The Multifaceted Role of TGF-β in Gastrointestinal Tumors.
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ABSTRACT:
SUBMITTER: Sabbadini F
PROVIDER: S-EPMC8391793 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:TGF-? and its signaling pathways are important mediators in the suppression of cancers of the gastrointestinal tract. TGF-? is released from cells in a latent complex consisting of TGF-?, the TGF-? propeptide [latency associated protein (LAP)], and a latent TGF-? binding protein (LTBP). We previously generated mice in which the LTBP-binding cysteine residues in LAP TGF-?1 were mutated to serine precluding covalent interactions with LTBP. These Tgfb1(C33S/C33S) mice develop multiorgan inflammation and tumors consistent with reduced TGF-?1 activity. To test whether further reduction in active TGF-? levels would yield additional tumors and a phenotype more similar to Tgfb1(-/-) mice, we generated mice that express TGF-?1(C33S) and are deficient in either integrin ?8 or TSP-1, known activators of latent TGF-?1. In addition, we generated mice that have one mutant allele and one null allele at the Tgfb1 locus, reasoning that these mice should synthesize half the total amount of TGF-?1 as Tgfb1(C33S/C33S) mice, and the amount of active TGF-?1 would be correspondingly decreased compared with Tgfb1(C33S/C33S) mice. These compound-mutant mice displayed more severe inflammation and higher tumor numbers than the parental Tgfb1(C33S/C33S) animals. The level of active TGF-?1 in compound mutant mice seemed to be decreased compared with Tgfb1(C33S/C33S) mice as determined from analyses of surrogate markers of active TGF-?, such as P-Smad2, C-Myc, KI-67, and markers of cell-cycle traverse. We conclude that these mutant mice provide a useful system for modulating TGF-? levels in a manner that determines tumor number and inflammation within the gastrointestinal tract.
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Project description:Early detection of gastrointestinal tumors improves patient survival. However, patients with these tumors are typically diagnosed at an advanced stage and have poor prognosis. The incidence and mortality of gastrointestinal cancers, including esophageal, gastric, liver, colorectal, and pancreatic cancers, are increasing worldwide. Novel diagnostic and therapeutic agents are required to improve patient survival and quality of life. The tumor microenvironment, which contains nontumor cells, signaling molecules such as growth factors and cytokines, and extracellular matrix proteins, plays a critical role in cancer cell proliferation, invasion, and metastasis. Transforming growth factor beta (TGF-?) signaling has dual roles in gastrointestinal tumor development and progression as both a tumor suppressor and tumor promoter. Here, we review the dynamic roles of TGF-? and its receptors in gastrointestinal tumors and provide evidence that targeting TGF-? signaling may be an effective therapeutic strategy.
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Project description:The appearance and growth of malignant tumors is a complicated process that is regulated by a number of genes. In recent years, studies have revealed that the transforming growth factor‑β (TGF‑β) signaling pathway serves an important role in cell cycle regulation, growth and development, differentiation, extracellular matrix synthesis and immune response. Notably, two members of the TGF‑β signaling pathway, TGF‑β1 and TGF‑β receptor 1 (TGF‑βR1), are highly expressed in a variety of tumors, such as breast cancer, colon cancer, gastric cancer and hepatocellular carcinoma. Moreover, an increasing number of studies have demonstrated that TGF‑β1 and TGF‑βR1 promote proliferation, migration and epithelial‑mesenchymal transition of tumor cells by activating other signaling pathways, signaling molecules or microRNAs (miRs), such as the NF‑κB signaling pathway and miR‑133b. In addition, some inhibitors targeting TGF‑β1 and TGF‑βR1 have exhibited positive effects in in vitro experiments. The present review discusses the association between TGF‑β1 or TGF‑βR1 and tumors, and the development of some inhibitors, hoping to provide more approaches to help identify novel tumor markers to restrain and cure tumors.
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Project description:In previous studies by the authors, aurora kinase A (AURKA) was demonstrated as an independent poor prognostic marker for the recurrence of localized gastrointestinal stromal tumors (GISTs) and for the progression of advanced GISTs. In the present study, the prognostic effect of genes involved in cell cycle regulation in GISTs was further examined. Leading edge analysis in gene set enrichment analysis was used to identify the most common genes in the top 10 enriched gene sets of high-risk patients with GISTs in a Japanese study. The obtained gene list was uploaded to the Pathway Interaction Database to search for critical pathways. Selected genes within the pathway were subsequently verified through immunohistochemistry (IHC) in another cohort of patients. A total of 5 genes in 'PLK1 signaling events,' namely AURKA, polo-like kinase 1 (PLK1), cell division cycle 25C (CDC25C), budding uninhibited by benzimidazoles (BUB1), and targeting protein for Xklp2 (TPX2), were identified for subsequent study. Among the Japanese cohort, all 5 genes, except BUB1, were significant prognostic factors for poor recurrence-free survival (RFS). Among 141 patients enrolled for the IHC study, all 5 genes exhibited variable expression patterns. In the association study, only AURKA exhibited significant overexpression in non-gastric tumors. Although all 5 genes were considered as risk factors for poor RFS based on a univariate analysis, only the mitotic count and expression levels of CDC25C, BUB1, and TPX2 retained prognostic effects in the multivariate analysis. The PLK1 signaling pathway is crucial in the disease progression of GISTs. Genes within this pathway may serve as predictive markers for adjuvant therapy.
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Project description:BackgroundKLF4 and KLF5 are members of the KLF transcription factor family, which play an important role in many gastrointestinal tumors. To gain a deeper insight into its function and role, bioinformatics was used to analyze the function and role of KLF4 and KLF5 in gastrointestinal tumors.MethodsData were collected from several online databases. Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN database analysis, Kaplan-Meier Plotter analysis, LOGpc system, the Pathology Atlas, and the STRING website were used to analyze the data. We download relevant data from TCGA and then perform GO enrichment and KEGG enrichment analysis. The effects of KLF5 on gastric cancer cell proliferation were measured by CCK-8 assay. The effect of KLF5 on the expression of CyclinD1 and MMP9 was detected by Western blot.ResultsKLF4 and KLF5 were differentially expressed in normal and tumor tissues of the gastrointestinal tract, and their differential expression is related to several genes or pathways. KEGG analysis showed that KLF5 was coexpressed with endocytosis-related genes. KLF5 promotes the proliferation of gastric cancer cells and the expression of metastasis-related molecules.ConclusionKLF4 and KLF5 are of great significance for developing gastrointestinal tumors and can be used as therapeutic targets.
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