A was also negatively associated with the levels of these proteins in human cervical cancer tissue samples. In conclusion, the results of the present study suggested that FAM83A may exert a tumor?suppressive role in cervical cancer by suppressing the expression of integrins, which may offer new insight into the biological basis of cervical cancer.

| S-EPMC7307588 | biostudies-literature

MiR-449a exerts tumor-suppressive functions in human glioblastoma by targeting Myc-associated zinc-finger protein.

Project description:Glioblastoma (GBM) is one of the most common and aggressive primary brain tumors in adults. Deregulated expression of microRNAs (miRNAs) has been associated with GBM progression through alterations in either oncogenic or tumor suppressor targets. Here, we elucidated the function and the possible molecular mechanisms of miR-449a in human GBM cell lines and tumor specimens-derived glioblastoma stem cells (GSCs). Quantitative real-time PCR demonstrated that miR-449a was down-regulated in human GBM cell lines and GSCs. Functionally, miR-449a acted as a tumor suppressor by reducing cell proliferation, migration and invasion as well as inducing apoptosis in human GBM cell lines and GSCs. Myc-associated zinc-finger protein (MAZ) was identified as a direct target of miR-449a, mediating these tumor-suppressive effects, demonstrated by Western blot assay and luciferase assays. Moreover, over-expression of miR-449a inhibited the expression of Podoplanin (PDPN) by down-regulating MAZ which could positively control the promoter activities via binding to the promoter of PDPN, demonstrated by luciferase assays and chromatin immunoprecipitation assays. Further, the PI3K/AKT pathway was blocked when MAZ was down-regulated by miR-449a. This process was coincided with the up-regulation of apoptotic proteins and the down-regulation of anti-apoptotic proteins, MMP2 and MMP9. Furthermore, nude mice carrying over-expressed miR-449a combined with knockdown MAZ tumors produced the smallest tumors and the highest survival. These results elucidated a novel molecular mechanism of GBM progression, and may thus suggest a promising application for GBM treatment.

| S-EPMC5528701 | biostudies-other

FGF14 Functions as a Tumor Suppressor through Inhibiting PI3K/AKT/mTOR Pathway in Colorectal Cancer.

Project description:We identified that Fibroblast Growth Factor 14 (FGF14) was preferentially methylated in colorectal cancer (CRC). In this study, we aimed to investigate the epigenetic regulation, biological function and molecular mechanism of FGF14 in CRC. The expression of FGF14 in CRC cell lines, normal human colon epithelial cell line, CRC tissues and paired adjacent normal tissues was detected by PCR and Western blot. The biological function of FGF14 in CRC was interrogated by cell viability assay, colony formation, flow cytometry, cell invasion and migration assay, as well as in vivo study. We found FGF14 was downregulated or silenced in all (10/10) CRC cell lines, while it was expressed in normal colonic tissues and normal human colon epithelial cell line. The expression of FGF14 was lower in primary CRCs as compared to their adjacent normal tissues. Significant higher methylation of FGF14 was observed in CRCs than that in normal tissues based on the data from TCGA database. The loss of FGF14 gene expression was restored by treatment with DNA methyltransferase inhibitor 5-Aza. Re-expression of FGF14 in CRC cell lines inhibited cell viability and colony formation, and induced cell apoptosis. FGF14 induced mitochondrial apoptosis and inhibited PI3K/AKT/mTOR pathway. In xenograft mouse model, overexpression of FGF14 significantly reduced tumor growth (P<0.001). In conclusion, FGF14 is a novel tumor suppressor, which suppresses cell proliferation and induces cell apoptosis via mediating PI3K/AKT/mTOR pathway.

