PEAK1, acting as a tumor promoter in colorectal cancer, is regulated by the EGFR/KRas signaling axis and miR-181d

Huang, Likun; Wen, Chuangyu; Yang, Xiangling; Lou, Qiong; Wang, Xiaoyan; Che, Jing; Chen, Junxiong; Yang, Zihuan; Wu, Xiaojian; Huang, Meijin; Lan, Ping; Wang, Lei; Iwamoto, Aikichi; Wang, Jianping; Liu, Huanliang

doi:10.1038/s41419-018-0320-8

Cited by 51 publications

(51 citation statements)

References 45 publications

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“…Mechanistically, DDR1 phosphorylation of BCR on tyrosine 177 alleviates a negative regulatory loop on β-catenin signaling to sustain its oncogenic activity, resulting in the induction of genes that are important for tumor cell dissemination and metastasis development, such as MYC, CYCD1, and LGR5 (42,48). Although not investigated in this study, DDR1 may also induce PEAK1 invasive activity (49,50), possibly via a YAP1dependent mechanism, as recently suggested (51). As nuclear YAP1 can form a β-catenin transcription complex that is essential for the transformation and survival of β-catenindriven cancer (52), we propose that DDR1 supports metastatic development in a collagen-rich environment via a BCR-and PEAK1-dependent mechanism.…”

Section: Ddr1 In Crc Metastasesmentioning

confidence: 85%

Collagen Kinase Receptors as Potential Therapeutic Targets in Metastatic Colon Cancer

2020

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Colorectal cancer (CRC) is one of the leading causes of tumor-related death worldwide. While surgery can cure patients with early stage CRC, the 5-year survival rate is only 10% for patients with metastatic disease. Therefore, new anti-metastatic therapies are needed for this cancer. Metastatic spread defines the dissemination of cancer cells with tumor-initiating capacities from the primary tumor and their colonization of distinct organs, mainly the liver, for secondary tumor formation. Although the underlying mechanisms are not fully understood, components of the tumor microenvironment have gained strong interest. Among the known metastatic-promoting factors, collagens are extracellular matrix components that are deposited within the tumor, the tumor microenvironment, and at metastatic site(s), and are recognized to play essential roles during metastasis development. Here, we review recent findings on the metastatic role of the collagen receptors Discoidin Domain Receptors 1 and 2 (DDR1 and DDR2) in CRC and discuss the therapeutic value of targeting these receptor tyrosine kinases in this cancer.

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Section: Ddr1 In Crc Metastasesmentioning

confidence: 85%

Collagen Kinase Receptors as Potential Therapeutic Targets in Metastatic Colon Cancer

2020

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“…Restoring miR-181b-5p expression inhibited cell growth, migration, and invasion in astrocytoma (57). In colorectal cancer, ectopic expression of miR-181d resulted in the inhibition of cell growth and metastasis in vitro by targeting PEAK1 (15). Another study conducted by Wang and his colleagues (44) demonstrated that ectopic expression of miR-181d impeded cell proliferation and induced cell cycle arrest and apoptosis in glioma.…”

Section: Discussionmentioning

confidence: 97%

“…The genes that were found with increased relevancy to other genes were located at the core of the network. IL6, DNA topoisomerase II␣, and CDKN3 presented with the relatively highest relevancy (15,20,29) to other genes, which may play a key role in NSCLC. A number of researches have focused on the impact of IL6 (1,20) and DNA topoisomerase II␣ (14, 31) on NSCLC.…”

Section: L922 Role Of Mir-181d-5p In Nsclc and Its Mechanismmentioning

confidence: 99%

Tumor-suppressive effects of microRNA-181d-5p on non-small-cell lung cancer through the CDKN3-mediated Akt signaling pathway in vivo and in vitro

