HES1 promotes metastasis and predicts poor survival in patients with colorectal cancer

Yuan, Ruixue; Ke, Jia; Sun, Lei; He, Zhen; Zou, Yifeng; He, Xiaosheng; Chen, Yufeng; Wu, Xianrui; Cai, Zerong; Wang, Lei; Wang, Jianping; Fan, Xinjuan; Wu, Xinglong; Lan, Ping

doi:10.1007/s10585-015-9700-y

Cited by 46 publications

(36 citation statements)

References 43 publications

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“…We observed that C-B and C-I treatment downregulated the expression Notch receptors, ligands, γ-secretase complex and target genes. Dysregulation of Notch signaling has been correlated with poor survival, CSC phenotype and EMT resulting in tumor progression in colon cancer 47 . Notch 1 and 2, as well as their ligands, are dysregulated in CRC.…”

Section: Discussionmentioning

confidence: 99%

Cucurbitacin B and I inhibits colon cancer growth by targeting the Notch signaling pathway

Dandawate

Subramaniam

Panovich

et al. 2020

Sci Rep

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cancer stem cells (cScs) have the ability to self-renew and induce drug resistance and recurrence in colorectal cancer (cRc). As current chemotherapy doesn't eliminate cScs completely, there is a need to identify novel agents to target them. We investigated the effects of cucurbitacin B (C-B) or I (C-I), a natural compound that exists in edible plants (bitter melons, cucumbers, pumpkins and zucchini), against cRc. c-B or c-i inhibited proliferation, clonogenicity, induced G 2 /M cell-cycle arrest and caspase-mediated-apoptosis of cRc cells. c-B or c-i suppressed colonosphere formation and inhibited expression of CD44, DCLK1 and LGR5. These compounds inhibited notch signaling by reducing the expression of Notch 1-4 receptors, their ligands (Jagged 1-2, DLL1,3,4), γ-secretase complex proteins (Presenilin 1, Nicastrin), and downstream target Hes-1. Molecular docking showed that C-B or C-I binds to the ankyrin domain of Notch receptor, which was confirmed using the cellular thermal shift assay. finally, c-B or c-i inhibited tumor xenograft growth in nude mice and decreased the expression of cScmarkers and notch signaling proteins in tumor tissues. together, our study suggests that c-B and c-i inhibit colon cancer growth by inhibiting notch signaling pathway. Colorectal cancer (CRC) is the third most commonly diagnosed cancer with an estimated 145600 new cases and 51020 deaths estimated to occur in the United States in 2019 1. A significant concern is that the frequency of individuals diagnosed with colon cancer below 50 years of age is steadily rising every year 2. Adjuvant chemotherapy and radiotherapy post-surgery is the primary choice of treatment for advanced CRC 3. Cancer stem cells (CSCs) are rare in number and possess the ability to self-renew with the capacity to generate a tumor 4,5. They also develop chemo-and radio-resistance, contributing to tumor progression and recurrence. As current chemotherapy is not able to achieve complete eradication of CSCs 6 , it is crucial to develop novel non-toxic drug therapies that effectively target both CSCs and proliferating cancer cells. CSC markers identified in CRC, include CD44, leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), c-Myc, ABCG2, CD133, ALDH1A1, epithelial cell adhesion molecule (EpCAM) and doublecortin-like kinase-1 (DCLK1) 7. CSCs rely on classic signaling pathways for growth such as the Notch signaling that plays an important role in transformation and CSC self-renewal 8. The Notch pathway consists of five ligands (Jagged-1, Jagged-2 and Delta-like ligands −1, −3 and −4 (Dll-1, −3 and −4) and four receptors (Notch 1-4) 9. Upon ligand binding, Notch receptors are cleaved twice. The first cleavage by ADAM/TACE is followed by a second cleavage by the γ-secretase enzyme complex releasing Notch intracellular domain (NICD). The NICD binds to MAML1-CSL-HAT-P300 complex to induce the target gene expression including but not limited to HES1, HEY1, Cyclin D1 and c-Myc 9. Hence, targeting the Notch signaling pathway may be an effective mechanism...

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Section: Discussionmentioning

confidence: 99%

Cucurbitacin B and I inhibits colon cancer growth by targeting the Notch signaling pathway

Dandawate

Subramaniam

Panovich

et al. 2020

Sci Rep

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“…Studies have demonstrated that HES1 affects cell proliferation and differentiation during embryogenesis, maintenance of stem cells, and the malignancy and maintenance of tumor cells (13). Overexpression of HES1 is associated with the development of several types of cancer, including lung cancer, cervical cancer, prostate cancer, oral squamous cell carcinoma, pancreatic cancer, colon carcinoma, and ovarian cancer (14)(15)(16). The function of HES1 and its involvement in the regulation in malignant breast cancer remain to be fully elucidated; therefore, it is necessary to investigate its function and underlying mechanisms in breast cancer proliferation and metastasis.…”

Section: Lutein Inhibits Proliferation Invasion and Migration Of Hypmentioning

confidence: 99%

Lutein inhibits proliferation, invasion and migration of hypoxic breast cancer cells via downregulation of HES1

