CREB is a key negative regulator of carbonic anhydrase IX (CA9) in gastric cancer

Evidence-Based Complementary and Alternative Medicine

et al. 2018

Background Hedyotis diffusa Willd. (HDW) is one of the renowned herbs often used in the treatment of gastric cancer (GC). However, its curative mechanism has not been fully elucidated. Objective To systematically investigate the mechanisms of HDW in GC. Methods A network pharmacology approach mainly comprising target prediction, network construction, and module analysis was adopted in this study. Results A total of 353 targets of the 32 bioactive compounds in HDW were obtained. The network analysis showed that CA isoenzymes, p53, PIK3CA, CDK2, P27Kip1, cyclin D1, cyclin B1, cyclin A2, AKT1, BCL2, MAPK1, and VEGFA were identified as key targets of HDW in the treatment of GC. The functional enrichment analysis indicated that HDW probably produced the therapeutic effects against GC by synergistically regulating many biological pathways, such as nucleotide excision repair, apoptosis, cell cycle, PI3K/AKT/mTOR signaling pathway, VEGF signaling pathway, and Ras signaling pathway. Conclusions This study holistically illuminates the fact that the pharmacological mechanisms of HDW in GC might be strongly associated with its synergic modulation of apoptosis, cell cycle, differentiation, proliferation, migration, invasion, and angiogenesis.

Section: Resultsmentioning

confidence: 99%

Network Pharmacology-Based Approach to Investigate the Mechanisms ofHedyotis diffusaWilld. in the Treatment of Gastric Cancer

Liu

Evidence-Based Complementary and Alternative Medicine

et al. 2018

“…CREB deacetylation status led to suppression of the forskolin-induced CREB phosphorylation, which was in accordance with the conclusions outlined above. 34 Additionally, it reported that p-CREB showed strong expression in the fringe of the gastric cancer tissue specimens, 35 which also helps to suggest the downexpression of SIRT1 in Lgr5 + GCSCs.…”

Section: Discussionmentioning

confidence: 98%

Upregulated miR‐132 in Lgr5⁺ gastric cancer stem cell‐like cells contributes to cisplatin‐resistance via SIRT1/CREB/ABCG2 signaling pathway

Guo

Molecular Carcinogenesis

et al. 2017

Cisplatin resistance has long been a major problem that restricts its use. A novel paradigm in tumor biology suggests that gastric tumor chemo-resistance is driven by gastric cancer stem cell-like (GCSCs). Growing evidence has indicated that microRNAs (miRNAs) contributes to chemo-resistance in gastric cancer (GC). Here, Lgr5 cells derived from gastric cancer cell lines displayed stem cell-like features. Flow cytometry demonstrated the presence of a variable fraction of Lgr5 in 19 out of 20 GC specimens. By comparing the miRNA expression profiles of Lgr5 GCSCs and Lrg5 cells, we established the upregulation of miR-132 in Lgr5 GCSCs. The enhanced miR-132 expression correlated chemo-resistance in GC patients. Kaplan-Meier survival curve showed that patients with low miR-132 expression survived obviously longer. Functional assays results indicated that miR-132 promoted cisplatin resistance in Lgr5 GCSCs in vitro and in vivo. Further dual-luciferase reporter gene assays revealed that SIRT1 was the direct target of miR-132. The expression of miR-132 was inversely correlated with SIRT1 in gastric cancer specimens. Furthermore, through PCR array we discovered ABCG2 was one of the downstream targets of SIRT1. Overexpression of SIRT1 down-regulated ABCG2 expression by promoting the de-acetylation of the transcription factor CREB. CREB was further activated ABCG2 via binding to the promoter of ABCG2 to induce transcription. Thus, we concluded that miR-132 regulated SIRT1/CREB/ABCG2 signaling pathway contributing to the cisplatin resistance and might serve as a novel therapeutic target against gastric cancer.

“… 22 , 25 On the contrary, CREB is a negative regulator of CA9 and AP2-alpha in gastric cancer and melanoma. 26 , 27 …”

Section: Discussionmentioning

confidence: 99%

CREB promotes laryngeal cancer cell migration via MYCT1/NAT10 axis

Sun

et al. 2018

OTT

PurposeCREB, MYCY1 and NAT10 are involved in cancer cell migration. However, the relationship between these three proteins and their role in laryngeal cancer cell migration remains unknown.MethodsTransient gene transfection was performed in laryngeal cancer cells. Bioinformatics analysis was used to predict the binding of CREB to MYCT1 promoter. Binding of CREB to the promoter of MYCT1 was monitored by luciferase reporter assay and chromatin immuno-precipitation method in vitro and in vivo, respectively. Real-time RT-PCR and Western bolt were applied to detect gene transcription and translation levels, respectively. Laryngeal cancer cell migration was assayed by transwell chamber experiment.ResultsCREB protein expression was significantly up-regulated in laryngeal cancer tissues and associated with cancer differentiation, tumor stage, and lymphatic metastasis. CREB inhibits MYCT1 expression by direct binding to its promoter. Meanwhile, MYCT1 has a negative impact on the NAT10 gene expression. Furthermore, CREB promotes NAT10 expression via down-regulating the MYCT1 gene expression. In addition, contrary to MYCT1, CREB and NAT10 enhanced laryngeal cancer cell migration. MYCT1 and NAT10 significantly rescued the effects of CREB and MYCT1 on Hep2 cell migration, respectively.ConclusionCREB promotes laryngeal cancer cell migration via MYCT1/NAT10 axis, suggesting that CREB might be a potential prognostic marker in laryngeal cancer.