The Epstein-Barr virus-miRNA-BART6-5p regulates TGF-β/SMAD4 pathway to induce glycolysis and enhance proliferation and metastasis of gastric cancer cells

Sep 21, 2026

Epstein–Barr virus (EBV) miRNA-BARTs show strong relevance in epithelial tumors, yet the mechanisms governing initiation and progression of gastric cancer remain insufficiently defined. This study evaluates EBV-miRNA-BART6-5p and its target SMAD4 in EBV-associated gastric cancer tissues and cell lines using expression assays and transfection. The work analyzes proliferation, migration, and glycolysis, with pathway effects tested using a TGF-β inhibitor. Results show BART6-5p upregulation, SMAD4 downregulation, and reduced glycolytic capacity when TGF-β/SMAD4 signaling is inhibited.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages11

Reading Time28 min

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Abstract

Introduction

Gastric cancer background and EBV subtype

EBV miRNAs and BART relevance

SMAD4 and glycolysis in cancer

ONCOLOGY RESEARCH 2024 32(5): 999-1009 The Epstein-Barr virus-miRNA-BART6-5p regulates TGF-β/SMAD4 pathway to induce glycolysis and enhance proliferation and metastasis of gastric cancer cells XUHUI ZHAO 1,2; XIAOMIN HUANG 1; CHUNYAN DANG2; XIA WANG 1; YUJIAO QI3; HONGLING LI2,* 1 The First Clinical Medical College, Gansu University of Traditional Chinese Medicine, Lanzhou, 730000, China 2 Department of Oncology, Gansu People’s Hospital, Lanzhou, 730000, China 3 The Clinical Medical College, Ningxia Medical University, Ningxia, 750004, China Key words: EBV, TGF-β/SMAD4, Glycolysis, Gastric cancer Abstract: Background: EBV-miR-BARTs exhibit signiﬁcant relevance in epithelial tumors, particularly in EBVassociated gastric and nasopharyngeal cancers. However, their speciﬁc mechanisms in the initiation and progression of gastric cancer remain insufﬁciently explored. Material and Methods: Initially, EBV-miRNA-BART6-5p and its target gene SMAD4 expression were assessed in EBV-associated gastric cancer tissues and cell lines. Subsequent transfection induced overexpression of EBV-miRNA-BART6-5p in AGS and MKN-45, and downregulation in EBVpositive cells (SUN-719) . The subsequent evaluation aimed to observe their impact on gastric cancer cell proliferation, migration, and glycolytic processes, with the TGF-β/SMAD4 signaling pathway value clariﬁed using a TGF-β inhibitor. Results: EBV-miRNA-BART6-5p exhibits pronounced upregulation in EBV-associated gastric cancer tissues and EBV-positive cells, while its target gene SMAD4 demonstrates downregulated expression. Upregulation of it can promote the proliferation and migration of gastric cancer cells. Additionally, We found EBV-miRNA-BART6-5p promotes glycolysis of gastric cancer cells. Inhibition of the TGF-β/SMAD4 signaling pathway resulted in suppressed proliferation and migration of gastric cancer cells, concomitant with a diminished glycolytic capacity. Conclusion: In this study, we found that EBV-miRNA-BART6-5p can target SMAD4, effectively increasing glycolysis in gastric cancer cells by regulating the TGF-β/SMAD4 signaling pathway, thereby enhancing the proliferation and metastasis of gastric cancer cells. Our ﬁndings may offer new insights into the metabolic aspects of gastric cancer. Introduction Gastric cancer is among the most prevalent malignancies of the digestive system, ranking as the fourth most common cancer globally and the second leading cause of cancerrelated deaths [1] . The 2014 TCGA database classiﬁed gastric cancer into four subtypes based on molecular typing and clinical features: EBV-associated, microsatellite instability (MSI), genome-stable (GS), and chromosomal instability (CIN) [2,3] . EBV-associated gastric carcinoma constitutes around 10% of all gastric carcinomas, exhibiting distinctive clinicopathological characteristics, such as male predominance, a relatively favorable prognosis, and localization in the gastric cardia with varying degrees of *Address correspondence to: Hongling Li, [lihongling1969@126.com](lihongling1969@126.com)[ ](lihongling1969@126.com)[Received: 10 October 2023](Received: 10 October 2023); [Accepted: 26 December 2023](Accepted: 26 December 2023); Published: 23 April 2024 Doi: 10.32604/or.2024.046679 lymphoid inﬁltration [4–6] . Therefore, exploring potential targets of EBV-associated gastric carcinoma (EBVaGC) may represent a new avenue for treating patients with gastric cancer (GC) . As a DNA virus, EBV can encode various miRNAs that interact with host genes, forming a complex regulatory network that plays a crucial role in the onset and development of EBV-associated gastric cancer. Currently, EBV miRNAs consist of two major classes: BHRF1 and BART miRNAs [7,8], with BHRF1 RNAs located in the introns of BHRF and BART miRNAs situated in the introns of BART transcripts. In EBVaGC, 99% of virus-derived polynucleotide transcripts originate from BARTs. In recent years, several studies have explored the expres

FAQs

What does EBV-miRNA-BART6-5p regulate in gastric cancer cells?

EBV-miRNA-BART6-5p targets SMAD4 and regulates the TGF-β/SMAD4 signaling pathway, affecting downstream cellular behaviors and glycolysis.

How were EBV-miRNA-BART6-5p effects assessed in the study?

Expression levels of EBV-miRNA-BART6-5p and SMAD4 were evaluated in gastric cancer tissues and cell lines, followed by transfection to overexpress or downregulate BART6-5p and measure proliferation, migration, and glycolytic changes.

What is the role of the TGF-β/SMAD4 pathway in the observed phenotype?

Inhibition of TGF-β/SMAD4 signaling suppressed proliferation and migration while diminishing the glycolytic capacity of gastric cancer cells.

Sep 21, 2026

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