Emerging Roles of Wnt Ligands in Human Colorectal Cancer

Nie, Xiaobo; Liu, Huiyang; Liu, Lei; Wang, Yandong; Chen, Weidong

doi:10.3389/fonc.2020.01341

Cited by 115 publications

(80 citation statements)

References 152 publications

(170 reference statements)

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“…We found that this pathway contains major Wnt ligands (Wnt5a, Wnt5b, Wnt6, Wnt10a, and Wnt10b) and the Wnt-upregulated genes (Adamts5, Bmp2, Bmp4, Itga3, Nfatc4, Ngf, Prkd3, and Sema3f) or downregulated genes (Mmp13, Pappa2, Prkd1, and Sema3e) (Fig. 5) (30)(31)(32)(33). Almost all of these Wnt ligands and Wnt-upregulated genes were upregulated in Colon 26 and all downregulated genes were downregulated in Colon 26 (Fig.…”

Section: Wnt Pathway Is Highlighted As One Of the Most Distinct Features Between Ct-26 And Colon 26mentioning

confidence: 91%

Tumor-immune Profiling of CT-26 and Colon 26 Syngeneic Mouse Models Reveals Mechanism to Anti-PD-1 response

Sato

Liu

et al. 2021

Preprint

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Background: Immune checkpoint blockade (ICB) therapies have changed the paradigm of cancer therapies. However, anti-tumor response of the ICB is insufficient for many patients and limited to specific tumor types. Despite many preclinical and clinical studies to understand the mechanism of anti-tumor efficacy of ICB, the mechanism is not completely understood. Harnessing preclinical tumor models is one way to understand the mechanism of treatment response.Methods: In order to delineate the mechanisms of anti-tumor activity of ICB in preclinical syngeneic tumor models, we selected two syngeneic murine colorectal cancer models based on in vivo screening for sensitivity with anti-PD-1 therapy. We performed tumor-immune profiling of the two models to identify the potential mechanism for anti-PD-1 response.Results: We performed in vivo screening for anti-PD-1 therapy across 23 syngeneic tumor models and found that CT-26 and Colon 26, which are murine colorectal carcinoma derived from BALB/c mice, showed different sensitivity to anti-PD-1. CT-26 tumor mice were more sensitive to the anti-PD-1 antibody than Colon 26, while both models show similarly sensitivity to anti-CTLA4 antibody. Immune-profiling and genomic/transcriptomic analysis showed that CT-26 tumor tissue was infiltrated with more immune cells than Colon 26 and that Wnt pathway was highlighted as one of the potential differences between CT-26 and Colon 26 and conferred sensitivity to anti-PD-1 therapy.Conclusions: CT-26 and Colon 26 syngeneic tumor models showed different sensitivity to anti-PD-1 therapy, although both tumor cells are murine colorectal carcinoma cell lines from BALB/c strain. By characterizing the mouse cells lines and tumor-immune context in the tumor tissues with comprehensive analysis approaches, we found that CT-26 showed “hot tumor” profile with more infiltrated immune cells than Colon 26. Further pathway analyses enable us to propose a hypothesis that Wnt pathway could be one of the major factors to differentiate CT-26 from Colon 26 model and link to anti-PD-1 response. Our approach to focus on preclinical tumor models with similar genetic background but different sensitivity to anti-PD-1 therapy would contribute to illustrating the potential mechanism of anti-PD-1 response and to generating a novel concept to synergize current anti-PD-1 therapies for cancer patients.

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Section: Wnt Pathway Is Highlighted As One Of the Most Distinct Features Between Ct-26 And Colon 26mentioning

confidence: 91%

Tumor-immune Profiling of CT-26 and Colon 26 Syngeneic Mouse Models Reveals Mechanism to Anti-PD-1 response

Sato

Liu

et al. 2021

Preprint

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“…Among them Wnt2b, Wnt3, Wnt3a, Wnt8a, Wnt8b, Wnt9a and Wnt10b mainly activate the canonical pathway, Wnt5b and Wnt11 activate the non‐canonical pathway, and Wnt1, Wnt2, Wnt4 Wnt5a, Wnt6, Wnt7a, Wnt7b, Wnt9b, Wnt10a and Wnt16 function as initiators for both signalling pathways. The structural characteristics and the maturation of all human Wnts have been elaborately summarized by our group and Kikuchi et al 19 , 30 However, the detailed mechanism by which single Wnt is chosen to produce and activate specific Wnt pathway has not been fully clarified. In the following parts, the exact role of each Wnt in the development of T2DM and related complications will be discussed separately (Table 1 ).…”

Section: Roles Of Wnts In T2dm and Related Complicationsmentioning

confidence: 99%

The complex role of Wnt ligands in type 2 diabetes mellitus and related complications

Nie

Wei

et al. 2021

J Cellular Molecular Medi

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“…On treating HCT 116 cells with purified Wnt3a protein, we observed an increase in both protein and mRNA levels of CHIP along with an increased β-catenin protein level. Cyclin D1 was used as a positive control 37 for the pathway (Figure 2B). LiCl, a pharmacological inhibitor of GSK3β and known activator of βcatenin pathway 38 , was used to enhance Wnt signaling in HCT 116 and HT29 cells.…”

Section: Canonical Wnt Signaling Enhances Chip Expression In Colorectal Cancermentioning

confidence: 99%

Wnt/β-catenin signaling and p68 conjointly regulate CHIP in colorectal cancer

Chakraborty

Karmakar

et al. 2021

Preprint

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The differential expression pattern of Carboxy terminus of Hsc70 Interacting Protein (CHIP, alias STIP1 Homology and U box Containing Protein 1 or STUB1) in cancers is associated with ubiquitination mediated degradation of its client proteins. Emerging evidences suggest its abundant expression of CHIP in colorectal cancer compared to normal tissues, but the mechanistic detail of this augmented expression pattern is unclear. The signature driver of canonical Wnt pathway, β catenin, and its co-activator RNA helicase p68, are also overexpressed in colorectal cancer. In this study, we describe a novel mechanism of Wnt/ β catenin and p68 mediated transcriptional activation of CHIP gene leading to enhanced proliferation of colorectal cancer cells. Wnt3A treatment and pharmacological activation of canonical Wnt signaling pathway resulted in increased nuclear translocation of β catenin and elevated expression of CHIP. Likewise, overexpression and knockdown of β catenin and p68 upregulated and downregulated CHIP expression, respectively, at both mRNA and protein levels. After cloning CHIP promoter, the increased and decreased promoter activities of CHIP induced by overexpression and knockdown of either β catenin or p68 further confirmed transcriptional regulation of CHIP gene by Wnt/ β catenin signaling cascade. p68 along with β catenin were found to occupy Transcription Factor 4 (TCF4) binding sites on endogenous CHIP promoter and regulate its transcription. Finally, enhanced cellular propagation and migration of colorectal cancer cells induced by Wnt/ β catenin p68 CHIP axis established the significance of this pathway in oncogenesis. To the best of our knowledge, this is the first report elucidating the mechanistic details of transcriptional regulation of CHIP (STUB1) gene expression.

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Emerging Roles of Wnt Ligands in Human Colorectal Cancer

Cited by 115 publications

References 152 publications

Tumor-immune Profiling of CT-26 and Colon 26 Syngeneic Mouse Models Reveals Mechanism to Anti-PD-1 response

Tumor-immune Profiling of CT-26 and Colon 26 Syngeneic Mouse Models Reveals Mechanism to Anti-PD-1 response

The complex role of Wnt ligands in type 2 diabetes mellitus and related complications

Wnt/β-catenin signaling and p68 conjointly regulate CHIP in colorectal cancer

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