The PEAK1–PPP1R12B axis inhibits tumor growth and metastasis by regulating Grb2/PI3K/Akt signalling in colorectal cancer

Ding, Chenbo; Tang, Wendong; Wu, Hao; Fan, Xuetong; Luo, Jie; Feng, Jing; Kong, Wen; Wu, Guoqiu

doi:10.1016/j.canlet.2018.11.014

Cited by 43 publications

(40 citation statements)

References 53 publications

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“…Fredericks and Ren, 2013). Recently, its tumor-promoting effects were shown in many malignancies including lung cancer (Yang et al, 2017a;Jiang et al, 2018;Mitra et al, 2018;Wang and Wang, 2020), gastric cancer (Ye et al, 2018), colorectal cancer (Ding et al, 2019), ovarian carcinoma (Huang et al, 2018), renal cell carcinoma (Gu et al, 2017), breast cancer (Lim et al, 2000;Haines et al, 2014;López-Cortés et al, 2020), and esophageal squamous cell carcinoma (Shi et al, 2018). In addition, in lung cancer (Chen et al, 2020), ovarian cancer (Xu et al, 2018), colorectal cancer (Agrawal et al, 2019), and breast cancer (Chen et al, 2018), its associations with the resistance of the tumors to chemotherapeutic drugs were presented, and its downregulation could reverse the resistant status or enhance the sensitivity to the drugs, indicating its potential as a chemotherapeutic target in the malignancies.…”

Section: Discussionmentioning

confidence: 99%

KPNA2-Associated Immune Analyses Highlight the Dysregulation and Prognostic Effects of GRB2, NRAS, and Their RNA-Binding Proteins in Hepatocellular Carcinoma

Zhang

Gao

et al. 2020

Front. Genet.

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Karyopherin α2 (KPNA2) was reported to be overexpressed and have unfavorable prognostic effects in many malignancies including hepatocellular carcinoma (HCC). Although its contributions to inflammatory response were reported in many studies, its specific associations with immune infiltrations and immune pathways during cancer progression were unclear. Here, we aimed to identify new markers for HCC diagnosis and prognosis through KPNA2-associated immune analyses. RNA-seq expression data of HCC datasets were downloaded from The Cancer Genome Atlas and International Cancer Genome Consortium. The gene expressions were counts per million normalized. The infiltrations of 24 kinds of immune cells in the samples were evaluated with ImmuCellAI (Immune Cell Abundance Identifier). The Spearman correlations of the immune infiltrations with KPNA2 expression were investigated, and the specific positive correlation of B-cell infiltration with KPNA2 expression in HCC tumors was identified. Fifteen genes in KEGG (Kyoto Encyclopedia of Genes and Genomes) B-cell receptor signaling pathway presented significant correlations with KPNA2 expression in HCC. Among them, GRB2 and NRAS were indicated to be independent unfavorable prognostic factors for HCC overall survival. Clinical Proteomic Tumor Analysis Consortium HCC dataset was investigated to validate the results at protein level. The upregulation and unfavorable prognostic effects of KPNA2 and GRB2 were confirmed, whereas, unlike its mRNA form, NRAS protein was presented to be downregulated and have favorable prognostic effects. Through receiver operating characteristic curve analysis, the diagnostic potential of the three proteins was shown. The RNA-binding proteins (RBPs) of KPNA2, NRAS, and GRB2, downloaded via The Encyclopedia of RNA Interactomes, were investigated for their clinical significance in HCC at protein level. An eight-RBP signature with independent prognostic value and dysregulations in HCC was identified. All the RBPs were significantly correlated with MKI67 expression and at least one of KPNA2, GRB2, and NRAS at protein level in HCC, indicating Zhang et al. KPNA2-Associated Immune Analyses in HCC Frontiers in Genetics | www.frontiersin.org 2 October 2020 | Volume 11 | Article 593273 their roles in HCC progression and the regulation of the three proteins. We concluded that KPNA2, GRB2, NRAS, and their RBPs might have coordinating roles in HCC immunoregulation and progression. They might be new markers for HCC diagnosis and prognosis predication and new targets for HCC immunotherapy.

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Section: Discussionmentioning

confidence: 99%

KPNA2-Associated Immune Analyses Highlight the Dysregulation and Prognostic Effects of GRB2, NRAS, and Their RNA-Binding Proteins in Hepatocellular Carcinoma

Zhang

Gao

et al. 2020

Front. Genet.

