Delta/Notch-like Epidermal Growth Factor-Related Receptor (DNER) - A Potential Prognostic Marker of Gastric Cancer Regulates Cell Survival and Cell Cycle Progression

Sep 24, 2026

Uploaded by Jake

Upregulation of Delta/notch-like epidermal growth factor-related receptor (DNER) and its oncogenic role have been reported across cancers, including gastric, breast, and prostate cancers. This study investigates DNER’s oncogenic function and mechanisms in gastric cancer. RNA-Seq analysis of TCGA gastric tumor data links DNER expression to advanced pathology and patient prognosis. DNER levels increase in stem cell-enriched cancer spheroids; DNER knockdown suppresses proliferation and invasion, triggers apoptosis, enhances chemosensitivity, and reduces spheroid formation. DNER silencing elevates p53, p21cip/waf, and p27 and shifts cells into G1 phase, while restoring p21 partially rescues viability and S-phase progression. Notch signaling through NICD counteracts DNER-silencing effects, supporting Notch activation by DNER. TGF-β signals contribute to DNER expression in both culture conditions, suggesting a pathway connection. Overall, DNER regulates gastric cancer cell proliferation, survival, and invasiveness and may serve as a prognostic marker and therapeutic target.

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CategoryHealthcare

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Pages24

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Article Delta/Notch-like Epidermal Growth Factor-Related Receptor (DNER), a Potential Prognostic Marker of Gastric Cancer Regulates Cell Survival and Cell Cycle Progression Han Thi Ngoc To 1,2, Ji-Hong Park 1,2, Jeong Won Kim 3 and Dongchul Kang 1,2, * Citation: To, H.T.N.; Park, J.-H.; Kim, J.W.; Kang, D. Delta/Notch-like Epidermal Growth Factor-Related Receptor (DNER), a Potential Prognostic Marker of Gastric Cancer Regulates Cell Survival and Cell Cycle Progression. Int. J. Mol. Sci. 2023, 24, 10077. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/ijms241210077](10.3390/ijms241210077) Academic Editor: Hidekazu Suzuki Received: 26 April 2023 Revised: 5 June 2023 Accepted: 7 June 2023 Published: 13 June 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Ilsong Institute of Life Science, Hallym University, Beodeunaru-ro 55, Yeongdeungpo-gu, Seoul 07247, Republic of Korea; [ngochantt.90@gmail.com](ngochantt.90@gmail.com) (H.T.N.T.); ﬂ[owjh@hallym.ac.kr](owjh@hallym.ac.kr) (J.-H.P.) 2 Department of Biomedical Gerontology, Hallym University Graduate School, Chuncheon 24252, Republic of Korea 3 Department of Pathology, Kangnam Sacred Heart Hospital, College of Medicine, Hallym University, Seoul 07441, Republic of Korea; [jwkim@hallym.or.kr](jwkim@hallym.or.kr) * Correspondence: [dckang@hallym.ac.kr](dckang@hallym.ac.kr); Tel.: +82-2-6923-8230 Abstract: Upregulation of the expression of Delta/notch-like epidermal growth factor-related receptor (DNER) and its oncogenic role have been reported in several cancers, including gastric, breast, and prostate cancers. This study aimed to investigate the oncogenic role of DNER and the mechanisms behind its oncogenic role in gastric cancer. Analysis of the RNASeq data of gastric cancer tissues obtained from the TCGA database revealed that the expression of DNER was associated with the pathology of advanced gastric cancer and the prognosis of patients. DNER expression was increased upon stem cell-enriching cancer spheroid culture. Knockdown of DNER expression inhibited cell proliferation and invasion, induced apoptosis, enhanced chemosensitivity, and decreased spheroid formation of SNU-638 gastric cancer cells. DNER silencing elevated the expression of p53, p21cip/waf, and p27, and increased G 1 phase cells at the expense of S phase cells. Knockdown of p21cip/waf expression in the DNER-silenced cells partially restored cell viability and S phase progression. DNER silencing also induced the apoptosis of SNU-638 cells. While both cleaved caspases-8 and 9 were detected in adherent cells, only cleaved caspase-8 was found to have increased in spheroid-cultured cells, suggesting a distinct activation pattern of caspase activation depending on the growth condition. Knockdown of p53 expression rescued the DNER-silenced cells from apoptosis and partially restored cell viability. In contrast, overexpression of the Notch intracellular domain (NICD) decreased the expression of p53, p21cip/waf, and cleaved caspase-3 in DNER-silenced cells. Moreover, NICD expression fully reverted the cell viability reduction, arrest in the G 1 phase, and elevated apoptosis caused by DNER silencing, thereby suggesting activation of Notch signaling by DNER. Expression of a membrane-unbound mutant of mDNER also decreased cell viability and induced apoptosis. On the other hand, TGF-􀀌 signals were found to be involved in DNER expression in both adherent and spheroid-cultured cells. DNER could therefore be a link connecting TGF-􀀌 signaling to Notch signaling. Taken together, DNER regulates cell proliferation, survival, and invasive capacity of the gastric cancer cells through

FAQs

What is the main research focus of the study?

The study examines the oncogenic role of DNER and the mechanisms by which DNER regulates gastric cancer cell survival and cell cycle progression.

How does DNER expression relate to gastric cancer prognosis?

TCGA RNA-Seq analysis shows DNER expression is associated with advanced gastric cancer pathology and patient prognosis.

What biological effects occur after DNER knockdown?

DNER knockdown inhibits cell proliferation and invasion, induces apoptosis, enhances chemosensitivity, decreases spheroid formation, and increases G1-phase cell accumulation.

How is Notch signaling connected to DNER in this work?

Overexpression of Notch intracellular domain (NICD) reverses DNER-silencing effects on cell viability, G1 arrest, and apoptosis, indicating that DNER activates Notch signaling.

Sep 24, 2026

Uploaded by Jake