GADD45B as a Prognostic and Predictive Biomarker in Stage II Colorectal Cancer

Zhao, Zhixun; Gao, Yibo; Guan, Xu; Liu, Zheng; Jiang, Zheng; Liu, Xiuyun; Lin, Huixin; Yang, Ming; Li, Chunxiang; Yang, Rulai; Zou, Shuangmei; Wang, Xishan

doi:10.3390/genes9070361

Cited by 28 publications

(21 citation statements)

References 20 publications

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“…In fact, this difference was not surprising because TCGA analysis was not always consistent with the experimental data. And the similar inconsistency between TCGA analysis and the experimental results had been reported before, which indicates that large numbers of samples or more patient cohorts are possibly helpful to further verify the prognostic role of Dyrk3 in HCC patients in future studies.…”

Section: Discussionsupporting

confidence: 60%

Dual‐Specificity Tyrosine Phosphorylation–Regulated Kinase 3 Loss Activates Purine Metabolism and Promotes Hepatocellular Carcinoma Progression

Zhu

Liu

et al. 2019

Hepatology

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Cancer cells metabolize different energy sources to generate biomass rapidly. The purine biosynthetic pathway was recently identified as an important source of metabolic intermediates for these processes. However, very little was known about the regulatory mechanisms of purine metabolism in hepatocellular carcinoma (HCC). We explored the role of dual-specificity tyrosine (Y) phosphorylation-regulated kinase 3 (Dyrk3) in HCC metabolism. Dyrk3 was significantly down-regulated in HCC compared with normal controls. Its introduction in HCC cells markedly suppressed tumor growth and metastasis in xenograft tumor models. Mass spectrometric analysis of metabolites suggests that the effect of Dyrk3 on HCC occurred at least partially through down-regulating purine metabolism, as evidenced by the fact that inhibiting purine synthesis reverted the HCC progression mediated by the loss of Dyrk3. We further provide evidence that this action of Dyrk3 knockdown requires nuclear receptor coactivator 3 (NCOA3), which has been shown to be a coactivator of activating transcription factor 4 (ATF4) to target purine pathway genes for transcriptional activation. Mechanistically, Dyrk3 directly phosphorylated NCOA3 at Ser-1330, disrupting its binding to ATF4 and thereby causing the inhibition of ATF4 transcriptional activity. However, the phosphorylation-resistant NCOA3-S1330A mutant has the opposite effect. Interestingly, the promoter activity of Dyrk3 was negatively regulated by ATF4, indicating a double-negative feedback loop. Importantly, levels of Dyrk3 and phospho-NCOA3-S1330 inversely correlate with the expression of ATF4 in human HCC specimens. Conclusion: Our findings not only illustrate a function of Dyrk3 in reprograming HCC metabolism by negatively regulating NCOA3/ATF4 transcription factor complex but also identify NCOA3 as a phosphorylation substrate of Dyrk3, suggesting the Dyrk3/NCOA3/ATF4 axis as a potential candidate for HCC therapy. (Hepatology 2019;70:1785-1803).D ual-specificity tyrosine (Y) phosphorylation-regulated kinase 3 (Dyrk3) is one of five members of the mammalian kinase family which includes Dyrk1A, Dyrk1B, Dyrk2, Dyrk3, and Dyrk4. (1) Although this family shares a highly conserved amino acid sequence in the catalytic domain with a Tyr-X-Tyr motif in the activation loop, the individual members are totally different in their N-terminal and C-terminal regions. Numerous studies have confirmed the critical role of Dyrk family kinases in

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Section: Discussionsupporting

confidence: 60%

Dual‐Specificity Tyrosine Phosphorylation–Regulated Kinase 3 Loss Activates Purine Metabolism and Promotes Hepatocellular Carcinoma Progression

