SPAG9/MKK3/p38 axis is a novel therapeutic target for liver cancer

Luo, Shudi; Ren, Baizhao; Zou, Guoying; Liu, Junlong; Chen, Wei; Huang, Yiran; Chen, Xing; Fu, Yaw-Syan

doi:10.3892/or.2019.6987

Cited by 11 publications

(14 citation statements)

References 30 publications

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“…Certainly, the MKK3/p38 axis has been increasingly studied in cancer. Studies have shown that the MKK3/p38 axis regulates cell proliferation, apoptosis, and cell cycle progression in hepatoma cells 27 . Furthermore, we have demonstrated that linc02381 was upregulated in RA tissues and RA cell line, and linc02381 activated MAPK signal pathway by absorbing miR-590-5p to promote RA-FLS proliferation and invasion.…”

Section: Discussionmentioning

confidence: 99%

Linc02381 Exacerbates Rheumatoid Arthritis Through Adsorbing miR-590-5p and Activating the Mitogen-Activated Protein Kinase Signaling Pathway in Rheumatoid arthritis-fibroblast-like synoviocytes

Wang

Zhao

2020

Cell Transplant

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Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease. New evidence suggested that linc02381 suppressed colorectal cancer progression by regulating PI3 K signaling pathway, but the role of linc02381 in other diseases, such as RA, remains unclear. This study aimed to reveal the mechanism of linc02381 in RA progression. In vivo and in vitro, we found that linc02381 was upregulated in RA synovial tissues or RA fibroblast-like synoviocytes (RA-FLSs, P < 0.01), which were detected by quantitative real-time polymerase chain reaction. Cell Counting Kit-8, EDU, and Transwell assays revealed that linc02381 overexpression enhanced cell proliferation and invasion, and linc02381 knockdown inhibited cell proliferation and invasion in FLSs. Moreover, the results of bioinformatics analysis, luciferase reporter gene assay, and pull-down assay verified that linc02381 could directly bind with miR-590-5p. MiR-590-5p was downregulated in RA-FLSs, and overexpression of linc02381 suppressed expression of miR-590-5p that post-transcriptionally suppressed the expression of mitogen-activated protein kinase kinase 3 (MAP2K3), and overexpression of miR-590-5p reversed the effect of linc02381 overexpression on MAP2K3 expression. MiR-590-5p inhibitor reversed the inhibition effect of linc02381 knockdown on proliferation and invasion of FLSs, which enhanced expression of MAP2K3, and activation of p38 and AP-1 in the MAPK signaling pathway. In summary, linc02381 was upregulated in RA synovial tissues and RA-FLSs, and it exacerbated RA by adsorbing miR-590-5p to activate the MAPK signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Linc02381 Exacerbates Rheumatoid Arthritis Through Adsorbing miR-590-5p and Activating the Mitogen-Activated Protein Kinase Signaling Pathway in Rheumatoid arthritis-fibroblast-like synoviocytes

Wang

Zhao

2020

Cell Transplant

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“…The loss of p38-activation may promote tumor growth in cancers with a decreased level of MKK3 [57,75], suggesting its tumor-suppressive function. On the other hand, the oncogenic role for MKK3 has been reported in multiple tumor types, including melanoma, colorectal, liver, esophageal, cervical, and breast cancers [51,52,[76][77][78][79][80]. Analysis of genomics data shows that MKK3 is either up-or downregulated in different cancer types and different groups of cancer patients.…”

Section: Discussionmentioning

confidence: 99%

High expression of MKK3 is associated with worse clinical outcomes in African American breast cancer patients

et al. 2020

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Background: African American women experience a twofold higher incidence of triple-negative breast cancer (TNBC) and are 40% more likely to die from breast cancer than women of other ethnicities. However, the molecular bases for the survival disparity in breast cancer remain unclear, and no race-specific therapeutic targets have been proposed. To address this knowledge gap, we performed a systematic analysis of the relationship between gene mRNA expression and clinical outcomes determined for The Cancer Genome Atlas (TCGA) breast cancer patient cohort. Methods: The systematic differential analysis of mRNA expression integrated with the analysis of clinical outcomes was performed for 1055 samples from the breast invasive carcinoma TCGA PanCancer cohorts. A deep learning fullyconvolutional model was used to determine the association between gene expression and tumor features based on breast cancer patient histopathological images. Results: We found that more than 30% of all protein-coding genes are differentially expressed in White and African American breast cancer patients. We have determined a set of 32 genes whose overexpression in African American patients strongly correlates with decreased survival of African American but not White breast cancer patients. Among those genes, the overexpression of mitogen-activated protein kinase kinase 3 (MKK3) has one of the most dramatic and race-specific negative impacts on the survival of African American patients, specifically with triple-negative breast cancer. We found that MKK3 can promote the TNBC tumorigenesis in African American patients in part by activating of the epithelial-to-mesenchymal transition induced by master regulator MYC. Conclusions: The poor clinical outcomes in African American women with breast cancer can be associated with the abnormal elevation of individual gene expression. Such genes, including those identified and prioritized in this study, could represent new targets for therapeutic intervention. A strong correlation between MKK3 overexpression, activation of its binding partner and major oncogene MYC, and worsened clinical outcomes suggests the MKK3-MYC protein-protein interaction as a new promising target to reduce racial disparity in breast cancer survival.

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“…47 Currently, newly discovered molecular markers related to liver cancer include SPAG9/MKK3/p38 axis, AKR1C3, B3GAT3, DYRK2 and BPTF. [48][49][50][51][52] The study showed that down-regulation of Sperm-associated antigen 9 (SPAG9) can reduce the expression of MKK3 and p38 proteins, inhibits cell proliferation and promotes cell apoptosis. Therefore, SPAG9 may be a potential new target for liver cancer treatment.…”

Section: Liver Cancer Related Somatic Mutationsmentioning

confidence: 99%

“…Therefore, SPAG9 may be a potential new target for liver cancer treatment. 48 In addition, it was found that AKR1C3 is an independent biomarker for the prognosis of liver cancer by database mining. However, the expression level of AKR1C3 was inversely correlated with the overall survival of liver cancer patients.…”

Section: Liver Cancer Related Somatic Mutationsmentioning

confidence: 99%