WDR5 facilitates EMT and metastasis of CCA by increasing HIF-1α accumulation in Myc-dependent and independent pathways

Chen, Tianli; Li, Kangshuai; Liu, Zengli; Li, Jialiang; Wang, Yue; Sun, Rongqi; Li, Zhipeng; Qiu, Bo; Zhang, Xiaoming; Ren, Guangli; Xu, Yaping; Zhang, Zongli

doi:10.1016/j.ymthe.2021.02.017

Cited by 52 publications

(44 citation statements)

References 62 publications

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“…The basic information of CCA patients is shown in Table 1 , including the sex, age, tumor size, differentiation, and T/N/M/TNM stage of the patients. The results of basic patients characters were consistent with previous studies ( 5 , 18 ), supporting the validation of our cohort.…”

Section: Resultssupporting

confidence: 92%

Dual-Specificity Phosphatase 11 Is a Prognostic Biomarker of Intrahepatic Cholangiocarcinoma

Wang

Zhang

et al. 2021

Front. Oncol.

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BackgroundCholangiocarcinoma (CCA), including intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA) CCA, is a highly aggressive malignancy originating from bile duct. The prognosis of CCA is very poor, and the biomarker study is unsatisfactory compared with other common cancers.Materials and methodsIn our study, we investigated the expression of dual-specificity phosphatase 11(DUSP11) in eight pairs of iCCAs, pCCAs, and dCCAs, and their corresponding tumor-adjacent tissues, as well as their tumor-adjacent tissues with qPCR. Moreover, we investigated the expression of DUSP11 in 174 cases of CCAs with immunohistochemistry, including 74 iCCAs, 64 pCCAs, and 36 dCCAs. We classified these patients into subsets with low and high expressions of DUSP11, and evaluated the correlations between the DUSP11 subsets and clinicopathological factors. With univariate and multivariate analyses, we assessed the correlation between DUSP11 and the overall survival (OS) rates in these CCA patients.ResultsIn all the CCA subtypes, DUSP11 was elevated in CCAs compared with their paired adjacent tissues. In iCCA, pCCA, and dCCA, the percentages of DUSP11 high expression were 44.59%, 53.85%, and 55.56%, respectively. In iCCA, high DUSP11 expression was significantly associated with an advanced T stage and a poor prognosis. However, the prognostic value of DUSP11 in pCCA and dCCA was not significant. To decrease the statistical error caused by the small sample size of the dCCA cohort, we merged pCCA and dCCA into extracellular CCA (eCCA). In the 101 cases of eCCA, DUSP11 expression was also not significantly associated with the prognosis.ConclusionsDUSP11 expression was associated with tumor infiltration and the OS rate in iCCA, but not in pCCA and dCCA. DUSP11 was an independent biomarker of iCCA indicating a poor prognosis. Our results suggested that a high expression of DUSP11 was a post-operational risk factor, and detecting DUSP11 could guide the individual treatment for patients with CCA.

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Section: Resultssupporting

confidence: 92%

Dual-Specificity Phosphatase 11 Is a Prognostic Biomarker of Intrahepatic Cholangiocarcinoma

Wang

Zhang

et al. 2021

Front. Oncol.

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“…Myc-WDR5 interaction stabilizes Myc/Max dimer on the promotor of pivotal protumorigenic target genes, accelerating the process of gene transcription ( Thomas et al, 2015a ). WDR5 could interact with the MBIIIb motif of c-Myc and facilitate Myc-induced HIF1- α transcription, therefore promoting the EMT, invasion and metastasis of cholangiocarcinoma (CCA) ( Chen et al, 2021 ). Myc also maintains the DNA replication in pancreatic ductal adenocarcinoma (PDAC) cells appropriately through interacting with WDR5 ( Carugo et al, 2016 ).…”

Section: Protein-protein Interaction Work On Myc Transcriptional Activationmentioning

confidence: 99%

Targeting Myc Interacting Proteins as a Winding Path in Cancer Therapy

et al. 2021

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MYC, as a well-known oncogene, plays essential roles in promoting tumor occurrence, development, invasion and metastasis in many kinds of solid tumors and hematologic neoplasms. In tumors, the low expression and the short half-life of Myc are reversed, cause tumorigenesis. And proteins that directly interact with different Myc domains have exerted a significant impact in the process of Myc-driven carcinogenesis. Apart from affecting the transcription of Myc target genes, Myc interaction proteins also regulate the stability of Myc through acetylation, methylation, phosphorylation and other post-translational modifications, as well as competitive combination with Myc. In this review, we summarize a series of Myc interacting proteins and recent advances in the related inhibitors, hoping that can provide new opportunities for Myc-driven cancer treatment.

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“…In clear cell renal cell carcinoma, Cripto-1 promoted EMT properties, including the down-regulation of E-cadherin and the up-regulation of Vimentin, N-cadherin, ZEB-1, and Snail ( 33 ). EMT has been reported to increase the motility and invasiveness of cholangiocarcinoma cells ( 40 – 42 ). Functional loss of E-cadherin has been considered a hallmark of EMT ( 43 ) and this study showed that Cripto-1 expression negatively correlated with E-cadherin expression in PHCCA tissues; this suggests that Cripto-1 may also play a role as an EMT inducer to promote PHCCA cell migration and invasion.…”

Section: Discussionmentioning

confidence: 99%

Exosomal Cripto-1 Serves as a Potential Biomarker for Perihilar Cholangiocarcinoma

Zhang

et al. 2021

Front. Oncol.

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Perihilar cholangiocarcinoma (PHCCA) has a poor prognosis, mainly due to diagnosis at an advanced stage. Cripto-1 functions as an oncogene and is highly expressed in several human cancers, however, its clinical application in PHCCA is poorly understood. Herein, we identified that Cripto-1 was released by PHCCA cells via exosomes in vitro and in vivo. Furthermore, an ELISA method was developed to detect exosomal Cripto-1 in the serum of 115 PHCCA patients, 47 cholangitis patients and 65 healthy controls, and it was found that exosomal Cripto-1 was increased in PHCCA patients and associated with metastasis. Compared with traditional serum tumor markers, CA19-9 and CEA, exosomal Cripto-1 demonstrated a larger area under ROC curve for PHCCA diagnosis. The cutoff value of exosomal Cripto-1 was 0.82, achieving a sensitivity of 79.1% and a specificity of 87.5%. As expected, exosomal Cripto-1 levels in immunohistochemically Cripto-1-high cases were significantly elevated compared to in Cripto-1-low cases. When measured 1-week postoperatively, Cripto-1 levels decreased on average from 1.25(0.96-3.26) to 0.85(0.62-1.82). Immunohistochemistry analysis showed Cripto-1 expression was negatively correlated with E-cadherin and was an independent prognostic biomarker for poor survival in PHCCA patients. In conclusion, exosomal Cripto-1 in sera can reflect its expression in the tissue of PHCAA patients and has the potential be a non-invasive biomarker for diagnosis and prognosis of PHCCA.

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WDR5 facilitates EMT and metastasis of CCA by increasing HIF-1α accumulation in Myc-dependent and independent pathways

Cited by 52 publications

References 62 publications

Dual-Specificity Phosphatase 11 Is a Prognostic Biomarker of Intrahepatic Cholangiocarcinoma

Dual-Specificity Phosphatase 11 Is a Prognostic Biomarker of Intrahepatic Cholangiocarcinoma

Targeting Myc Interacting Proteins as a Winding Path in Cancer Therapy

Exosomal Cripto-1 Serves as a Potential Biomarker for Perihilar Cholangiocarcinoma

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