Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA267201 | ENA |
REPOSITORIES: ENA
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Project description:Background Worldwide, gastric cancer is the fourth most common malignancy and the most common cancer in East Asia. Development of targeted therapies for this disease has focused on a few known oncogenes but has had limited effects. Objective To determine oncogenic mechanisms and novel therapeutic targets specific for gastric cancer by identifying commonly dys-regulated genes from the tumors of both Asian-Pacific and Caucasian patients. Design We generated transcriptomic profiles of 22 Caucasian gastric cancer tumors and their matched non-cancerous samples, and performed an integrative analysis across different gastric cancer gene expression datasets. We examined the inhibition of commonly overexpressed oncogenes and their constituent signaling pathways by RNAi and/or pharmacologic inhibition. Results We found that HNF4α upregulation was a key signaling event in gastric tumors from both Caucasian and Asian patients, and HNF4α antagonism was antineoplastic. Perturbation experiments in GC tumor cell lines and xenograft models further demonstrated that HNF4α is downregulated by AMPKα signaling and the AMPK agonist metformin; blockade of HNF4α activity resulted in cyclin downregulation, cell cycle arrest, and tumor growth inhibition. HNF4α also regulated WNT signaling through its target gene WNT5A, a potential prognostic marker of diffuse type gastric tumors. Conclusions Our results indicate that HNF4α is a targetable oncoprotein in gastric cancer, is regulated by AMPK signaling through AMPKα, and resides upstream of WNT signaling. HNF4α may regulate “metabolic switch” characteristic of a general malignant phenotype and its target WNT5A has potential prognostic values. The AMPKα-HNF4α-WNT5A signaling cascade represents a potentially targetable pathway for drug development. Integrative analysis of Caucasian and Asian-Pacific gastric tumor expression datasets (including newly generated transcriptomic profiling of 22 tumors in this study) revealed a relatively small common sets of highly overexpressed genes.
2014-11-15 | E-GEOD-63288 | biostudies-arrayexpress
Project description:Background Worldwide, gastric cancer is the fourth most common malignancy and the most common cancer in East Asia. Development of targeted therapies for this disease has focused on a few known oncogenes but has had limited effects. Objective To determine oncogenic mechanisms and novel therapeutic targets specific for gastric cancer by identifying commonly dys-regulated genes from the tumors of both Asian-Pacific and Caucasian patients. Design We generated transcriptomic profiles of 22 Caucasian gastric cancer tumors and their matched non-cancerous samples, and performed an integrative analysis across different gastric cancer gene expression datasets. We examined the inhibition of commonly overexpressed oncogenes and their constituent signaling pathways by RNAi and/or pharmacologic inhibition. Results We found that HNF4α upregulation was a key signaling event in gastric tumors from both Caucasian and Asian patients, and HNF4α antagonism was antineoplastic. Perturbation experiments in GC tumor cell lines and xenograft models further demonstrated that HNF4α is downregulated by AMPKα signaling and the AMPK agonist metformin; blockade of HNF4α activity resulted in cyclin downregulation, cell cycle arrest, and tumor growth inhibition. HNF4α also regulated WNT signaling through its target gene WNT5A, a potential prognostic marker of diffuse type gastric tumors. Conclusions Our results indicate that HNF4α is a targetable oncoprotein in gastric cancer, is regulated by AMPK signaling through AMPKα, and resides upstream of WNT signaling. HNF4α may regulate “metabolic switch” characteristic of a general malignant phenotype and its target WNT5A has potential prognostic values. The AMPKα-HNF4α-WNT5A signaling cascade represents a potentially targetable pathway for drug development.
2014-11-15 | GSE63288 | GEO
Project description:Gastric cancer is the most common cancer in Asia and most developing countries. To identify the molecular underpinnings of gastric cancer in the Asian population, we applied an RNA-sequencing approach to gastric tumor and noncancerous specimens to quantitatively characterize the entire transcriptome of gastric cancer (including mRNAs and microRNAs). A multi-layer analysis was then developed to identify multiple types of transcriptional aberrations associated with different stages of gastric cancer, including differentially expressed mRNAs, recurrent somatic mutations and key differentially expressed microRNAs. Through this approach, we identified the central metabolic regulator AMPK-α as a potential functional target in Asian gastric cancer. Further, we experimentally demonstrated the translational relevance of this gene as a potential therapeutic target for early-stage gastric cancer in Asian patients. Together, our findings not only provide a valuable information resource for identifying and elucidating the molecular mechanisms of Asian gastric cancer, but also represent a general integrative framework to develop more effective therapeutic targets.
2012-04-03 | GSE36968 | GEO
Project description:Gastric cancer is the most common cancer in Asia and most developing countries. To identify the molecular underpinnings of gastric cancer in the Asian population, we applied an RNA-sequencing approach to gastric tumor and noncancerous specimens to quantitatively characterize the entire transcriptome of gastric cancer (including mRNAs and microRNAs). A multi-layer analysis was then developed to identify multiple types of transcriptional aberrations associated with different stages of gastric cancer, including differentially expressed mRNAs, recurrent somatic mutations and key differentially expressed microRNAs. Through this approach, we identified the central metabolic regulator AMPK-M-NM-1 as a potential functional target in Asian gastric cancer. Further, we experimentally demonstrated the translational relevance of this gene as a potential therapeutic target for early-stage gastric cancer in Asian patients. Together, our findings not only provide a valuable information resource for identifying and elucidating the molecular mechanisms of Asian gastric cancer, but also represent a general integrative framework to develop more effective therapeutic targets. Using Life Technologies SOLiDM-bM-^DM-" sequencing platform, we performed transcriptome-wide profiling of gastric cancer samples from 30 anonymous, unrelated Asians of both sexes. Included were six noncancerous gastric tissue samples and 24 gastric tumor samples that represented stages I through IV of tumor development. From the WT-seq protocol we generated a WT-seq dataset of 2.1 billion 50-nt short reads from the 30 samples; Applying the second small RNA-seq protocol to 19 gastric tumor samples (5 of the original 24 yielded insufficient sample amounts) and 6 noncancerous gastric tissue samples resulted in a small RNA-seq dataset.
