Janus Kinase 1 Plays a Critical Role in Mammary Cancer Progression

Wehde, Barbara L.; Rädler, Patrick D.; Shrestha, Hridaya; Johnson, Stevi J.; Triplett, Aleata A.; Wagner, Kay Uwe

doi:10.1016/j.celrep.2018.10.063

Cited by 42 publications

(29 citation statements)

References 42 publications

(64 reference statements)

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“…Janus kinase (JAK) 1, a member of receptor protein tyrosine kinases (RPTKs) which integrates signals from many cytokines and associate with the intracellular domains of surface cytokine receptors, can phosphorylate the signal transducers and activators of transcription (STATs) to modulate gene expression.46 In the present study, the influence of CTBP1 on the JAK1/Stat3 signaling pathway in GC cells was explored, and the results suggested that CtBP1 markedly promoted the JAK1/Stat3 signaling pathway. Moreover, to further confirm our results, an GC cell line (SGC-790) with CtBP1 knockout was also established.…”

Section: Discussionmentioning

confidence: 90%

<p>C-terminal of E1A binding protein 1 enhances the migration of gastric epithelial cells and has a clinicopathologic significance in human gastric carcinoma</p>

Wang¹,

Wang

Xing³

et al. 2019

OTT

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Background Recent studies have claimed that the C-terminal of E1A binding proteins (CtBPs) influence tumorigenesis through participating in cell signal transduction in various human tumors. However, the detailed expression profiles of CtBP isoforms in human gastric cancer (GC) and the molecular mechanisms of CtBP involvement in tumor cell phenotypes warrant further investigation. Materials and methods The expression of CtBPs in GC cell lines and a human gastric epithelial cell line were explored via RT-qPCR and Western blotting assays. Moreover, the expression profiles of CtBPs in GC and histologically noncancerous tissues were explored by immunohistochemistry. To explore the effects of CtBP1 on the metastatic phenotype in GC, gastric epithelial cells were transfected with a eukaryotic expression plasmid to overexpress CTBP1, and the endogenous CtBP1 or JAK1 in GC cells was silenced through an RNA interference (RNAi) method. These transfections were validated via Western blotting, and the activation state of the JAK1/Stat3 signaling pathway was also explored via Western blotting. Furthermore, the malignant phenotype of GC cells was evaluated via a Cell Counting Kit-8 (CCK8) assay, colony formation assay, transwell assay, and wound-healing experiment. Results Our data revealed that the expression of CtBP1, but not CTBP2, was upregulated in 102 GC tissue samples compared with 98 noncancerous tissue samples, and the elevated expression level of CtBP1 was notably associated with distant metastasis. CTBP1 modulated cell migration and invasion through the JAK1/Stat3 signaling pathway in gastric epithelial cells. In addition, genetic silence of CtBP1 expression in GC cells notably constrained cell proliferation, invasion and migration abilities through inhibiting the activation of the JAK1/Stat3 pathway in GC cells. Conclusion Our data reveal that the knockout of CtBP1 notably constrains distant metastasis in GC through the JAK1/Stat3 pathway, suggesting that targeting CtBP1 is a practical anti-tumor approach to restrain tumor progression in GC.

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Section: Discussionmentioning

confidence: 90%

<p>C-terminal of E1A binding protein 1 enhances the migration of gastric epithelial cells and has a clinicopathologic significance in human gastric carcinoma</p>

Wang¹,

Wang

Xing³

et al. 2019

OTT

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“…Janus kinase-1 (JAK1) is one of the Janus kinase family members. JAK1 is essential for IL-6-class inflammatory cytokine signaling, plays a critical role in metastatic cancer progression, and mediates the persistent oncogenic activation of STAT3 in mammary cancer cells that are driven by ERBB2 receptor tyrosine kinase signaling [3]. JAK1 -deficient cell lines were found to be more tumorigenic than wild-type cells [4].…”

Section: Introductionmentioning

confidence: 99%

JAK1 as a prognostic marker and its correlation with immune infiltrates in breast cancer