Zhang

Liu

et al. 2018

Int J Oncol

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An intratumoral hypoxic microenvironment is frequently observed in solid tumors, including breast cancer. Lutein, a plant-derived compound and non-vitamin A carotenoid, has been demonstrated to possess multiple protective properties including anti-inflammation, anti-oxidative stress and antitumor effects. The main objective of the present research was to elucidate the involvement of lutein in the production of reactive oxygen species (ROS) under hypoxia, the activation of hairy and enhancer of split 1 (HES1), and the proliferation, invasion and migration of breast cancer cells. The human breast cancer cell lines MDA‑MB‑157 and MCF‑7 were exposed to hypoxic conditions and various concentrations of lutein. An MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay was performed to examine cell proliferation, and Annexin V-fluorescein isothiocyanate/propidium iodide staining was performed to analyze the apoptosis ratio. The levels of hypoxia inducible factor-1α (HIF‑1α), NOTCH signaling molecules, HES1 and epithelial-mesenchymal transition (EMT)-associated factors were examined by reverse transcription-quantitative polymerase chain reaction and western blot analysis. Wound healing and Transwell invasion assays were used to detect the invasion and migration of breast cancer cells. Intracellular ROS levels were examined using 2,7-dichlorodihydrofluorescein-diacetate and flow cytometry. The results revealed that cell proliferation was inhibited by lutein in a dose-dependent manner, and the apoptosis ratio gradually increased with lutein treatment under hypoxia as evident from flow cytometry-based analysis. Exposure to lutein inhibited hypoxia-mediated activation of HIF‑1α, NOTCH signaling and HES1 expression, and suppressed the hypoxia-induced expression of EMT-associated factors. Lutein markedly inhibited the invasion and migration of breast cancer cells under hypoxia. Hypoxia-induced production of ROS was also decreased by lutein. Furthermore, the ROS scavenger N‑acetylcysteine also suppressed hypoxia inducible factor 1α and HES1 expression in breast cancer cells during hypoxia, but hydrogen peroxide (H2O2) levels were increased. Taken together, the results of the present study suggested that lutein may be a novel candidate for the chemoprevention of breast cancer. Furthermore, HES1 may be crucial in mediating the involvement of lutein in the suppression of hypoxia-driven ROS-induced breast cancer progression.

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“…Up-regulation of NOTCH1, JAG ligands and HES1 in CRC cell lines results in the increased expression of the EMT/stemness-associated proteins: CD44, SLUG, and SMAD3 (7,8). High expression of HES1 is significantly correlated with distal metastasis at diagnosis, and unfavorable prognostic outcome for CRC patients (9). Activation of NOTCH signaling also protects CSCs from apoptosis (10).…”

Section: Introductionmentioning

confidence: 99%

STRAP Promotes Stemness of Human Colorectal Cancer via Epigenetic Regulation of the NOTCH Pathway

Lin

Yuan

et al. 2017

Cancer Research

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NOTCH signaling exerts essential roles in normal and malignant intestinal physiology and the homeostasis of cancer stem-like cells (CSC), but the basis for this latter role remains obscure. The signaling scaffold protein STRAP is upregulated in several cancers where it promotes tumorigenicity and metastasis. Here we report a novel oncogenic function for STRAP in maintaining CSC subpopulations in a heterogeneous mixture by antagonizing formation of the chromatin modifier PRC2 and by epigenetically activating NOTCH signals in human colorectal cancer (CRC). Silencing STRAP sensitized CRC cells to chemotherapeutic drugs in vitro and in vivo. STRAP depletion also contributed to a reduced stem-like phenotype of CRC cells, as indicated by reduced expression of the CSC signature and NOTCH signaling regulators in vitro and by diminished tumorigenesis in vivo. Genes encoding some upstream activators of NOTCH were highly enriched for H3K27me3, which form repressive chromatin domains upon STRAP silencing. Mechanistically, STRAP competitively disrupted association of the PRC2 subunits EZH2 and SUZ12, thereby inhibiting PRC2 assembly. Restoring the NOTCH pathway by lentiviral expression of NICD1 or HES1 in STRAP-depleted tumor cells reversed the CSC phenotype. In 90 CRC clinical specimens, a significant positive correlation was documented between the expression of STRAP and HES1. Overall, our findings illuminated a novel STRAP-NOTCH1-HES1 molecular axis as a CSC regulator in CRC, with potential implications to improve treatment of this disease.

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HES1 promotes metastasis and predicts poor survival in patients with colorectal cancer

Cited by 46 publications

References 43 publications

Cucurbitacin B and I inhibits colon cancer growth by targeting the Notch signaling pathway

Cucurbitacin B and I inhibits colon cancer growth by targeting the Notch signaling pathway

Lutein inhibits proliferation, invasion and migration of hypoxic breast cancer cells via downregulation of HES1

STRAP Promotes Stemness of Human Colorectal Cancer via Epigenetic Regulation of the NOTCH Pathway

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