Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in APC/beta-catenin resulting in an aberrant activation of Wnt/beta-catenin pathway are common in colorectal cancer (CRC), suggesting that targeting the beta-catenin pathway with chemopreventive/anticancer agents could be a potential translational approach to control CRC. Using human CRC cell lines harboring mutant (SW480) versus wildtype (HCT116) APC gene and alteration in beta-catenin pathway, herein we performed both in vitro and in vivo studies to examine for the first time whether silibinin targets beta-catenin pathway in its efficacy against CRC. Silibinin treatment inhibited cell growth, induced cell death, and decreased nuclear and cytoplasmic levels of beta-catenin in SW480 but not in HCT116 cells, suggesting its selective effect on the beta-catenin pathway and associated biologic responses. Other studies, therefore, were performed only in SW480 cells where silibinin significantly decreased beta-catenin-dependent T-cell factor-4 (TCF-4) transcriptional activity and protein expression of beta-catenin target genes such as c-Myc and cyclin D1. Silibinin also decreased cyclin-dependent kinase 8 (CDK8), a CRC oncoprotein that positively regulates beta-catenin activity, and cyclin C expression. In a SW480 tumor xenograft study, 100- and 200-mg/kg doses of silibinin feeding for 6 weeks inhibited tumor growth by 26% to 46% (P < .001). Analyses of xenografts showed that similar to cell culture findings, silibinin decreases proliferation and expression of beta-catenin, cyclin D1, c-Myc, and CDK8 but induces apoptosis in vivo. Together, these findings suggest that silibinin inhibits the growth of SW480 tumors carrying the mutant APC gene by down-regulating CDK8 and beta-catenin signaling and, therefore, could be an effective agent against CRC.
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PMID:Silibinin suppresses growth of human colorectal carcinoma SW480 cells in culture and xenograft through down-regulation of beta-catenin-dependent signaling. 2045 13

MicroRNAs (miRNAs) are important gene regulators that play key roles in tumor genesis. In this study, we investigate the role of miR-148a in the development of papillary thyroid cancer (PTC). Data from the cancer genome atlas (TCGA) indicate that miR-148a is downregulated in PTC tissues; we also find that miR-148a is downregulated in tissue samples from PTC patients and PTC cell lines. Overexpression of miR-148a significantly suppresses PTC cell proliferation, migration and invasiveness in vitro, and inhibits tumor growth in vivo as well. We have identified the cyclin-dependent kinase 8 (CDK8) gene as a direct target of miR-148a using the online software packages TargetScan and miRanda. Overexpression of miR-148a significantly represses CDK8 expression by directly targeting the 3'-untranslated region (3'-UTR) of the CDK8 gene in PTC tissues and cell lines; overexpression of CDK8 reverses the inhibitory effects of miR-148a on PTC cell growth, migration and invasiveness. Taken together, our results indicate that miR-148a functions as a tumor suppressor in PTC by repressing CDK8 expression.
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PMID:Downregulation of cyclin-dependent kinase 8 by microRNA-148a suppresses proliferation and invasiveness of papillary thyroid carcinomas. 2911 56

A flavonoid glycoside, quercitrin (1), and two phenylpropanoyl sucrose derivatives, vanicoside B (2) and lapathoside C (3), were isolated for the first time from the herb Persicaria dissitiflora. Vanicoside B (2) exhibited antiproliferative activity against a panel of cancer cell lines in triple-negative breast cancer (TNBC) MDA-MB-231 cells. The underlying mechanisms of the antitumor activity of 2 were investigated in TNBC cells. Upregulation of cyclin-dependent kinase 8 (CDK8) was observed in a claudin-low molecular subtype of TNBC cells. A molecular modeling study indicated that 2 showed a high affinity for CDK8. Further investigations revealed that 2 suppressed CDK8-mediated signaling pathways and the expression of epithelial-mesenchymal transition proteins and induced cell cycle arrest and apoptosis in MDA-MB-231 and HCC38 TNBC cells. Moreover, 2 inhibited tumor growth without overt toxicity in a nude mouse xenograft model implanted with MDA-MB-231 cells. Taken together, these findings demonstrate the significance of CDK8 activity in TNBC and suggest a potential use of 2 as a therapeutic candidate for the treatment of aggressive human triple-negative breast cancer.
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PMID:Antitumor Activity of Vanicoside B Isolated from Persicaria dissitiflora by Targeting CDK8 in Triple-Negative Breast Cancer Cells. 3162 95

Background: Pancreatic cancer (PC) is a leading cause of cancer-related deaths worldwide. Human leukocyte antigen complex P5 (HCP5), a member of long noncoding RNAs (lncRNAs), was reported to be associated with the poor prognosis of PC. However, the mechanism of HCP5 in regulating the progression of PC remains poorly defined. Materials and Methods: Quantitative real-time polymerase chain reaction was performed to detect the expression levels of HCP5, microRNA (miR)-140-5p, and cyclin-dependent kinase 8 (CDK8) in PC tissues and cells. Cell counting kit-8 (CCK-8) assay was utilized to check cell proliferation. Transwell assay was employed to evaluate the abilities of cell migration and invasion. Xenograft tumor model was established to investigate the biological role of HCP5 in PC in vivo. The interaction between miR-140-5p and HCP5 or CDK8 was predicted by starBase or TargetScan, respectively. The dual-luciferase reporter assay was conducted to corroborate the interaction. The protein level of CDK8 was measured by Western blot. Results: HCP5 and CDK8 were significantly upregulated in PC tissues and cells, opposite to the expression of miR-140-5p. High expression of HCP5 contributed to the low survival rate and HCP5 silencing inhibited proliferation, migration, and invasion of PC cells in vitro. Simultaneously, in vivo experiments indicated that downregulation of HCP5 suppressed tumor growth. In addition, miR-140-5p was a target of HCP5 and bound to the 3'-untranslated region (3'UTR) of CDK8. Further studies revealed that overexpression of CDK8 reversed the miR-140-5p-mediated inhibitory effect on PC progression. Moreover, downregulation of miR-140-5p or upregulation of CDK8 inverted the silencing-mediated repressive impact of HCP5 on PC progression. Conclusion: Downregulation of HCP5 impeded PC progression by downregulating CDK8 via sponging miR-140-5p.
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PMID:LncRNA HCP5 Regulates Pancreatic Cancer Progression by miR-140-5p/CDK8 Axis. 3240 43