The <scp>N</scp>otch pathway in colorectal cancer

Vinson, Kaitlyn E.; George, Dennis C.; Fender, Alexander W.; Bertrand, F. E.; Sigounas, George

doi:10.1002/ijc.29800

Cited by 152 publications

(124 citation statements)

References 87 publications

(140 reference statements)

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“…Two additional pathways cooperate with Wnt in CC tumorigenesis: Hippo (Rosenbluh et al ., ), proposed as potential target in diabetes (S.‐P. Wang and Wang, ), and Notch (Vinson et al ., ) that plays an important role in B cells under hyperglycemia (Darville and Eizirik, ). Lastly, angiogenesis resulting from VEGF activation is known to contribute to cancer and to diabetes complications and recent evidences indicate an angiogenic switch mediated by VEGF in premalignant tissues such as atypical colon adenomas (Cheng and Ma, ).…”

Section: Discussionmentioning

confidence: 99%

Molecular evidence of field cancerization initiated by diabetes in colon cancer patients

et al. 2019

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The potential involvement of type 2 diabetes mellitus (T2 DM ) as a risk factor for colon cancer ( CC ) has been previously reported. While several clinical studies show a higher incidence of CC and a lower survival rate in diabetics, others report no association. Our own experience indicates that diabetes does not seem to worsen the prognosis once the tumor is present. Despite this controversy, there are no wide‐spectrum molecular studies that delve into the impact of T2 DM ‐related mechanisms in colon carcinogenesis. Here, we present a transcriptomic and proteomic profiling of paired tumor and normal colon mucosa samples in a cohort of 42 CC patients, 23 of which have T2 DM . We used gene set enrichment and network approaches to extract relevant pathways in diabetics, referenced them to current knowledge, and tested them using in vitro techniques. Through our transcriptomics approach, we identified an unexpected overlap of pathways overrepresented in diabetics compared to nondiabetics, in both tumor and normal mucosa, including diabetes‐related metabolic and signaling processes. Proteomic approaches highlighted several cancer‐related signaling routes in diabetics found only in normal mucosa, not in tumors. An integration of the transcriptome and proteome analyses suggested the deregulation of key pathways related to colon carcinogenesis which converged on tumor initiation axis TEAD / YAP ‐ TAZ as a potential initiator of the process. In vitro studies confirmed upregulation of this pathway in nontumor colon cells under high‐glucose conditions. In conclusion, T2 DM associates with deregulation of cancer‐related processes in normal colon mucosa adjacent to tissue which has undergone a malignant transformation. These data support that in diabetic patients, the local microenvironment in normal colon mucosa may be a factor driving field cancerization promoting carcinogenesis. Our results set a new framework to study links between diabetes and colon cancer, including a new role of the TEAD / YAP ‐ TAZ complex as a potential driver.

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Section: Discussionmentioning

confidence: 99%

Molecular evidence of field cancerization initiated by diabetes in colon cancer patients

et al. 2019

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“…To date, great efforts have been made to understand how EMT is regulated during cancer progression [14–16]. Therefore, identification of biomarkers and investigation of their molecular and biological cellular functions in controlling EMT are important.…”

Section: Introductionmentioning

confidence: 99%

Mammalian Eps15 homology domain 1 promotes metastasis in non-small cell lung cancer by inducing epithelial-mesenchymal transition

et al. 2016

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The identification of the earliest molecular events responsible for the metastatic dissemination of non-small cell lung cancer (NSCLC) remains critical for early detection, prevention, and treatment interventions. In this study, we hypothesized that Mammalian Eps15 homology domain 1 (EHD1) might be responsible for the metastatic behavior of cells in NSCLC. We demonstrated that upregulation of EHD1 is associated with lymph nodes metastasis and unfavorable survival in patients with NSCLC. EHD1 knockdown inhibited the invasion and migration of human NSCLC cells, and overexpression of EHD1 increased the metastatic potential of lung cancer cells. Using the Affymetrix Human Gene 1.0 ST platform, microarray analysis revealed that an association between EHD1 and epithelial-mesenchymal transition (EMT), supported by downregulation of mesenchymal markers and upregulation of epithelial markers following knockdown of EHD1 in cell lines. Moreover, overexpression of EHD1 induced the EMT and increased the metastatic potential of lung cancer cells in vitro and in vivo. These results provide a model to illustrate the relationship between EHD1 expression and lung cancer metastasis, opening up new avenues for the prognosis and therapy of lung cancer.

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“…In the nucleus, NICD interacts with the CBF1/Suppressor of Hairless/Lag1 (CSL) and recruits coactivators, allowing for transcriptional activation of Hey genes (4,70,71). Intriguingly, Notch receptors or Notch ligands show little selectivity for the induction of individual Hey proteins.…”

Section: Notch-hey Signaling Pathwaymentioning

confidence: 99%

Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment

Liu

Sanders

Liang

et al. 2017

Molecular Cancer Therapeutics

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Hairy and Enhancer-of-split related with YRPW motif (Hey) transcription factors are important regulators of stem cell embryogenesis. Clinical relevance shows that they are also highly expressed in malignant carcinoma. Recent studies have highlighted functions for the Hey factors in tumor metastasis, the maintenance of cancer cell self-renewal, as well as proliferation and the promotion of tumor angiogenesis. Pathways that regulate Hey gene expression, such as Notch and TGFb signaling, are frequently aberrant in numerous cancers. In addition, Hey factors control downstream targets via recruitment of histone deacetylases (HDAC). Targeting these signaling pathways or HDACs may reverse tumor progression and provide clinical benefit for cancer patients. Thus, some small molecular inhibitors or monoclonal antibodies of each of these signaling pathways have been studied in clinical trials. This review focuses on the involvement of Hey proteins in malignant carcinoma progression and provides valuable therapeutic information for anticancer treatment.

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The Notch pathway in colorectal cancer

Cited by 152 publications

References 87 publications

Molecular evidence of field cancerization initiated by diabetes in colon cancer patients

Molecular evidence of field cancerization initiated by diabetes in colon cancer patients

Mammalian Eps15 homology domain 1 promotes metastasis in non-small cell lung cancer by inducing epithelial-mesenchymal transition

Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment

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