Gao

Zheng

Wang

et al. 2019

American Journal of Physiology-Lung Cellular and Molecular Phys

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The involvement of several microRNAs (miRs) in the initiation and development of tumors through the suppression of the target gene expression has been highlighted. The aberrant expression of miR-181d-5p and cyclin-dependent kinase inhibitor 3 (CDKN3) in non-small-cell lung cancer (NSCLC) was then screened by microarray analysis. In the present study, we performed a series of in vivo and in vitro experiments for the purpose of investigating their roles in NSCLC and the underlying mechanism. There was a high expression of CDKN3, whereas miR-181d-5p was downregulated in NSCLC. Quantitative RT-PCR, Western blot analysis, and dual-luciferase reporter gene assay further identified that CDKN3 could be negatively regulated by miR-181d-5p. Moreover, the upregulation of miR-181d-5p or silencing of CDKN3 could inactivate the Akt signaling pathway. A549 with the lowest miR-181d-5p and H1975 with the highest CDKN3 among the five NSCLC cell lines (H1299, A549, H1975, NCI-H157, and GLC-82) were adopted for in vitro experiments, in which expression of miR-181d-5p and CDKN3 was altered by transfection of miR-181d-5p mimic/inhibitor or siRNA-targeting CDKN3. Afterwards, cell proliferation, apoptosis, invasion, migration, and angiogenesis, as well as epithelial-mesenchymal transition (EMT), were evaluated, and tumorigenicity was assessed. In addition, an elevation in miR-181d-5p or depletion in CDKN3 led to significant reductions in proliferation, invasion, migration, angiogenesis, EMT, and tumorigenicity of NSCLC cells, coupling with increased cell apoptosis. In conclusion, this study highlights the tumor-suppressive effects of miR-181d-5p on NSCLC via Akt signaling pathway inactivation by suppressing CDKN3, thus providing a promising therapeutic strategy for the treatment of NSCLC.

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“…The variant had not been described in the ClinVar or COSMIC databases. However, numerous studies have reported the involvement of PEAK1 in tumorigenesis [41][42][43][44][45].…”

Section: Patientmentioning

confidence: 99%

Mutation profiling in eight cases of vagal paragangliomas

et al. 2020

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Background Vagal paragangliomas (VPGLs) belong to a group of rare head and neck neuroendocrine tumors. VPGLs arise from the vagus nerve and are less common than carotid paragangliomas. Both diagnostics and therapy of the tumors raise significant challenges. Besides, the genetic and molecular mechanisms behind VPGL pathogenesis are poorly understood. Methods The collection of VPGLs obtained from 8 patients of Russian population was used in the study. Exome library preparation and high-throughput sequencing of VPGLs were performed using an Illumina technology. Results Based on exome analysis, we identified pathogenic/likely pathogenic variants of the SDHx genes, frequently mutated in paragangliomas/pheochromocytomas. SDHB variants were found in three patients, whereas SDHD was mutated in two cases. Moreover, likely pathogenic missense variants were also detected in SDHAF3 and SDHAF4 genes encoding for assembly factors for the succinate dehydrogenase (SDH) complex. In a patient, we found a novel variant of the IDH2 gene that was predicted as pathogenic by a series of algorithms used (such as SIFT, PolyPhen2, FATHMM, MutationTaster, and LRT). Additionally, pathogenic/likely pathogenic variants were determined for several genes, including novel genes and some genes previously reported as associated with different types of tumors. Conclusions Results indicate a high heterogeneity among VPGLs, however, it seems that driver events in most cases are associated with mutations in the SDHx genes and SDH assembly factor-coding genes that lead to disruptions in the SDH complex.

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PEAK1, acting as a tumor promoter in colorectal cancer, is regulated by the EGFR/KRas signaling axis and miR-181d

Cited by 51 publications

References 45 publications

Collagen Kinase Receptors as Potential Therapeutic Targets in Metastatic Colon Cancer

Collagen Kinase Receptors as Potential Therapeutic Targets in Metastatic Colon Cancer

Tumor-suppressive effects of microRNA-181d-5p on non-small-cell lung cancer through the CDKN3-mediated Akt signaling pathway in vivo and in vitro

Mutation profiling in eight cases of vagal paragangliomas

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