| S-EPMC6959027 | biostudies-literature

Tumor suppressive function of IGF2BP1 in gastric cancer through decreasing MYC

Project description:Gastric cancer is one of the most common causes of cancer-related death worldwide. The N6-methyladenosine (m6A) reader IGF2BP1 (insulin-like growth factor-2 mRNA binding protein 1) has been reported to promote cancer progression by stabilizing oncogenic mRNAs through its m6A-binding activity in some tumors. However, the role of IGF2BP1 in gastric carcinogenesis remains unclear. In this study, we find that IGF2BP1 is significantly downregulated in tumor tissues from patients with gastric cancer. Lower expression of IGF2BP1 is associated with poor prognosis. IGF2BP1 suppresses gastric cancer cell proliferation in an m6A-dependent manner. Additionally, IGF2BP1 is able to significantly attenuate tumor growth of gastric cancer cells. Further m6A sequencing and m6A-RIP (RNA immunoprecipitation) assays show that MYC (c-myc proto-oncogene) mRNA is a target transcript of IGF2BP1 in gastric cancer cells. IGF2BP1 inhibits gastric cancer cell proliferation by reducing the mRNA and protein expression of MYC. Mechanistically, IGF2BP1 promotes the degradation of MYC mRNA and inhibits its translation efficiency. Taken together, these data suggest that IGF2BP1 plays a tumor-suppressive role in gastric carcinogenesis by downregulating MYC in an m6A-dependent manner, thereby making the IGF2BP1-MYC axis a potential target for gastric cancer treatment.

2024-02-26 | GSE243617 | GEO

Sophoridine exerts tumor-suppressive activities via promoting ESRRG-mediated ?-catenin degradation in gastric cancer.

Project description:BackgroundAs a natural alkaloid product isolated from Sophora alopecuroides. L, Sophoridine reshapes gastric cancer immune microenvironment via inhibiting chemotaxis and M2 polarization of tumor-associated macrophages (TAMs). However, the exact effects and underlying mechanism of Sophoridine on gastric cancer cells remains poorly known.MethodsThe potential anti-tumor effects of Sophoridine on gastric cancer cell lines, including AGS and SGC7901 cells, were detected by CCK-8, EDU and colony forming assay, immunofluorescence, transwell assay, and flow cytometry. Molecular mechanisms of Sophoridine were investigated by siRNA transfection, nuclear/cytoplasmic extraction and western blot. The synergistic effects of Sophoridine with cisplatin on gastric cancer cells were further investigated in in vitro functional studies.ResultsSophoridine exhibited potent tumor-suppressive activities in gastric cancer cells, including inhibition of proliferation, colony formulation, migration and invasion, as well as induction of apoptosis. In addition, we further showed that Sophoridine induced G2/M cell cycle arrest via inhibiting double-stranded DNA breaks repair and enhanced the efficacy of cisplatin in gastric cancer cells. Molecular studies further revealed that Sophoridine promoted ?-catenin degradation by enhancing Estrogen-related receptor gamma (ESRRG) expression, but not depended on ubiquitination-proteasome pathway, either TRIM33-mediated (GSK3?-independent) or altered GSK3? activity, and thus exerted potent tumor-suppressive activities.ConclusionSophoridine depends on targeting ESRRG/?-catenin pathway to exert tumor-suppressive activities in gastric cancer cells and enhances the anti-tumor effect of cisplatin. Our study provided the promising preclinical anti-tumor evidence for the potential application of Sophoridine against gastric cancer.

| S-EPMC7310191 | biostudies-literature

Tumor-suppressive microRNA-218 inhibits tumor angiogenesis via targeting the mTOR component RICTOR in prostate cancer.

Project description:MicroRNAs, a kind of small non-coding RNAs, can regulate gene expression by targeting mRNAs for translational repression or degradation. Much evidence has suggested that miR-218 was a tumor suppressor in many human cancers including prostate cancer. However, the underlying role of miR-218 in tumor angiogenesis and the mechanisms in PCa and other cancers remains to be unclear. Here in this present study, we demonstrated that miR-218 inhibited the tumor angiogenesis of PCa cells in vitro and in vivo. RICTOR, the mTOR component 2, was a direct target of miR-218 and miR218-RICTOR-VEGFA axis was the mechanism inhibiting the tumor angiogenesis of PCa cells. RICTOR knockdown phenocopied miR-218 overexpression in inhibiting prostate cancer angiogenesis. Altogether, our findings indicate that down-regulation of miR-218 contributes to tumor angiogenesis through RICTOR/VEGFA axis in PCa, providing new insights into the potential mechanisms of PCa oncogenesis and revealing the potential of miR-218 as a useful serum biomarker and a new therapeutic target for human PCa.

| S-EPMC5352391 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data