Chen

Lai

Dai

et al. 2019

Aging

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Clinical trials testing Janus kinase-1 (JAK1) inhibitors in cancers are under way. Whether the JAK1 mRNA levels in breast tumors correlates with outcome has not been evaluated. JAK1 expression was analyzed via the Oncomine database and Tumor IMmune Estimation Resource site. Tumor tissues from 57 breast cancer patients were used for qRT-PCR and immune infiltration assessment. JAK1 expression was significantly lower in breast invasive carcinoma compared with adjacent normal tissues. Public databases (Kaplan-Meier plotter and PrognoScan) showed that low JAK1 expression was associated with poorer survival. Data from The Cancer Genome Atlas (TCGA) showed that high JAK1 expression was associated with increased survival in both TNM I-II and TNM III-IV patients. JAK1 was inversely correlated with tumor size status, lymph node status, and TNM of breast cancer patients. JAK1 levels were correlated with the T cell transcript-enriched LYM metagene signature and was significantly lower in the low tumor infiltrating lymphocytes (TILs) group. JAK1 expression levels had significant positive correlations with infiltrating levels of CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells in breast cancer and not with other B cells. In conclusion, JAK1 mRNA levels were correlated with prognosis and immune infiltrating levels in breast cancer.

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“…In the METABRIC breast cancer dataset, out of twenty five genes identified by QuaDMutNetEx, six are very rare -each mutated in only two out of 696 patients. Of these, JAK1 is known for its key role in breast cancer progression [62]. EGFR signaling pathway also has a crucial role in mammary cancers [63], and polymorphism in the EGFR ligand, EGF, was found to affect cancer progression [64].…”

Section: Quantitative and Qualitative Assessment Of Quadmutnetex Resultsmentioning

confidence: 99%

QuaDMutNetEx: a method for detecting cancer driver genes with low mutation frequency

2020

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Background: Cancer is caused by genetic mutations, but not all somatic mutations in human DNA drive the emergence or growth of cancers. While many frequently-mutated cancer driver genes have already been identified and are being utilized for diagnostic, prognostic, or therapeutic purposes, identifying driver genes that harbor mutations occurring with low frequency in human cancers is an ongoing endeavor. Typically, mutations that do not confer growth advantage to tumors-passenger mutations-dominate the mutation landscape of tumor cell genome, making identification of low-frequency driver mutations a challenge. The leading approach for discovering new putative driver genes involves analyzing patterns of mutations in large cohorts of patients and using statistical methods to discriminate driver from passenger mutations. Results: We propose a novel cancer driver gene detection method, QuaDMutNetEx. QuaDMutNetEx discovers cancer drivers with low mutation frequency by giving preference to genes encoding proteins that are connected in human protein-protein interaction networks, and that at the same time show low deviation from the mutual exclusivity pattern that characterizes driver mutations occurring in the same pathway or functional gene group across a cohort of cancer samples. Conclusions: Evaluation of QuaDMutNetEx on four different tumor sample datasets show that the proposed method finds biologically-connected sets of low-frequency driver genes, including many genes that are not found if the network connectivity information is not considered. Improved quality and interpretability of the discovered putative driver gene sets compared to existing methods shows that QuaDMutNetEx is a valuable new tool for detecting driver genes. QuaDMutNetEx is available for download from https://github.com/bokhariy/QuaDMutNetEx under the GNU GPLv3 license.

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Janus Kinase 1 Plays a Critical Role in Mammary Cancer Progression

Cited by 42 publications

References 42 publications

<p>C-terminal of E1A binding protein 1 enhances the migration of gastric epithelial cells and has a clinicopathologic significance in human gastric carcinoma</p>

<p>C-terminal of E1A binding protein 1 enhances the migration of gastric epithelial cells and has a clinicopathologic significance in human gastric carcinoma</p>

JAK1 as a prognostic marker and its correlation with immune infiltrates in breast cancer

QuaDMutNetEx: a method for detecting cancer driver genes with low mutation frequency

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