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“…More recently, Ding et al . also reported downregulation of SgK269 in colorectal cancer, while its overexpression resulted in suppression of cell growth and metastasis, suggesting a role as a tumour suppressor. These studies suggest that the effects of SgK269 (and more broadly PEAK family proteins) on signalling outcomes are context dependent and may be either oncogenic or tumour suppressive depending on the type of cancer and the stage of its progression.…”

Section: Peak Family: Expression In Cancer and Mutationsmentioning

confidence: 79%

“…Matrigel assays using MCF‐10A cells overexpressing SgK269 generated acini with increased diameter and a multilobular morphology, thereby confirming the role of a late‐phase Shc1–SgK269 complex in regulating acinar morphogenesis . Interestingly, SgK269 downregulation in colorectal cancer inhibits the Grb2/PI3K/Akt pathway and hence tumourigenesis by regulating protein phosphatase 1 regulatory subunit (PPP1R12B) expression and Shc binding, which implicates SgK269 as a tumour suppressor in colorectal cancers . This, however, contradicts previous reports of SgK269 acting in colorectal cancers as a tumour promoter as a result of the activation of EGFR/KRas signalling and highlights the need to carefully delineate the PEAK family signalling pathways in cancer.…”

Section: Peak Family: Localisation and Signallingmentioning

confidence: 84%

The PEAK family of pseudokinases, their role in cell signalling and cancer

et al. 2019

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The study of pseudokinases has uncovered that catalysis-independent functions play a critical role in cell signalling regulation. However, how pseudokinases dynamically assemble and regulate oncogenic signalling pathways remains, in most cases, unclear due to a limited knowledge of the structural determinants that are critical for their functions. Here, we review the recent progress made to unravel the role of the PEAK family of pseudokinases, which comprises SgK269, SgK223 and the recently identified PEAK3, in assembling specific oncogenic signalling pathways that contribute to the progression of several aggressive cancers. We focus on recent structural advances revealing that SgK269 and SgK223 can homo-and heteroassociate via a unique dimerisation domain, comprising conserved regulatory helices directly surrounding the pseudokinase domain, which is also conserved in PEAK3. We also highlight a potential oligomerisation mechanism driven by the pseudokinase domain. While it is likely that homo-or heterodimerisation and oligomerisation mechanisms contribute to the assembly of complex signalling hubs and provide a means to spatially and temporally modulate and diversify signalling outputs, the exact role that these oncogenic scaffolds play in regulating cell migration, invasion and morphology remains unclear. Here, we attempt to link their structural characteristics to their cellular functions by providing a thorough analysis of the signalling transduction pathways they are known to modulate.

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“…Seven genes that were signi cantly associated with survival were screened, suggesting that these can be used as diagnostic and prognostic indicators for gastrointestinal tumors. It has been reported that PPP1R12B is signi cantly downregulated in colon cancer and participates in tumor progression by regulating actin cytoskeleton and cell adhesion [28][29][30].…”

Section: Discussionmentioning

confidence: 99%

Integrated analysis of coexpression and competitive endogenous RNA networks identified survival-related genes in gastrointestinal tumors

Bai

Feng

Yang

et al. 2021

Preprint

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Early diagnosis and prognosis rely on the successful identification of biomarkers and understanding the mechanisms. Through pan-cancer analysis amongst three types of gastrointestinal tumors, we constructed competitive endogenous RNA (ceRNA) networks, differentially expressed set of genes were distinguished, validated, and analyzed, their relevance to survival elucidated with immune infiltration profiles. Shared genes in esophageal, gastric and colon cancers were found significantly enriched in the processes of cell cycle, cell differentiation, DNA replication, synaptic transmission, the cyclic guanosine monophosphate protein-dependent protein kinase (cGMP-PKG) signaling pathway, and the glutamate receptor and other functions. Principal component analysis of the ceRNA network suggested the expression patterns of identified genes. Using Cox regression analysis of mRNAs, miRNAs and lncRNAs in the ceRNA network, genes including hsa-mir-196b, hsa-mir-584, PPP1R12B, SYNM, PDE2A, ALDH6A1 and MIR22HG were found significantly survival-related. Receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA) showed that the identified genes were not related to the survival in thyroid nor breast cancers, but effective for the prognosis of gastrointestinal tumors. These results could provide new theoretical and experimental clues, unravel the mechanisms, assisting molecular diagnosis and prognosis of gastrointestinal tumors.

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The PEAK1–PPP1R12B axis inhibits tumor growth and metastasis by regulating Grb2/PI3K/Akt signalling in colorectal cancer

Cited by 43 publications

References 53 publications

KPNA2-Associated Immune Analyses Highlight the Dysregulation and Prognostic Effects of GRB2, NRAS, and Their RNA-Binding Proteins in Hepatocellular Carcinoma

KPNA2-Associated Immune Analyses Highlight the Dysregulation and Prognostic Effects of GRB2, NRAS, and Their RNA-Binding Proteins in Hepatocellular Carcinoma

The PEAK family of pseudokinases, their role in cell signalling and cancer

Integrated analysis of coexpression and competitive endogenous RNA networks identified survival-related genes in gastrointestinal tumors

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