OCT1 is a determinant of synbindin-related ERK signalling with independent prognostic significance in gastric cancer

Qian³

et al. 2014

Cancer Research

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234

147

It is increasingly evident that long noncoding RNAs (lncRNA) have causative roles in carcinogenesis. In this study, we report findings implicating a novel lncRNA in gastric cancer, termed GAPLINC (gastric adenocarcinoma predictive long intergenic noncoding RNA), based on the use of global microarray and in situ hybridization (ISH) analyses to identify aberrantly expressed lncRNA in human gastric cancer specimens. GAPLINC is a 924-bp-long lncRNA that is highly expressed in gastric cancer tissues. GAPLINC suppression and with gene expression profiling in gastric cancer cells revealed alterations in cell migration pathways, with CD44 expression the most highly correlated. Manipulating GAPLINC expression altered CD44 mRNA abundance and the effects of GAPLINC on cell migration and proliferation were neutralized by suppressing CD44 expression. Mechanistic investigations revealed that GAPLINC regulates CD44 as a molecular decoy for miR211-3p, a microRNA that targets both CD44 and GAPLINC. Tissue ISH analysis suggested that GAPLINC overexpression defines a subgroup of patients with gastric cancer with very poor survival. Taken together, our results identify a noncoding regulatory pathway for the CD44 oncogene, shedding new light on the basis for gastric cancer cell invasiveness. Cancer Res; 74(23); 6890-902. Ó2014 AACR.

Section: Introductionmentioning

confidence: 99%

Long Noncoding RNA GAPLINC Regulates CD44-Dependent Cell Invasiveness and Associates with Poor Prognosis of Gastric Cancer

Qian³

et al. 2014

Cancer Research

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234

147

“…The synbindin protein contains an atypical PDZ domain and a longin domain [6] . Truncation of the longin domain abolished the interaction between synbindin and ERK [3] , and mutation of the ERK DEF domain produced the same result [2] . Therefore, we concluded that the synbindin-longin domain binds the DEF domain of ERK.…”

Section: Synbindin Is a Scaffold Protein Of Erk Signaling On The Golgmentioning

confidence: 52%

“…Therefore, we concluded that the synbindin-longin domain binds the DEF domain of ERK. The expression level of synbindin is strongly correlated with the phosphorylation of ERK protein in gastric cancer tissues [2] , which elucidates a noncanonical mechanism for ERK hyperactivation in gastric cancers. Targeting synbindin significantly decreased ERK phosphorylation in a nude mouse model, and tumor growth was also significantly inhibited in the synbindin-inhibited group [3] .…”

Section: Synbindin Is a Scaffold Protein Of Erk Signaling On The Golgmentioning

confidence: 98%

“…However, a discrepancy has been found between the widespread activation of ERK (in approximately 90% of GI tumors) and limited genetic alterations of upstream elements (in <50% of GI tumors) [2] . Therefore, how ERK is activated without significant alteration of RAS , RAF , and MEK is a major question in the field.…”

Section: Mitogen-activated Protein Kinase Signaling Plays Crucial Rolmentioning

confidence: 99%

“…The expression of OCT1 and synbindin was strongly correlated in gastric cancer tissues, and OCT1 expression displayed a significant correlation with ERK phosphorylation. Importantly, gene copy amplification, messenger RNA upregulation, and protein overexpression of OCT1 all were significantly associated with poor survival of gastric cancer patients [2] . Moreover, the prognostic significance of OCT1 was confirmed in independent patient cohorts.…”

Section: Synbindin Is Regulated By the Oct1 Transcription Factormentioning

confidence: 99%

See 2 more Smart Citations

Scaffold Proteins in Gastrointestinal Tumors as a Shortcut to Oncoprotein Activation

Yao

et al. 2017

Gastrointest Tumors

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Background: The development of cancer involves uncontrolled cell proliferation, and multiple signaling pathways that regulate cell proliferation have been found to be dysregulated in cancers. Extracellular signal-regulated protein kinase (ERK) is one of three major subtypes in the mitogen-activated protein kinase (MAPK) families. The MAPK/ERK pathway (RAS/RAF1/MEK/ERK) plays an important part in promoting cell proliferation in response to growth factors, thereby serving as a driving signal in gastrointestinal (GI) tumors. In contrast, the p53 tumor suppressor functions as a “guardian of the genome” and stops cell proliferation when oncogenic signaling is activated. Summary: Both pathways constrain each other in healthy GI epithelium, facilitating controlled proliferation that is essential for tissue repair and regeneration. However, in GI tumors, the MAPK/ERK and p53 pathways are commonly dysregulated, in part due to abnormal posttranslational modifications. Hyperphosphorylation of the ERK protein causes sustained activation of cell proliferation, whereas hypoacetylation of the p53 protein impairs its transcriptional function and blocks cell apoptosis. Multiple scaffold proteins have been found to regulate the posttranslational modifications of ERK and p53 proteins in GI tumors. Key Message: Abnormal expression of scaffold proteins may contribute to the dysregulation of the MAPK and p53 signaling pathways and thereby contribute to the development of GI tumors. Practical Implications: Scaffold proteins are potential biomarkers and therapeutic targets in GI tumors.

A novel mechanism of rs763110 polymorphism contributing to cervical cancer risk by affecting the binding affinity of C/EBPβ and OCT1 complex to chromatin

et al. 2016

Intl Journal of Cancer

Recently, several studies have showed that FAS (rs2234767, rs1800682) and FASL (rs763110) functional single nucleotide polymorphisms (SNPs) were associated with the risk of various cancers. However, the association between cervical cancer risk and the three SNPs above remained inconclusive. In this work, we performed a two-stage case-control study on 1155 cervical cancer patients and 1252 matched healthy controls to determine the roles of the mentioned SNPs in cervical cancer susceptibility. We genotyped the FAS rs2234767, rs1800682, and FASL rs763110 polymorphisms using PCR-TaqMan assays. Results revealed that the rs763110 TT genotype significantly increased the risk of cervical cancer compared with the CC/CT genotype (adjusted OR = 1.70, 95% CI = 1.19-2.42). However, we did not observe any association between the cervical cancer risk and the rs2234767 and rs1800682 polymorphisms. The immunohistochemistry assay showed that patients carrying the rs763110 TT genotype presented a lower cancerous FASL expression than that of the CC/CT genotypes. Chromatin immunoprecipitation (ChIP) and Sequential Chromatin immunoprecipitation assays also demonstrated that OCT1 was recruited to the FASL promoter region and regulated the FASL gene transcription by interacting with C/EBPβ. In conclusion, this study provided evidence indicating that the rs763110 variant in the FASL promoter was associated with the risk of cervical cancer by affecting the binding affinity of the C/EBPβ/OCT1 complex to chromatin.