Zhu

Liu

et al. 2019

Hepatology

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“…Higher expression of GADD45B was an independent factor for shorter disease-free survival in our internal dataset and shorter overall survival in the TCGA cohort. Likewise, high GADD45B protein expression was an independent marker of poorer prognosis in stage II colorectal cancer and a potential marker to indicate post-operative chemotherapy (71). In thyroid cancer, an accurate recurrence predictive biomarker could aid in the de-intensification of the treatment in low risk patients (72).…”

Section: Discussionmentioning

confidence: 99%

GADD45B Transcript Is a Prognostic Marker in Papillary Thyroid Carcinoma Patients Treated With Total Thyroidectomy and Radioiodine Therapy

et al. 2020

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Currently, there is a lack of efficient recurrence prediction methods for papillary thyroid carcinoma (PTC). In this study, we enrolled 202 PTC patients submitted to total thyroidectomy and radioiodine therapy with long-term follow-up (median = 10.7 years). The patients were classified as having favorable clinical outcome (PTC-FCO, no disease in the follow-up) or recurrence (PTC-RE). Alterations in BRAF, RAS, RET, and TERT were investigated (n = 202) and the transcriptome of 48 PTC (>10 years of follow-up) samples was profiled. Although no mutation was associated with the recurrence risk, 68 genes were found as differentially expressed in PTC-RE compared to PTC-FCO. Pathway analysis highlighted a potential role of cancer-related pathways, including signal transduction and FoxO signaling. Among the eight selected genes evaluated by RT-qPCR, SLC2A4 and GADD45B showed down-expression exclusively in the PTC-FCO group compared to non-neoplastic tissues (NT). Increased expression of GADD45B was an independent marker of shorter disease-free survival [hazard ratio (HR) 2.9; 95% confidence interval (CI95) 1.2-7.0] in our cohort and with overall survival in the TCGA dataset (HR = 4.38, CI95 1.2-15.5). In conclusion, GADD45B transcript was identified as a novel prognostic marker candidate in PTC patients treated with total thyroidectomy and radioiodine therapy.

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“…The relationship between GADD45B expression and colorectal cancer progression has been recently investigated, and the results showed that overexpression of GADD45B is associated with poorer prognosis for CRC patients both in overall survival and disease-free survival and that, regarding protein levels, GADD45B was gradually upregulated in normal mucosa, primary tumors, and liver metastases tissues in ascending order, with a prognostic role in terms of progression. The authors underlined the significant longer overall survival and disease-free survival among patients with low GADD45B expression pointing at the high expressor-subgroup as one which might benefit from adjuvant chemotherapy [ 60 ].…”

Section: Resultsmentioning

confidence: 99%

Molecular and Immunohistochemical Markers with Prognostic and Predictive Significance in Liver Metastases from Colorectal Carcinoma

Lopez

Boggio

Ferrero

et al. 2018

IJMS

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Despite the significant recent achievements in the diagnosis and treatment of colorectal cancer (CRC), the prognosis of these patients has currently plateaued. During the past few years, the opportunity to consider multiple treatment modalities (including surgery and other locoregional treatments, systemic therapy, and targeted therapy) led to the research of novel prognostic and predictive biomarkers in CRC liver metastases (CRCLM) patients. In this review, we seek to describe the current state of knowledge of CRCLM biomarkers and to outline impending clinical perspectives, in particular focusing on the cutting-edge tools available for their characterization.

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GADD45B as a Prognostic and Predictive Biomarker in Stage II Colorectal Cancer

Cited by 28 publications

References 20 publications

Dual‐Specificity Tyrosine Phosphorylation–Regulated Kinase 3 Loss Activates Purine Metabolism and Promotes Hepatocellular Carcinoma Progression

Dual‐Specificity Tyrosine Phosphorylation–Regulated Kinase 3 Loss Activates Purine Metabolism and Promotes Hepatocellular Carcinoma Progression

GADD45B Transcript Is a Prognostic Marker in Papillary Thyroid Carcinoma Patients Treated With Total Thyroidectomy and Radioiodine Therapy

Molecular and Immunohistochemical Markers with Prognostic and Predictive Significance in Liver Metastases from Colorectal Carcinoma

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