2012-04-03 | E-GEOD-36968 | biostudies-arrayexpress
Project description:Gastric cancer (GC) is a highly heterogeneous disease, having few “targeted” therapeutic drugs. Previously, we demonstrated involvement of HNF4α and WNT5A, as a prognostic GC biomarker. One previously discovered HNF4α antagonist, BI6015, demonstrated potent in vitro and in vivo hepatocellular cancer models. We extensively characterized the antineoplastic activity of derivatives of BI6015, including transfer of a nitro group from a para position to the ortho- and meta-positions. Biologic activity was assessed by treatment efficacy against a panel of GC cell lines, including pathway and functional analysis. The para positioned BI6105 compound was found substantially more growth-inhibitory, and effective in downregulating numerous oncogenic signal pathways, including the embryonic cascade WNT, and suggested WNT5A as a possible therapeutic biomarker. Here, we present a strategy for identifying effective transcription factor inhibitors and their impact on specific signaling pathways, which may provide prognostic and therapeutic biomarkers.
2019-04-17 | GSE114626 | GEO
Project description:In this study we show that UC.145 may serve as an effective therapeutic target for molecular-targeted therapy resulting in the inhibition of Wnt signaling within gastric cancer cells.
2021-05-25 | GSE175423 | GEO
Project description:Gastric cancer is a global health concern. Molecular alterations in various signaling pathways have been implicated in the development and late-stage progression/metastasis of gastric cancer. Reports have suggested that Wnt signaling pathway might contribute to gastric carcinogenesis by stimulating migration and invasion of gastric cancer cells. This study aimed at analysing the proteome change upon CAMKK2 inhibition in gastric cancer cells using LC-MS/MS based quantitative proteomic approach. A TMT based quantitative approach was used to identify the significantly altered proteins upon CAMKK2 inhibition. Gene Ontology (GO) analysis and pathway analysis was done for the significantly altered proteins and was later validated by immunoblotting.
2021-04-13 | PXD023423 | Pride
Project description:Hepatocyte-nuclear-factor-4α (Hnf4α) is a transcription factor that controls epithelial cell polarity and maturation during embryogenesis. Hnf4α conditional deletion during post-natal development results in minor consequences on intestinal epithelium integrity but promotes activation of the Wnt/β-catenin pathway. Here we show that Hnf4α does not act as a tumor suppressor gene but is crucial to promote gut tumorigenesis in mice. Polyp multiplicity in ApcMin mice that lacks Hnf4α is suppressed in comparison to littermate ApcMin controls. Analysis of microarray gene expression profiles from mice lacking Hnf4α in the intestinal epithelium identifies its novel function in regulating the expression of reactive oxygen species (ROS) detoxifying genes. This role is supported with the demonstration that HNF4α is functionally involved in the protection against spontaneous and 5-fluorouracil chemotherapy-induced production of intracellular ROS in colorectal cancer cell lines. The analysis of a colorectal cancer patient cohort establishes that HNF4α is significantly up-regulated at both gene transcript and protein levels in tumors relative to adjacent benign epithelial resections. Several genes involved in ROS neutralization are also up-regulated in correlation with HNF4α expression. All together, the findings point to the nuclear receptor HNF4α as a potential therapeutic target to eradicate aberrant epithelial cell resistance to ROS production during intestinal tumorigenesis.
2011-01-01 | GSE20968 | GEO
Project description:Most gastric cancer (GC) patients with early stage often have no lymph node (LN) metastases, while LN metastases appear in the advanced stage. However, there are some patients who present with early stage LN metastases and no LN metastases in the advanced stage. To explore the deeper molecular mechanisms involved, we collected clinical samples from early and advanced stage GC with and without LN metastases, as well as metastatic lymph nodes. Herein, we identified a keytarget, HOXA11, that was upregulated in GC tissues and closely associated with lymphatic metastases. HOXA11 transcriptionally regulates TGFβ1 expression and activates the TGFβ1/Smad2 pathway, which in turn promotes the development of EMT. In addition, enhanced Smad2 expression promotes the secretion of VEGF-C, which in turn induces lymphangiogenesis. These findings provide a plausible mechanism forHOXA11-modulated tumor in lymphatic metastasis and suggest thatHOXA11 may represent a potential therapeutic target for clinical intervention in LN-metastatic gastric cancer.
2023-11-08 | GSE246963 | GEO
Project description:Wnt signaling is intrinsic to mouse embryonic stem cell self-renewal. Therefore it is surprising that reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) is not strongly enhanced by Wnt signaling. Here, we demonstrate that active Wnt signaling inhibits the early stage of reprogramming to iPSCs, while it is required and even stimulating during the late stage. Mechanistically, this biphasic effect of Wnt signaling is accompanied by a change in the requirement of all four of its transcriptional effectors: Tcf1, Lef1, Tcf3, and Tcf4. For example, Tcf3 and Tcf4 are stimulatory early but inhibitory late in the reprogramming process. Accordingly, ectopic expression of Tcf3 early in reprogramming combined with its loss-of-function late enables efficient reprogramming in the absence of ectopic Sox2. Together, our data indicate that the step-wise process of reprogramming to iPSCs is critically dependent on the stage-specific control and action of all four Tcfs and Wnt signaling.
2013-05-01 | GSE46532 | GEO